AU2015207903A1 - Retinal derivatives and methods for the use thereof for the treatment of visual disorders - Google Patents

Abstract

RETINAL DERIVATIVES AND METHODS FOR THE USE THEREOF FOR THE TREATMENT OF VISUAL DISORDERS Abstract Compositions of and methods for using synthetic retinal derivatives as retinoid replacements and opsin agonists are provided.

Description

RETINAL DERIVATIVES AND METHODS FOR THE USE THEREOF FOR THE TREATMENT OF VISUAL DISORDERS CONTINUITY [00011 This application claims the benefit of U.S. Provisional Application No. 60/580,889, filed June 18, 2004, the disclosure of which is incorporated herein by reference for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [00021 This research was supported by United States Public Health Service Grants EY09339 from the National Eye Institute of the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND OF THE INVENTION [0003] A diminished visual acuity or total loss of vision may result from a number of eye diseases or disorders caused by dysfunction of tissues or structures in the anterior segment of the eye and/or posterior segment of the eye. Disease or disorders of the posterior segment of the eye in general are retinal or choroidal vascular diseases or hereditary diseases such as Leber Congenital Amaurosis. Age related macular degeneration (AMD) is one of the specific diseases associated with the posterior portion of the eyeball and is the leading cause of blindness among older people. AMD results in damage to the macula, a small circular area in the center of the retina. Because the macula is the area which enables one to discern small details and to read or drive, its deterioration may bring about diminished visual acuity and even blindness. The retina contains two forms of light receiving cells, rods and cones, that change light into electrical signals. The brain then converts these signals into the images. The macula is rich in cone cells, which provides central vision. People with AMD suffer deterioration of central vision but usually retain peripheral sight. [0004] Slightly blurred or distorted vision is the most common early symptom of AMD. Visual loss with dry AMD usually progresses slowly while visual loss with wet AMD 1 proceeds more rapidly and may occur over days or weeks. Patients who have wet AMD in one eye are at increased risk of developing choroidal neo-vascularization (CNV) in the other eye. The magnitude of the risk varies, depending on the appearance of the second eye. The risk is greater in eyes with numerous large drusen, with abnormal pigment 5 changes in the macula, and in patients with a history of high blood pressure. Reactions that go on in the RPE lead to oxidative products leading to cell death and neovascularization. This excess metabolism leads to the formation of drusen under the RPE. [0005] Other eye diseases also affect photoreceptor function in the eye. Retinitis 10 Pigmentosa represents disease caused by defects in many different genes. They all have a final common pathway of night blindness and peripheral vision loss that can lead to narrowing of the visual field and eventual loss of all vision in many patients. The rod photoreceptors are usually primarily affected and most of the gene defects leading to the disease occur in genes that are expressed predominantly or only in the rod cells. 15 [0006] One autosomal dominant form of Retinitis Pigmentosa comprises an amino acid substitution in opsin, a proline to histidine substitution at amino acid 23. This defect compromises 10-20% of all Retinitis Pigmentosa cases. This abnormal opsin protein forms a protein aggregate that eventually leads to cell death. [00071 Leber Congenital Amaurosis is a very rare childhood condition that affects 20 children from birth or shortly thereafter. It affects both rods and cones. There are a few different gene defects that have been associated with the disease. These include the genes encoding the RPE65 and LRAT proteins. Both result in a person's inability to make 11 cis-retinal in adequate quantities. In the RPE65-defective individuals, retinyl esters build up in the retinal pigment epithelium (RPE). LRAT-defective individuals are unable to 25 make esters and subsequently secrete any excess retinoids. [0008] Retinitis Punctata Albesciens is another form of Retinitis Pigmentosa that exhibits a shortage of 1 1-cis-retinal in the rods. Aging also leads to the decrease in night vision and loss of contrast sensitivity due to a shorting of 1 1-cis-retinal. Excess unbound opsin is believed to randomly excite the visual transduction system. This can create noise 30 in the system, and thus more light and more contrast is necessary to see well. 2 100091 Congenital Stationary Night Blindness (CSNB) and Fundus Albipunctatus are a group of diseases that are manifested as night blindness, but there is not a progressive loss of vision as in the Retinitis Pigmentosa. Some forms of CSNB are due to a delay in the recycling of 1 l-cis-retinal. Fundus Albipunctatus until recently was thought to be a 5 special case of CSNB where the retinal appearance is abnormal with hundreds of small white dots appearing in the retina. It has been shown recently that this is also a progressive disease although much slower than Retinitis Pigmentosa. It is caused by a gene defect that leads to a delay in the cycling of 1 1-cis-retinal. [00101 Currently, there are few treatments for retinoid deficiency. One treatment, a 10 combination of antioxidant vitamins and zinc, produces only a small restorative effect. Thus, there is a need for compositions and methods of restoring or stabilizing photoreceptor function and ameliorating the effects of deficient levels of endogenous retinoids. BRIEF SUMMARY OF THE INVENTION 15 [00111 The present invention provides compounds and methods of using such compound to restore and/or stabilize photoreceptor function in a vertebrate visual system. Synthetic retinal derivatives can be administered to human or non-human vertebrate subjects to restore or stabilize photoreceptor function, and/or to ameliorate the effects of a deficiency in retinoid levels. 20 100121 In one aspect, synthetic retinal derivatives are provided. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some embodiments, the synthetic retinal derivatives is a retinyl ester, such -as a 9-cis-retinyl ester or an 11 -cis-retinyl ester. The ester substituent can be, for example, a carboxylate radical of a C 3 to C 2 2 polycarboxylic 25 acid (polycarboxylate). For example, the substituent can be succinate, citrate, ketoglutarate, fumarate, malate and oxaloacetate. In some embodiments, the ester substituent is not tartarate. 100131 In some embodiments, the retinyl ester is a 9-cis-retinyl ester of a C 3 to C 22 carboxylate. In other embodiments, the retinyl ester is a 9-cis-retinyl ester of a C 3 to CIO 30 carboxylate. In some embodiments, the retinyl ester is an 11 -cis-retinyl ester of a C 3 to

C

22 carboxylate. In other embodiments, the retinyl ester is an 11 -cis-retinyl ester of a C 3 to CIO carboxylate. 3 [0014] Also provided are pharmaceutical compositions comprising the synthetic retinal derivative and a pharmaceutically acceptable vehicle. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some embodiments, the synthetic retinal derivatives is a 5 retinyl ester, such as a 9-cis-retinyl ester or an 1 l-cis-retinyl ester. The ester substituent can be, for example, a carboxylate radical of a C 3 to C 22 polycarboxylic acid. The pharmaceutical composition can be compounded, for example, as an opthalmological composition in an opthalmologically acceptable vehicle for administration to the eye topically or by intra-ocular injection. 10 [0015] In another aspect, a method of restoring photoreceptor function in a mammal is provided. The method includes administering to a mammalian subject having an endogenous retinoid deficiency an effective amount of a synthetic retinal derivative, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex. The synthetic retinal derivative can be, for example, a 9 15 cis-retinyl ester, an 1 l-cis-retinyl ester, or a combination thereof. The ester substituent can be a carboxylate radical of a CI-C 1 o monocarboxylic acid or a C 2 to C 2 2 polycarboxylic acid. In some embodiments, synthetic retinal derivative is 9-cis-retinyl acetate or 1 1-cis retinyl acetate. In other embodiments, the ester substituent comprises a carboxylate radical of a polycarboxylic acid of C 3 to CIO. For example, the ester substituent can be 20 succinate, citrate, ketoglutarate, fumarate, malate and oxaloacetate. The mammalian subject can be, for example, human or other mammal. [00161 In another aspect, a method of ameliorating loss of photoreceptor function in a mammal is provided. The method includes administering an effective amount of a synthetic retinal derivative to the vertebrate eye, wherein the synthetic retinal derivative is 25 converted into a retinal capable of forming a functional opsin/retinal complex. The synthetic retinal derivative can be, for example, a 9-cis-retinyl ester, an 11 -cis-retinyl ester, or a combination thereof. The ester substituent can'be a carboxylate radical of a Ci CIO monocarboxylic acid or a C 2 to C 2 2 polycarboxylic acid. In some embodiments, synthetic retinal derivative is 9-cis-retinyl acetate or 11-cis-retinyl acetate. In other 30 embodiments, the ester substituent comprises a carboxylate radical of a polycarboxylic acid of C 3 to CIO. For example, the ester substituent can be succinate, citrate, ketoglutarate, fumarate, malate and oxaloacetate. The mammalian subject can be, for example, human or other mammal. 4 [00171 In an aspect, a method of restoring photoreceptor function in a vertebrate eye is provided. The method can include administering to the vertebrate in need thereof having an endogenous retinoid deficiency an effective amount of a synthetic retinal derivative in a pharmaceutically acceptable vehicle, wherein the synthetic retinal derivative is converted 5 into a retinal capable of forming a functional opsin/retinal complex. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C 1 to CIO ester. In some methods, if the synthetic retinal derivative is an 11 10 cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis-retinyl

C

1 to CIO ester. [00181 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the 15 like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, l l-cis-retinyl fumarate, 11 -cis-retinyl malate, l l-cis-retinyl oxaloacetate, or the like. [00191 In some methods, the synthetic retinal derivative can be administered to a 20 vertebrate in need thereof. For example, the vertebrate can have, or be predisposed to developing, an endogenous retinoid deficiency associated with Age-Related Macular Degeneration, Leber Congenital Amaurosis, Retinitis Punctata Albesciens, Congenital Stationary Night Blindness, Fundus Albipunctatus, or other disease or condition associated with an endogenous retinoid deficiency. 25 100201 In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, the vertebrate is a human. [0021] In another aspect, a method of sparing the requirement for endogenous retinoid 30 in a vertebrate eye is provided. The method can include administering to the eye a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle, wherein the synthetic retinal derivative is converted into a retinal capable of 5 forming a functional opsin/ retinal complex. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C, to Cio ester. In 5 some methods, if the synthetic retinal derivative is an 1 1-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1-cis-retinyl C 1 to C 1 0 ester. [0022] In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the 10 like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. [0023] In some methods, the synthetic retinal derivative can be administered to a 15 vertebrate in need thereof. For example, the vertebrate can have, or be predisposed to developing, an endogenous retinoid deficiency associated with Age-Related Macular Degeneration, Leber Congenital Amaurosis, Retinitis Punctata Albesciens, Congenital Stationary Night Blindness, Fundus Albipunctatus, or other disease or condition associated with an endogenous retinoid deficiency. 20 [0024] In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, the vertebrate is a human. [0025] In yet another aspect, a method of ameliorating loss of photoreceptor function in 25 a vertebrate eye is provided. The method can include prophylactically administering an effective amount of a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle to the vertebrate eye, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/ retinal complex. The synthetic retinal derivative can be, for example, a derivative of Formula I, 30 II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl Ci to Clo ester. In some methods, if the synthetic 6 retinal derivative is an 11 -cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis-retinyl C 1 to C 1 o ester. [00261 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl 5 ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. 10 [00271 In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, the vertebrate is a human. [00281 In yet a further aspect, a method of selecting a treatment for a subject having 15 diminished visual capacity is provided. The method can include determining whether the subject has a deficient endogenous retinoid level, as compared with a standard subject; and administering to the subject an effective amount of a synthetic retinal derivative in a pharmaceutically acceptable vehicle (e.g., an ophthalmologically acceptable vehicle), wherein the synthetic retinal derivative is converted into a retinal capable of forming a 20 functional opsin/ retinal complex. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C 1 to C 1 o ester. In some methods, if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a 25 monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl CI to C 1 0 ester. [00291 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, 30 for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. 7 [00301 In some methods, the endogenous retinoid is an 11-cis-retinyl ester. In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, 5 the vertebrate is a human. [00311 In yet a further aspect, pharmaceutical compositions and oral dosage forms are provided. The compositions can include a synthetic retinal derivative in a pharmaceutically acceptable vehicle (e.g., an ophthalmologically acceptable vehicle). The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, 10 VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C 1 to C 1 o ester. In some methods, if the synthetic retinal derivative is an 11 -cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11-cis-retinyl C 1 to C 10 ester. 15 [00321 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis 20 retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. [00331 The pharmaceutical composition can be, for example, an intraocular injectable solution or a periocular injectable solution. The oral dosage form can be, for example, a pill, tablet, capsule, gel cap, or the like. 25 [0034] In yet another aspect, a method of treating Leber Congenital Amaurosis in a human subject is provided. The method generally includes administering to a subject in need thereof an effective amount of a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, 30 XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C, to Cio ester. In 8 some methods, if the synthetic retinal derivative is an 1 1-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis-retinyl C 1 to C 1 0 ester. [00351 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl 5 ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11-cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. 10 [0036] In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, the vertebrate is a human. [0037] In another aspect, a method of treating Retinitis Punctata Albesciens, Congenital 15 Stationary Night Blindness or Fundus Albipunctatus in a human subject is provided. The method can include administering to the subject in need thereof an effective amount of a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle. The method generally includes administering to a subject in need thereof an effective amount of a synthetic retinal derivative in a pharmaceutically or 20 ophthalmologically acceptable vehicle. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl Ci to CIO ester. In some methods, if the synthetic retinal derivative is an 11 -cis-retinyl ester comprising a 25 monocarboxylic acid ester substituent, it is an 1-cis-retinyl C 1 to C 10 ester. [00381 In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11-cis-retinyl ester, such as, 30 for example, 11 -cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. 9 [00391 In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In some methods, the vertebrate is a human. 5 [0040] In yet another aspect, a method of treating Age-Related Macular Degeneration in a human subject is provided. The method can include administering to the subject in need thereof an effective amount of a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle. The synthetic retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, 10 XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C 1 to CIO ester. In some methods, if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl C 1 to C 10 ester. [00411 In some methods, the synthetic retinal derivative is converted into a synthetic 15 retinal that binds to free opsin in the eye. In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl 20 succinate, 11 -cis-retinyl citrate, 11 -cis-retinyl ketoglutarate, 1 l-cis-retinyl fumarate, 11 cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. [00421 In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In 25 some methods, the vertebrate is a human. [00431 In yet a further aspect, a method of treating or preventing loss of night vision or contrast sensitivity in an aging human subject is provided. The method can include administering to the subject in need thereof an effective amount of a synthetic retinal derivative in a pharmaceutically or ophthalmologically acceptable vehicle. The synthetic 30 retinal derivative can be, for example, a derivative of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and/or XVI. In some methods, if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 10 9-cis-retinyl C 1 to Cio ester. In some methods, if the synthetic retinal derivative is an 11 cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis-retinyl C, to Cio ester. [00441 In some methods, the synthetic retinal derivative is converted into a synthetic 5 retinal that binds to free opsin in the eye. In some methods, the synthetic retinal derivative is a 9-cis-retinyl ester, such as, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, or the like. In some methods, the synthetic retinal derivative is an 11 -cis-retinyl ester, such as, for example, 11 -cis-retinyl acetate, 11 -cis-retinyl 10 succinate, 11 -cis-retinyl citrate, 11 -cis-retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 cis-retinyl malate, 11 -cis-retinyl oxaloacetate, or the like. 100451 In some methods, the synthetic retinoid derivative can be administered locally, such as by eye drops, intraocular injection, periocular injection or the like. In other methods, the synthetic retinal derivative can be orally administered to the vertebrate. In 15 some methods, the vertebrate is a human. BRIEF DESCRIPTION OF THE DRAWINGS [00461 Figure 1. HPLC chromatogram showing retinoid elution in treated and control mice eye and liver tissue. A. Eyes from dark adapted LRAT-/- mouse. B. Eyes from 20 dark-adapted LRAT-/- mouse gavaged with 5 mg all-trans-retinyl palmitate 2 days prior. C. Eyes from dark-adapted LRAT-/- mouse gavaged with 5 mg all-trans-retinyl acetate 2 days prior. D. Eyes from dark-adapted LRAT-/- mouse gavaged with 6.5 mg 9-cis-retinyl acetate 3 days prior. E. Liver tissue from dark adapted LRAT-/- mouse. F. Liver tissue from dark-adapted LRAT-/- mouse gavaged with 5 mg all-trans-retinyl palmitate 2 days 25 prior. G. Liver tissue from dark-adapted LRAT-/- mouse gavaged with 5 mg all-trans retinyl acetate 2 days prior. H. Liver tissue from dark-adapted LRAT-/- mouse gavaged with 6.5 mg 9-cis-retinyl acetate 3 days prior. [0047] Figure 2. Eye 9-cis-retinal oximes and 9-cis-retinol time course, 20 pLM gavage. [00481 Figure 3. UV isomerization of all-trans-retinyl acetate to 9-cis-retinyl acetate. 30 [0049] Figure 4. HPLC separation of 13-cis-retinyl acetate (1), 9-cis-retinyl acetate (2), and all-trans-retinyl acetate (3). 11 [00501 Figure 5. Levels of 9-cis-retinal oximes in the eyes of Lrat-/- mice after a single or multiple dose of 9-cis-R-Acetate. (a) The level of 9-cis-RAL in Lrat-/- mouse eyes after a varying dose of 9-cis-R-Ac. (b) The level of 9-cis-RAL in Lrat-/- mouse eyes after a varying size and number of doses of 9-cis-R-Ac. 5 [00511 Figure 6. Chromophore levels (as 9-cis-retinal oximes) in the eyes of Lrat-/ mice after administration of all-trans-retinoid isomers or 9-cis-retinyl succinate). The structures of the all-trans-retinoid isomers and 9-cis-retinyl succinate are also shown. [0052] Figure 7. A comparison of the chromophore levels (as 9-cis-retinal oximes) in the eyes of Lrat-/- mice after administration of 9-cis-retinal or 9-cis-retinyl acetate at low 10 and high doses. DETAILED DESCRIPTION OF THE INVENTION [00531 The present invention provides synthetical retinal derivatives and methods of using such derivatives to restore or stabilize photoreceptor function in a vertebrate visual 15 system. The synthetic retinal derivative is a derivative of 9-cis-retinal or 11 -cis-retinal in which the aldehydic group in the polyene chain is modified. The synthetic retinal derivative can be converted directly or indirectly into a retinal or a synthetic retinal analog. Thus, in some aspects, the compounds according to the present invention can be described as a pro-drug, which upon metabolic transformation is converted into 9-cis-retinal, 11 -cis 20 retinal or a synthetic retinal analog thereof. Metabolic transformation can occur, for example by acid hydrolysis, esterase activity, acetyltransferase activity, dehydrogenase activity, or the like. [00541 The synthetic retinal derivative can be a retinoid replacement, supplementing the levels of endogenous retinoid. In some embodiments, the synthetic retinal can bind to 25 opsin, and function as an opsin agonist. As used herein, the term "agonist" refers to a synthetic retinal that binds to opsin and facilitates the ability of an opsin/synthetic retinal complex to respond to light. As an opsin agonist, a synthetic retinal can spare the requirement for endogenous retinoid (e.g., 11 -cis-retinal). A synthetic retinal also can restore or improve function (e.g., photoreception) to opsin by binding to opsin and 30 forming a functional opsin/synthetic retinal complex, whereby the opsin/synthetic retinal complex can respond to photons when part of a rod or cone membrane. 12 10055] Synthetic retinal derivatives can be administered to restore or stabilize photoreceptor function, and/or to ameliorate the effects of a deficiency in retinoid levels. Photoreceptor function can be restored or stabilized, for example, by providing a synthetic retinal derivative as an 11 -cis-retinoid replacement and/or an opsin agonist. The synthetic 5 retinal derivative also can ameliorate the effects of a retinoid deficiency on a vertebrate visual system. The synthetic retinal derivative can be administered prophylactically or therapeutically to a vertebrate. Suitable vertebrates include, for example, human and non human vertebrates. Suitable non-human vertebrates include, for example, mammals, such as dogs (canine), cats (feline), horses (equine) and other domesticated animals. 10 [00561 In one aspect, synthetic retinal derivatives are provided. The synthetic retinal derivatives are derivatives of 9-cis-retinal or 11 -cis-retinal in which the aldehydic group in the polyene chain is converted to an ester, ether, alcohol, hemi-acetal, acetal, oxime, as further described herein. Such synthetic retinal derivatives include 9-cis-retinyl esters, 9 cis-retinyl ethers, 9-cis-retinol, 9-cis-retinal oximes, 9-cis-retinyl acetals, 9-cis-retinyl 15 hemiacetals, 11 -cis-retinyl esters, 11 -cis-retinyl ethers, 11 -cis-retinol, 11 -cis-retinyl oximes, 11 -cis-retinyl acetals and 11 -cis-retinyl hemiacetals, as further described herein. The synthetic retinal derivative can be metabolized to release a natural or synthetic retinal, such as for example, 9-cis-retinal, 11 -cis-retinal or a synthetic retinal analog thereof, such as those described herein or in co-pending International Application No. 20 PCT/USO4/07937, filed March 15, 2004, (Attorney Docket No. 016336-00201OPC) (the disclosure of which is incorporated by reference herein). [00571 In one aspect, the synthetic retinal derivative is a retinyl ester. In some embodiments, the retinyl ester is a 9-cis-retinyl ester or an 11 -cis-retinyl ester having a. The ester substituent can be, for example, a carboxylic acid, such as a mono- or 25 polycarboxylic acid. As used herein, a "polycarboxylic acid" is a di-, tri- or higher order carboxylic acid. In some embodiments, the carboxylic acid is a C 1

-C

2 2 , C 2

-C

2 2 , C 3

-C

2 2 , C-CIO, C 2 -CIO, C 3

-C

10 , C 4 -Cio, C 4

-C

8 , C 4

-C

6 or C 4 monocarboxylic acid, or polycarboxylic acid. [00581 Suitable carboxylic acid groups include, for example, acetic acid, propionic acid, 30 butyric acid, valeric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, oleic acid, stearic acid, palmitic acid, myristic acid or linoleic acid. The carboxylic acid also can be, for example, oxalic acid (ethanedioic acid), malonic acid (propanedioic 13 acid), succinic acid (butanedioic), fumaric acid (butenedioic acid), malic acid (2 hydroxybutenedioic acid), glutaric acid (pentanedioic acid), adipic acid (hexanedioic acid), pimelic acid (heptanedioic), suberic acid (octanedioic), azelaic acid (nonanedioic acid), sebacic acid (decanedioic acid), citric acid, oxaloacetic acid, ketoglutaratic acid, or 5 the like. [00591 In an exemplary embodiment, the retinyl ester is a 9-cis-retinyl ester or an 11 -cis retinyl ester including a C 3

-C

10 polycarboxylic acid substituent. (In this context, the terms "substituent" or "group" refer to a radical covalently linked to the terminal oxygen in the polyene chain.) In another exemplary embodiment, the retinyl ester is a 9-cis-retinyl ester 10 or an 11 -cis-retinyl ester including a C 2

-C

2 2 or C 3

-C

2 2 polycarboxylic acid substituent. The polycarboxylic acid substituent can be, for example, succinate, citrate, ketoglutarate, fumarate, malate or oxaloacetate. In another exemplary embodiment, the retinyl ester is a 9-cis-retinyl ester or an 11 -cis-retinyl ester including a C 3

-C

2 2 di-carboxylic acid (di-acid) substituent. In some embodiments, the polycarboxylic acid is not 9-cis-retinyl tartarate or 15 11 -cis-retinyl tartarate. In some embodiments, the retinyl ester is not a naturally occurring retinyl ester normally found in the eye. In some embodiments, the retinyl ester is an isolated retinyl ester. As used herein, "isolated" refers to a molecule that exists apart from its native environment and is therefore not a product of nature. An isolated molecule may exist in a purified form or may exist in a non-native environment. 20 [00601 In another aspect, the retinal derivative can be a 9-cis-retinyl ester or ether of the following formula I: A [00611 In some embodiments, A is CH 2 OR, where R can be an aldehydic group, to form 25 a retinyl ester. A suitable aldehydic group is a C, to C 24 straight chain or branched 14 aldehydic group. The aldehydic group also can be a C 1 to C 14 straight chain or branched aldehydic group. The aldehydic group can be a C, to C 1 2 straight chain or branched aldehydic group, such as, for example, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, hexanal, heptanal, octanal, nonanal, decanal, undecanal, dodecanal. R can 5 be a C 1 to C 1 o straight chain or branched aldehydic group, a CI to C 8 straight chain or branched aldehydic group or a C, to C 6 straight chain or branched aldehydic group. [00621 R further can be a carboxylate group of a dicarboxylic acid or other carboxylic acid (e.g., a hydroxyl acid) to form a retinyl ester (some of which are also referred to as retinoyl esters). The carboxylic acid can be, for example, oxalic acid (ethanedioic acid), 10 malonic acid (propanedioic acid), succinic acid (butanedioic), fumaric acid (butenedioic acid), malic acid (2-hydroxybutenedioic acid), glutaric acid (pentanedioic acid), adipic acid (hexanedioic acid), pimelic acid (heptanedioic), suberic acid (octanedioic), azelaic acid (nonanedioic acid), sebacic acid (decanedioic acid), citric acid, oxaloacetic acid, ketoglutaratic acid, or the like. 15 [0063] R can also be an alkane group, to form a retinyl alkane ether. Suitable alkane groups include, for example, C 1 to C 2 4 straight chain or branched alkyls, such as, for example, methane, ethane, butane, isobutane, pentane, isopentane, hexane, heptane, octane or the like. For example, the alkane group can be a linear, iso-, sec-, tert- or other branched lower alkyl ranging from Ci to C 6 . The alkane group also can be a linear, iso-, 20 see-, tert- or other branched medium chain length alkyl ranging from C 8 to C 14 . The alkane group also can be a linear, iso-, sec-, tert- or other branched long chain length alkyl ranging from C 16 to C 24 . [0064] R further can be an alcohol group, to form a retinyl alcohol ether. Suitable alcohol groups can be linear, iso-, sec-, tert- or other branched lower alcohols ranging 25 from C 1 to C 6 , linear, iso-, see-, tert- or other branched medium chain length alcohols ranging from Cs to C 14 , or linear, iso-, see-, tert- or other branched long chain length alkyl ranging from C 16 to C 2 4 . The alcohol group can be, for example, methanol, ethanol, butanol, isobutanol, pentanol, hexanol, heptanol, octanol, or the like [0065] R also can be a carboxylic acid, to form a retinyl carboxylic acid ether. Suitable 30 alcohol groups can be linear, iso-, sec-, tert- or other branched lower carboxylic acids ranging from C 1 to C 6 , linear, iso-, sec-, tert- or other branched medium chain length carboxylic acids ranging from C 8 to C 14 , or linear, iso-, see-, tert- or other branched long 15 chain length carboxylic acids ranging from C 16 to C 2 4 . Suitable carboxylic acid groups include, for example, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, oleic acid, stearic acid, palmitic acid, myristic acid, linoleic acid, succinic acid, fumaric acid or the like. 5 [0066] The retinyl derivative can be a retinyl hemiacetal, where A is CH(OH)OR. R can be any of the R groups set forth above in Formula I. R is typically a lower alkane, such as a methyl or ethyl group, or a C, to C 7 saturated and unsaturated, cyclic or acyclic alkane, with or without hetero atoms, as described herein. [00671 The retinyl derivative can be a retinyl acetal, where A is CH (ORa)ORb. Each of 10 Ra and Rb can be independently selected from any of the R groups set forth above in Formula I. Ra and Rb are typically a Ci to C 7 saturated and unsaturated, cyclic or acyclic alkane, with or without hetero atoms, as described herein. [00681 The retinyl derivative also can be a retinyl oxime, where A is CH:NOH or CH:NOR. R can be any of the R groups set forth above in Formula I. R is typically a 15 hydrogen, or an alkane. [00691 Examples of suitable synthetic retinal derivatives include, for example, 9-cis retinyl acetate, 9-cis-retinyl formate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, 9-cis-retinal oxime, 9-cis-retinal 0-methyl oximes, 9-cis-retinal O-ethyl 20 oximes, and 9-cis-retinal methyl acetals and hemi acetals, 9-cis-retinyl methyl ether, 9-cis retinyl ethyl ether, and 9-cis-retinyl phenyl ether. [00701 In a related aspect, the retinal derivative can be an 1 1-cis-retinyl ester or ether of the following formula II: A 25 (II) A can be any of the groups set forth above in Formula I. 16 [0071] Examples of suitable synthetic retinal derivatives include, for example, 11 -cis retinyl acetate, 11 -cis-retinyl formate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 cis-retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate, 11 -cis-retinal oxime, 11 -cis-retinal 0-methyl oxime, 11 -cis-retinal O-ethyl oximes and 11 -cis-retinal 5 methyl acetals and hemi acetals, 11 -cis-retinyl methyl ether, 11 -cis-retinyl ethyl ether. [00721 In additional aspects, the synthetic retinal derivatives can be, for example, a derivative of a 9-cis-retinyl ester, a 9-cis-retinyl ether, an 11 -cis-retinyl ester or an 11 -cis retinyl ethers such as, for example, an acyclic retinyl ester or ethers, a retinyl ester or ether with a modified polyene chain length, such as a trienoic or tetraenoic retinyl ester or ether; 10 a retinyl ester or ether with a substituted polyene chain, such as alkyl, halogen or heteratom-substituted polyene chains; a retinyl ester or ether with a modified polyene chain, such as a trans- or cis- locked polyene chain, or with, for example, allene or alkyne modifications; and a retinyl ester or ether with a ring modification(s), such as heterocyclic, heteroaromatic or substituted cycloalkane or cycloalkene rings. 15 [00731 The synthetic retinal derivative can be a retinyl ester or ether of the following formula III: R2 R1 (III) A 20 [00741 A can be any of the groups set forth above for formula (I). Ri and R 2 can be independently selected from linear, iso-, sec-, tert- and other branched alkyl groups as well as substituted alkyl groups, substituted branched alkyl, hydroxyl, hydroalkyl, amine, amide, or the like. R, and R 2 can independently be lower alkyl, which means straight or 25 branched alkyl with 1-6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like. Suitable substituted alkyls and substituted branch alkyls include, for example, alkyls, branched alkyls and cyclo-alkyls substituted with oxygen, hydroxyl, nitrogen, amide, amine, halogen, heteroatom or other groups. Suitable heteroatoms include, for example, sulfur, silicon, and fluoro- or bromo 30 substitutions. 17 [00751 R, or R 2 also can be a cyclo-alkyl such as, for example, hexane, cyclohexene, benzene as well as a substituted cyclo-alkyl. Suitable substituted cyclo-alkyls include, for example, cyclo-alkyls substituted with oxygen, hydroxyl, nitrogen, amide, amine, halogen, heteroatom and/or other groups. Suitable heteroatoms include, for example, sulfur, 5 silicon, and fluoro- or bromo- substitutions. [00761 The synthetic retinal derivative also can have a modified polyene chain length, such as the following formula IV: n (IV) 10 A can be any of the groups set forth above for formula (I). The polyene chain length can be extended by 1, 2, or 3 alkyl, alkene or alkylene groups. According to formula (IV), each n and ni can be independently selected from 1, 2, or 3 alkyl, alkene or alkylene 15 groups, with the proviso that the sum of the n and ni is at least 1. [00771 The synthetic retinal derivative also can have a substituted polyene chain of the following formula V:

R

1

R

3

R

5 (V)M 20

R

2

R

4 R8 R7 A A can be any of the groups set forth above for formula (I). Each of R, to R 8 can be independently selected from hydrogen, alkyl, branched alkyl, cyclo-alkyl, halogen, a heteratom, or 'the like. Suitable alkyls include, for example, methyl, ethyl, propyl, 25 substituted alkyl (e.g., alkyl with hydroxyl, hydroalkyl, amine, amide) or the like. Suitable branched alkyls can be, for example, isopropyl, isobutyl, substituted branched alkyl, or the like. Suitable cyclo-alkyls can include, for example, cyclohexane, cycloheptane, and other cyclic alkanes as well as substituted cyclic alkanes such as substituted cyclohexane or substituted cycloheptane. Suitable halogens include, for example, bromine, chlorine, 18 fluorine, or the like. Suitable heteroatoms include, for example, sulfur, silicon, and fluoro or bromo- substitutions. Suitable substituted alkyls, substituted branch alkyls and substituted cyclo-alkyls include, for example, alkyls, branched alkyls and cyclo-alkyls substituted with oxygen, hydroxyl, nitrogen, amide, amine, halogen, heteroatom or other 5 groups. [0078] For example, the synthetic retinal derivative can be selected from the following: a 9-ethyl-I 1 -cis-retinyl ester, ether, oxime, acetal or hemiacetal; a 7-methyl-1 1-cis-retinyl ester, ether, oxime, acetal or hemiacetal; a 13 -desmethyl- 11 -cis-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis- 10-F-retinyl ester, ether, oxime, acetal or hemiacetal; an 10 11 -cis- 10-Cl-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis- 1 0-methyl-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis- 10-ethyl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis-1 O-F-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis 10-Cl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis- 1 0-methyl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis-O-ethyl-retinyl ester, ether, oxime, acetal or 15 hemiacetal; an 11 -cis- 1 2-F-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis- 12 Cl-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis-1 2-methyl-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 -cis-1 0-ethyl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis-12-F-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis-12-Cl retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis- 1 2-methyl-retinyl ester, ether, 20 oxime, acetal or hemiacetal; an 1 1-cis-14-F-retinyl ester, ether, oxime, acetal or hemiacetal; an 1 1-cis-14-methyl-retinyl ester, ether, oxime, acetal or hemiacetal; an 11 cis- I 4-ethyl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis- 1 4-F-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis- 1 4-methyl-retinyl ester, ether, oxime, acetal or hemiacetal; a 9-cis-1 4-ethyl-retinyl ester, ether, oxime, acetal or hemiacetal; or the like. 25 [00791 The synthetic retinal derivative further can have a modified ring structure. Suitable examples include, for example, derivatives containing ring modifications, aromatic analogs and heteroaromatic analogs of the following formulae VI, VII and VIII, respectively: 19 R5 R6 R5 R4 R4 R3 R1 R3 R1 R2 (VI) A R2(VI) A 5 R5 R4X R3 1 R1 R2 A (Vill) [00801 A can be any of the groups set forth above for formula (I). Each of R 1 to R 6 , as 10 applicable, can be independently selected from hydrogen, alkyl, substituted alkyl, hydroxyl, hydroalkyl, amine, amide, halogen, a heteratom, or the like. Suitable alkyls include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like. Suitable halogens include, for example, bromine, chlorine, fluorine, or the like. Suitable heteroatoms include, for example, sulfur, silicon, or nitrogen. In formulae VII, X can be, 15 for example, sulfur, silicon, nitrogen, fluoro- or bromo- substitutions. Similarly, 9-cis synthetic retinal derivatives containing ring modifications, aromatic analogs and heteroaromatic analogs of those shown in formulae VI, VII and VIII are contemplated. [00811 The synthetic retinal derivative also can have a modified polyene chain. Suitable derivatives include, for example, those with a trans/cis locked configuration, 6s-locked 20 analogs, as well as modified allene, alkene, alkyne or alkylene groups in the polyene chain. In one example, the derivative is an 11 -cis-locked analog of the following formula IX: R3 25 (M A (IX) 20 A can be any of the groups set forth above for formula (I). R 3 can be, for example, hydrogen, methyl or other lower alkane or branch alkane. n can be 0 to 4. m plus 1 equals 1, 2 or 3. 100821 In one embodiment, the synthetic retinal derivative can be an 11-cis-locked 5 analog of the following formula X: n A (X) 10 n can be 1 to 4. A can be any of the groups set forth above for formula (I). [0083] The synthetic retinal derivative is a 9,11,13-tri-cis-7-ring retinyl ester or ether, an 11,13-di-cis-7-ring retinyl ester or ether, an 1 1-cis-7-ring retinyl ester or ether or a 9,11-di cis-7-ring retinyl ester or ether. [00841 In another example, the synthetic retinal derivative is a 6s-locked analog of 15 formula XI. A can be any of the groups set forth above for formula (I). Ri and R 2 can be independently selected from hydrogen, methyl and other lower alkyl and substituted lower alkyl. R 3 can be independently selected from an alkene group at either of the indicated positions. (XII) 20 A (XIII) R1 R2 R3 A 25 A (XI) (XIV) A 21 [00851 The synthetic retinal derivative can be a 9-cis-ring-fused derivative, such as, for example, those shown in formulae XII-XIV. A can be any of the groups set forth above for formula (I). 5. [00861 The synthetic retinal derivative also can be of the following formula XV or XVI.

R

16

R

17

R

7

R

9 R2 I Rio R3 R5 R8Rii RR4 R4 R13 )n1 (XV) R16 R17 Rr R9 R1 R8 10 . 14 R R 5

R

13 R4 A (XVI) 10 A can be any of the groups set forth above for formula (I). Each of R 2 to R 5 , R 7 to R 14 , R 16 and R 1 7 can be absent or independently selected from hydrogen, alkyl, branched alkyl, halogen, hydroxyl, hydroalkyl, amine, amide, a heteratom, or the like. Suitable alkyls include, for example, methyl, ethyl, propyl, substituted alkyl (e.g., alkyl with hydroxyl, 15 hydroalkyl, amine, amide), or the like. Suitable branched alkyl can be, for example, isopropyl, isobutyl, substituted branched alkyl, or the like. Suitable halogens include, for example, bromine, chlorine, fluorine, or the like. Suitable heteroatoms include, for example, sulfur, silicon, and fluoro- or bromo- substitutions. Suitable substituted alkyls and substituted branch alkyls include, for example, alkyls and branched alkyls substituted 20 with oxygen, hydroxyl, nitrogen, amide, amine, halogen, heteroatom or other groups. 22 Each of n and ni can be independently selected from 1, 2, or 3 alkyl, alkene or alkylene groups, with the proviso that the sum of the n and ni is at least 1. In addition, R 3 -R4 and/or

R

2

-R

1 6 can comprise an alkene group in the cyclic carbon ring, in which case R 1 7 is absent. Rio and R 1 3 together can form a cyclo-alkyl, such as a five, six, seven or eight member 5 cyclo-alkyl or substituted cyclo-alkyl, such as, for example, those shown in Formulae IX, X, XII, XIII and XIV. [00871 Methods of making synthetic retinals and derivatives are disclosed in, for example, the following references: Anal. Biochem. 272:232-42 (1999); Angew. Chem. 36:2089-93 (1997); Biochemistry 14:3933-41 (1975); Biochemistry 21:384-93 (1982); 10 Biochemistry 28:2732-39 (1989); Biochemistry 33:408-16 (1994); Biochemistry 35:6257 62 (1996); Bioorganic Chemistry 27:372-82 (1999); Biophys. Chem. 56:31-39 (1995); Biophys. J. 56:1259-65 (1989); Biophys. J. 83:3460-69 (2002); Chemistry 7:4198-204 (2001); Chemistry (Europe) 5:1172-75 (1999); FEBS 158:1 (1983); J. Am. Chem. Soc. 104:3214-16 (1982); J. Am. Chem. Soc. 108:6077-78 (1986); J. Am. Chem. Soc. 109:6163 15 (1987); J. Am. Chem. Soc. 112:7779-82 (1990); J. Am. Chem. Soc. 119:5758-59 (1997); J. Am. Chem. Soc. 121:5803-04 (1999); J. American Chem. Soc. 123:10024-29 (2001); J. American Chem. Soc. 124:7294-302 (2002); J. Biol. Chem. 276:26148-53 (2001); J. Biol. Chem. 277:42315-24 (2004); J. Chem. Soc. - Perkin T. 1:1773-77 (1997); J. Chem. Soc. Perkin T. 1:2430-39 (2001); J. Org. Chem. 49:649-52 (1984); J. Org. Chem. 58:3533-37 20 (1993); J. Physical Chemistry B 102:2787-806 (1998); Lipids 8:558-65; Photochem. Photobiol. 13:259-83 (1986); Photochem. Photobiol. 44:803-07 (1986); Photochem. Photobiol. 54:969-76 (1991); Photochem. Photobiol. 60:64-68 (1994); Photochem. Photobiol. 65:1047-55 (1991); Photochem. Photobiol. 70:111-15 (2002); Photochem. Photobiol. 76:606-615 (2002); Proc. Natl Acad. Sci. USA 88:9412-16 (1991); Proc. Natl 25 Acad. Sci. USA 90:4072-76 (1993); Proc. NatlAcad. Sci. USA 94:13442-47 (1997); and Proc. R. Soc. Lond. Series B, Biol. Sci. 233(1270): 55-76 1988) (the disclosures of which are incorporated by reference herein). [00881 Retinyl esters can be formed by methods known in the art such as, for example, by acid-catalyzed esterification of a retinol with a carboxylic acid, by reaction of an acyl 30 halide with a retinol, by transesterification of a retinyl ester with a carboxylic acid, by reaction of a primary halide with a carboxylate salt of a retinoic acid, by acid-catalyzed reaction of an anhydride with a retinol, or the like. In an example, retinyl esters can be formed by acid-catalyzed esterification of a retinol with a carboxylic acid, such as, acetic 23 acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, oleic acid, stearatic acid, palmitic acid, myristic acid, linoleic acid, succinic acid, fumaric acid or the like. In another example, retinyl esters can be formed by reaction of an acyl halide with a retinol (see, e.g., Van Hooser et al., Proc. Natl. Acad. Sci. 5 USA, 97:8623-28 (2000)). Suitable acyl halides include, for example, acetyl chloride, palmitoyl chloride, or the like. [00891 Retinyl ethers can be formed by methods known in the art, such as for example, reaction of a retinol with a primary alkyl halide. [00901 Trans-retinoids can be isomerized to cis-retinoids by exposure to UV light. For 10 example, all-trans-retinal, all-trans-retinol, all-trans-retinyl ester or all-trans-retinoic acid can be isomerized to 9-cis-retinal, 9-cis-retinol, 9-cis-retinyl ester or 9-cis -retinoic acid, respectively. trans-Retinoids can be isomerized to 9-cis-retinoids by, for example, exposure to a UV light having a wavelength of about 365 nm, and substantially free of shorter wavelengths that cause degradation of cis-retinoids, as further described herein. 15 [00911 Retinyl acetals and hemiacetals can be prepared, for example, by treatment of 9 cis- and 11 -cis- retinals with alcohols in the presence of acid catalysts. Water formed during reaction is removed, for example by A1 2 0 3 of a molecular sieve. [00921 Retinyl oximes can be prepared, for example, by reaction of a retinal with hydroxylamine, 0-methyl- or O-ethylhydroxyl amine, or the like. 20 [00931 For a specific opsin protein, a suitable synthetic retinal derivatives can be identified, for example, by an expression system expressing the opsin protein. Suitable animal models include, for example, RPE65-/- or LRAT -/- mice (see, e.g., Van Hooser et al., J. Biol. Chem. 277:19173-82 (2002); Baehr et al., Vision Res. 43:2957-58 (2003); Batten et al., J. Biol. Chem. 279:10422-32 (2004); Kuksa et al., Vision Res. 43:2959-81 25 (2003); Thompson et al., Dev. Ophthalmol. 37:141-54 (2003)). Other suitable non-human animal models further include other mouse, rat or primate systems. Such animal models can be prepared, for example, by promoting homologous recombination between a nucleic acid encoding an opsin in its chromosome and an exogenous nucleic acid encoding a mutant opsin. In one aspect, homologous recombination is carried out by transforming 30 embryo-derived stem (ES) cells with a vector containing an opsin gene, such that homologous recombination occurs, followed by injecting the ES cells into a blastocyst, 24 and implanting the blastocyst into a foster mother, followed by the birth of the chimeric animal (see, e.g., Capecchi, Science 244:1288-92 (1989)). The chimeric animal can be bred to produce additional transgenic animals. 100941 Suitable expression systems also can include, for example, in vitro or in vivo 5 systems. Suitable in vitro systems include for example, coupled transcription-translation systems. Suitable in vivo systems include, for example, cells expressing an opsin protein. For example, cells of a vertebrate visual system can be adapted for culture in vitro, or recombinant cell lines expressing an opsin protein can be used. The cell lines are typically stable cell lines expressing the opsin protein. A synthetic retinal or synthetic retinal 10 derivative can be added to the cell culture media, and the cells cultured for a suitable period of time to allow the production of opsin/rhodopsin. Opsin and/or rhodopsin can be isolated (e.g., by immunoaffinity). Isolated protein samples are examined to determine the amount of pigment formed, and absorbance maxima. Methods of introducing nucleic acids into vertebrate cells are disclosed in, for example, Sambrook et al., Molecular 15 Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (Cold Spring Harbor, New York, 2001). 10095] Recombinant cell lines expressing opsin protein can be prepared by, for example, introducing an expression construct encoding an opsin protein into a suitable cell line. The expression construct typically includes a promoter operably linked to a nucleic acid 20 encoding an opsin protein, and optionally a termination signal(s). Nucleic acids encoding opsin can be obtained, for example, by using information from a database (e.g., a genomic or cDNA library), by polymerase chain reaction, or the like. For example opsin-encoding nucleic acids can be obtained by hybridization. (See generally Sambrook et al. (supra).) An opsin encoding nucleic acid can be obtained by hybridization under conditions of low, 25 medium or high stringency. [0096] Opsin-encoding nucleic acids can be obtained under conditions of high stringency hybridization. By way of example, and not limitation, procedures using conditions of high stringency are as follows: Prehybridization of filters containing DNA is carried out for 8 hours to overnight at 65*C in buffer composed of 6x SSC, 50 mM Tris 30 HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 ptg/ml denatured salmon sperm DNA. Filters are hybridized for 48 hours at 65*C in prehybridization mixture containing 100 tg/ml denatured salmon sperm DNA and 5-20 x 25 106 cpm of 32 P-labeled probe. Washing of filters is done at 65'C for 1 hour in a solution containing 2x SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA. This is followed by a wash in 0.lx SSC at 50'C for 45 minutes before autoradiography. Other conditions of high stringency which can be used are well known in the art. (See generally Sambrook et 5 al. (supra).) [0097] The expression construct can optionally include one or more origins of replication and/or selectable marker(s) (e.g., an antibiotic resistance gene). Suitable selectable markers include, for example, those conferring resistance to ampicillin, tetracycline, neomycin, G418, and the like. Suitable cell lines include, for example, 10 HEK293 cells, T-REx

TM

-293 cells, CHO cells and other cells or cell lines. [00981 The UV-visible spectra of rhodopsin (comprising opsin and a synthetic retinal) can be monitored to determine whether the synthetic retinal has formed a Schiff's base with the opsin protein. For example, acid-denatured, purified protein can be analyzed to determine whether an absorbance maxima of approximately 490 nm is present, providing 15 evidence that the synthetic retinal derivative forms a Schiff's base with the opsin protein. Hydroxylamine treatment can be used to confirm the Schiff's base is sequestered from the external environment. [0099] Suitable synthetic retinal derivatives also can be selected by molecular modeling of rhodopsin. The coordinates for rhodopsin crystal structure are available from the 20 Protein Data Bank (1HZX) (Teller et al., Biochemistry 40:7761-72 (2001)). The effects of amino acid substitutions on the structure of rhodopsin, and on the contacts between opsin and 11 -cis-retinal, or a synthetic retinal, can be determined by molecular modeling. [01001 The coordinates for the rhodopsin crystal structure from the Protein Data Bank (IHZX) (Teller et al., Biochemistry 40:7761-72 (2001)) can be used to generate a 25 computer model. The addition of hydrogen atoms and optimization can be done, for example, using Insight II (InsightIl release 2000, Accelrys, Inc., San Diego, CA). Crystallographic water can be removed, and water molecules introduced based on the accessible space in the extracellular region. Typically, no minimization is performed before water is added. A water layer (e.g., 5 A thick) can be used to coat the extracellular 30 part of rhodopsin as well as residues in contact with polar phospholipids heads. All of the water molecules can be allowed to move freely, as is the extracellular half of rhodopsin, 26 with retinal. If no water cap is put on the cytoplasmic part of rhodopsin, this part of the molecule can be frozen to prevent degradation of the model. [01011 A water cap can be put on the extracellular part of rhodopsin (together with that part buried in membrane in contact with polar heads of phospholipids). Water and the 5 extracellular part of rhodopsin can be allowed to move and the movement modeled at any suitable frequency. For example, the movement of the modeled rhodopsin can be modeling at 100 ps simulations. [0102] Synthetic retinals can be contacted with an opsin protein under conditions suitable and for a period of time sufficient for the formation of an opsin protein/synthetic 10 retinal complex. The stability of the opsin/synthetic retinal complex can be determined by methods described herein or as known to the skilled artisan. The opsin in the opsin/synthetic retinal complex is stabilized when it exhibits increased stability (e.g., increased half-life when bound to the synthetic retinal as compared with free opsin (i.e., not bound to retinoid), is less sensitive to hydroxylamine, exhibits less accumulation in 15 aggresomes, or the like). [01031 The synthetic retinal can be contacted with the opsin protein in vitro or in vivo. For example, the opsin protein can be synthesized in an in vitro translation system (e.g., a wheat germ or reticulocyte lysate expression system) and the synthetic retinal added to the expression system. The opsin protein can be contacted with the opsin protein ex vivo, and 20 then the complex can be administered to a vertebrate eye. [01041 In another aspect, methods of using a synthetic retinal derivative are provided to restore or stabilize photoreceptor function, or to ameliorate photoreceptor loss, in a vertebrate visual system. A synthetic retinal derivative can be administered to a vertebrate eye(s) having a retinoid deficiency (e.g., a deficiency of 11 -cis-retinal), an excess of free 25 opsin, an excess of retinoid waste (e.g., degradation) products or intermediates in the recycling of all-trans-retinal, or the like. The vertebrate eye typically comprises a wild type opsin protein. Methods of determining endogenous retinoid levels in a vertebrate eye, and a deficiency of such retinoids, are disclosed in, for example, U.S. Provisional Patent Application No. 60/538,051 (filed Feb. 12, 2004) (the disclosure of which is 30 incorporated by reference herein). Other methods of determining endogenous retinoid levels in a vertebrate eye, and a deficiency of such retinoids, include for example, analysis by high pressure liquid chromatography (HPLC) of retinoids in a sample from a subject. 27 For example, retinoid levels or a deficiency in such levels can be determined from a blood sample from a subject. [0105] A blood sample can be obtained from a subject and retinoid types and levels in the sample can be separated and analyzed by normal phase high pressure liquid 5 chromatography (HPLC) (e.g., with a HP1 100 HPLC and a Beckman, Ultrasphere-Si, 4.6 mm x 250 mm column using 10% ethyl acetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids can be detected by, for example, detection at 325 nm using a diode-array detector and HP Chemstation A.03.03 software. A deficiency in retinoids can be determined, for example, by comparison of the profile of retinoids in the sample with a 10 sample from a control subject (e.g., a normal subject). 10106] As used herein, absent, deficient or depleted levels of endogenous retinoid, such as 11 -cis-retinal, refer to levels of endogenous retinoid lower than those found in a healthy eye of a vertebrate of the same species. A synthetic retinal derivative can spare the requirement for endogenous retinoid. 15 [01071 As used herein, "prophylactic" and "prophylactically" refer to the administration of a synthetic retinal derivative to prevent deterioration or further deterioration of the vertebrate visual system, as compared with a comparable vertebrate visual system not receiving the synthetic retinal derivative. The term "restore" refers to a long-term (e.g., as measured in weeks or months) improvement in photoreceptor function in a vertebrate 20 visual system, as compared with a comparable vertebrate visual system not receiving the synthetic retinal derivative. The term "stabilize" refers to minimization of additional degradation in a vertebrate visual system, as compared with a comparable vertebrate visual system not receiving the synthetic retinal derivative. [0108] In one aspect, the vertebrate eye is characterized as having Leber Congenital 25 Amaurosis ("LCA"). This disease is a very rare childhood condition that effects children from birth or shortly there after. It affects both rods and cones in the eye. For example, certain mutations in the genes encoding RPE65 and LRAT proteins are involved in LCA. Mutations in both genes result in a person's inability to make 11 -cis-retinal in adequate quantities. Thus, 11-cis-retinal is either absent or present in reduced quantities. In 30 RPE65-defective individuals, retinyl esters build up in the RPE. LRAT-defective individuals are unable to make esters and subsequently secrete any excess retinoids. For 28 LCA, a synthetic retinal derivative can be used to replace the absent or depleted 11 -cis retinal. [0109] In another aspect, the vertebrate eye is characterized as having Retinitis Punctata Albesciens. This disease is a form of Retinitis Pigmentosa that exhibits a shortage of 11 5 cis-retinal in the rods. A synthetic retinal derivative can be used to replace the absent or depleted 1 1-cis retinal. 10110] In another aspect, the vertebrate eye is characterized as having Congenital Stationary Night Blindness ("CSNB") or Fundus Albipunctatus. This group of diseases is manifested by night blindness, but there is not a progressive loss of vision as in the 10 Retinitis Pigmentosa. Some forms of CSNB are due to a delay in the recycling of 11 -cis retinal. Fundus Albipunctatus until recently was thought to be a special case of CSNB where the retinal appearance is abnormal with hundreds of small white dots appearing in the retina. It has been shown recently that this is also a progressive disease, although with a much slower progression than Retinitis Pigmentosa. It is caused by a gene defect that 15 leads to a delay in the cycling of 11 -cis-retinal. Thus, a synthetic retinal derivative(s) can be administered to restore photoreceptor function by retinoid replacement. [01111 In yet another aspect, the vertebrate eye is characterized as having age-related macular degeneration ("AMD"). AMD can be wet or dry forms. In AMD, vision loss occurs when complications late in the disease either cause new blood vessels to grow 20 under the retina or the retina atrophies. Without intending to be bound by any particular theory, excessive production of waste products from the photoreceptors may overload the RPE. This is due to a shortfall of 11 -cis-retinal available to bind opsin. Free opsin is not a stable compound and can spontaneously cause firing of the biochemical reactions of the visual cascade without the addition of light. 25 [0112] Administration of a synthetic retinal derivative to the vertebrate eye can reduce the deficiency of 11 -cis-retinal and quench spontaneous misfiring of the opsin. Administration of a synthetic retinal derivative can lessen the production of waste products and/or lessen drusen formation, and reduce or slow vision loss (e.g., choroidal neovascularization and/or chorioretinal atrophy). 30 [0113] In yet other aspects, a synthetic retinal derivative is administered to an aging subject, such as a human. As used herein, an aging human subject is typically at least 45, 29 or at least 50, or at least 60, or at least 65 years old. The subject has an aging eye, which is characterized as having a decrease in night vision and/or contrast sensitivity. Excess unbound opsin randomly excites the visual transduction system. This creates noise in the system and thus more light and more contrast are necessary to see well. Quenching these 5 free opsin molecules with a synthetic retinal will reduce spontaneous misfiring and increase the signal to noise ratio, thereby improving night vision and contrast sensitivity. [01141 Synthetic retinal derivatives can be administered to human or other non-human vertebrates. The synthetic retinal derivative can be substantially pure, in that it contains less than about 5% or less than about 1 %,or less than about 0.1%, of other retinoids. A 10 combination of synthetic retinal derivatives can be administered. [01151 Synthetic retinal derivatives can be delivered to the eye by any suitable means, including, for example, oral, intravenous, intramuscular or local administration. Modes of local administration can include, for example, eye drops, intraocular injection or periocular injection. Periocular injection typically involves injection of the synthetic 15 retinal derivative into the conjunctiva or to the tennon (the fibrous tissue overlying the eye). Intraocular injection typically involves injection of the synthetic retinal derivative into the vitreous. The administration can be non-invasive, such as by eye drops or oral dosage form. [0116] Synthetic retinal derivatives can be formulated, for example, as pharmaceutical 20 compositions for local administration to the eye and/or for intravenous, intramuscular or oral administration. In some embodiments, the pharmaceutical composition is not a topical formulation. In other embodiments, the pharmaceutical composition is not a cosmetic formulation. [01171 Synthetic retinal derivatives can be formulated for administration using 25 pharmaceutically acceptable vehicles as well as techniques routinely used in the art. A vehicle can be selected according to the solubility of the synthetic retinal derivative. Suitable pharmaceutical compositions include those that are administrable locally to the eye, such as by eye drops, injection or the like. In the case of eye drops, the formulation can also optionally include, for example, ophthalmologically compatible agents such as 30 isotonizing agents such as sodium chloride, concentrated glycerin, and the like; buffering agents such as sodium phosphate, sodium acetate, and the like; surfactants such as polyoxyethylene sorbitan mono-oleate (also referred to as Polysorbate 80), polyoxyl 30 stearate 40, polyoxyethylene hydrogenated castor oil, and the like; stabilization agents such as sodium citrate, sodium edentate, and the like; preservatives such as benzalkonium chloride, parabens, and the like; and other ingredients. Preservatives can be employed, for example, at a level of from about 0.001 to about 1.0% weight/volume. The pH of the 5 formulation is usually within the range acceptable to ophthalmologic formulations, such as within the range of about pH 4 to 8. [0118] Suitable pharmaceutical compositions also include those formulated for injection. For example, the synthetic retinal derivative can be provided in an injection grade saline solution, in the form of an injectable liposome solution, or other carriers or 10 vehicles. Intraocular and periocular injections are known to those skilled in the art and are described in numerous publications including, for example, Ophthalmic Surgery: Principles ofPractice, Ed., G. L. Spaeth, W. B. Sanders Co., Philadelphia, Pa., U.S.A., pages 85-87 (1990). [0119] A synthetic retinal derivative also can be administered in a time release 15 formulation, for example in a composition which includes a slow release polymer. The synthetic retinal derivative can be prepared with a carrier(s) that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, 20 polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art. [01201 Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers can be used which 25 include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington "Pharmaceutical Sciences", 17 Ed., Gennaro (ed.), Mack Publishing Co., Easton, Pennsylvania (1985).) [0121] The doses of the synthetic retinal derivatives can be suitably selected depending 30 on the clinical status, condition and age of the subject, dosage form and the like. In the case of eye drops, a synthetic retinal derivative can be administered, for example, from about 0.01 mg, about 0.1 mg, or about 1 mg, to about 25 mg, to about 50 mg, or to about 31 90 mg per single dose. Eye drops can be administered one or more times per day, as needed. In the case of injections, suitable doses can be, for example, about 0.0001 mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, to about 25 mg, to about 50 mg, or to about 500 mg of the synthetic retinal derivative, one to four times per week. 5 In other embodiments, about 1.0 to about 300 mg of synthetic retinal derivative can be administered one to three to five times per week. [01221 Oral doses can typically range from about 1.0 to about 1000 mg, one to four times, or more, per day. An exemplary dosing range for oral administration is from about 10 to about 250 mg one to three times per day. 10 [0123] The following examples are provided merely as illustrative of various aspects of the invention and shall not be construed to limit the invention in any way. EXAMPLES [01241 Example 1: 15 [0125] 9-cis-retinyl ester restores visual pigment in an LCA mouse model. LRAT-/ mice were gavaged with all-trans-retinyl palmitate, all-trans-retinyl acetate or 9-cis-retinyl acetate as indicated in the legend to Figure 1. Following treatment, retinoids were extracted from the eye and liver, and analyzed by HPLC. As shown in Figure 1 left, treatment of mice only with 9-cis-retinyl acetate, but not with all-trans-retinyl analogs 20 restored the presence of syn-9-cis-retinal oxime, indicating formation of the chromophore and restoration vision in these mice. No significant retention of retinoids was observed in liver, where LRAT is highly expressed, indicating low or no toxicity by retinoids in this animal model of human LCA. 9-cis-retinyl ester restores visual pigment in approximately 5 hr (Figure 2), while excess of retinoid is removed and metabolized (as illustrated for 9 25 cis-retinol). [0126] Example 2: [0127] Vitamin A and its derivatives can isomerized upon exposure to light. For example, Rao et al. (Tetrahedron Letters 31:3441-44 (1990)) showed photoisomerization of all-trans-retinol acetate (a derivative of Vitamin A) using a broad wavelength UV light 30 could produce a mixture of all-trans, 13-cis, and 9-cis retinol acetate isomers. However, this methods is generally inefficient and produces small amounts of such retinoid. 32 [0128] Methods 101291 Solutions of all-trans-retinoids are made to concentrations of 1 mg/mL in methanol. The solutions are added to a glass petri dish and subjected to 365 nm UV light using a Bio-Rad GS Genelinker with the stock bulbs replaced with 8 watt F8T5 bulbs, for 5 varying lengths of time dependent on the target retinoid. This wavelength is beneficial, as shorter wave length light quickly destroys retinoids. Following UV-treatment, the solutions are dried down, dissolved in hexane, and purified using normal phase HPLC. Conversion yields vary for each all-trans derivative. Nonisomerized all-trans derivatives, or 13-cis and 11 -cis derivatives can be reused in subsequent repetitions, thereby increasing 10 yields. [01301 Results [0131] Production of 9-cis-retinyl acetate from all-trans-retinyl acetate. All-trans retinyl acetate (Sigma # R4632) was dissolved in methanol to a concentration of 1 mg/mL. The solution was poured into a glass petri dish and irradiated with 365 nm UV light, 15 inducing isomerization (Figure 3). Two minutes of irradiation yields a mix of isomers, ~25% 9-cis-retinyl acetate, as shown by HPLC (Figure 4). [01321 The following diagram illustrates some other compounds that can be made with this method. R R R R R R R R 0 R R R R R R R R R R R R R R R R RR RR R all-trans-retinals 0 9-cis-retinals R R R R R R R R R R R -- ~-R R_ OH R RH3 RR R R R R R R R R _______ R RR RR R R all-trans-retinols RR R OH 9-cis-retinols 33 R R0 R R R R 0 R RR R R R O R R R R R R R R R 11#41 ~ ~ ~ ~ R R____________ R R all-trans-retinyl esters R R 0 R' O 9-cis-retinyl esters R R R R R OH R RR R R R R 0 R RR R R R NR R R R R R RR R R all-trans-retinoic acids HO 0 9-cis-retinoic acids [0133] R is hydrogen or lower alkyls ranging from C1 to C 6 . R' is R or any higher alkyls such as palmitate, oleate, or complex groups such as succinate, fumarate, and other functional groups. 5 [01341 Example 3: [0135] Levels of 9-cis-RAL oximes (measured as syn- and anti-9-cis-retinyl aldehyde) in the eyes of Lrat-/- mice after a single dose or multiple doses of 9-cis-retinyl-acetate (9 cis-R-Ac). Doses of 9-cis-R-Ac were administered to Lrat-/- mice by oral gavage in vegetable oil (100% canola oil) in a volume of 500 tl (2.5 mg/ml). The mice weighed 10 about 30-50 g. After 3 days, 9-cis-RAL oximes levels were determined by HPLC. Briefly, all experimental procedures related to extraction, derivatization, and separation of retinoids from dissected mouse eyes were carried out as described previously. See Van Hooser et al., J. Biol. Chem. 277:19173-182 (2002); Van Hooser et al., Proc. Natl. Acad. Sci. USA 97:8623-28 (2000); Maeda et al., J. Neurochem. 85:944-56 (2003). All 15 reactions involving retinoids were carried out under dim red light. [0136] Referring to Figure 5a, the level of 9-cis-RAL in Lrat-/- in mouse eyes after a varying dose of 9-cis-R-Ac is shown. Peaks were identified by retention time and UV spectra and compared to standards. The spike around 19 min resulted from changes in the solvent composition. Retinoid analysis was performed on an HP 1100 HPLC equipped 20 with a diode array detector and HP Chemstation (A.07.01) software, allowing identification of retinoid isomers according to their specific retention time and absorption maxima. A normal-phase column (Beckman Ultrasphere Si 5i, 4.6 mm x 250 mm) and an 34 isocratic solvent system of 0.5% ethyl acetate in hexane (v/v) for 15 min, followed by 4% ethyl acetate in hexane for 60 min at a flow rate of 1.4 ml/min (total 80 min), with detection at 325 nm allowed the partial separation of 11-cis-retinyl esters, 13-cis-retinyl esters, and all-trans-retinyl esters at 20 0 C. 5 [0137] Levels of 9-cis-RAL per eye leveled off at doses of about 4-6 tmole. Referring to Figure 5b, the level of 9-cis-RAL in Lrat-/- mouse eyes after a varying size and number of doses of 9-cis-R-Ac is shown. Levels of 9-cis-RAL accumulated over time. -Tshe levels of 9-cis-RAL increased from about 50 pmole per eye to about 600 pLmole per eye. The gray solid line represents a maximal level of isorhodopsin as measured by the level of 9 10 cis-retinal oximes in Lrat-/- mouse eyes after 10 gavages; dashed gray lines indicate the standard deviations. The maximal level of isorhodopsin is comparable to the level of rhodopsin in wildtype (WT) mice. [01381 Example 4 [0139] Levels of chromophore (opsin/retinal complexes) were measured in the eyes of 15 mice after dosing with all-trans-retinoid isoforms or 9-cis-retinyl succinate. All-trans retinyl-palmitate, all-trans-retinyl acetate, all-trans-retinal (vitamin A aldehyde), all-trans retinol (vitamin A), all-trans-retinyl succinate and 9-cis-retinyl succinate were administered to Lrat-/- mice by oral gavage. Five milligrams of the retinoid isoforms or 9 cis-retinyl succinate were administered in 100% canola oil at a concentration of 40 mg/ml. 20 After 3 days, chromophore levels (as all-trans-retinal oximes or 9-cis-retinal oximes) were determined as described previously. See Van Hooser et al., J. Biol. Chem. 277:19173-182 (2002); Van Hooser et al., Proc. Natl. Acad. Sci. USA 97:8623-28 (2000); Maeda et al., J. Neurochem. 85:944-56 (2003). All reactions involving retinoids were carried out under dim red light. 25 [0140] Referring to Figure 6, the all-trans retinoid isoforms had essentially no effect on restoration of chromophore levels. In contrast, administration of 9-cis-retinyl succinate restored chromophore levels. [01411 Example 5 [0142] A comparison of the bioavailability of orally delivered 9-cis-retinaldehyde and 9 30 cis-retinyl acetate in an LRAT -/- model. 9-cis-retinaldehyde and 9-cis-retinyl acetate were administered at low (10 ptmoles) and high (15 moles) doses to LRAT-/- mice. 35 Chromophore levels (as 9-cis-retinal oximes) were determined as described previously. See Van Hooser et al., J. Biol. Chem. 277:19173-182 (2002); Van Hooser et al., Proc. Natl. Acad. Sci. USA 97:8623-28 (2000); Maeda et al., J. Neurochem. 85:944-56 (2003). All reactions involving retinoids were carried out under dim red light. 5 [0143] Referring to Figure 7, at low and high doses, administration of 9-cis-retinyl acetate more efficiently restores chromophore levels than 9-cis-retinaldehyde. This effect is more pronounced at low (10 pimoles) doses. Because administration of retinoids can lead to toxicity, pro-drugs such as retinyl esters (e.g., 9-cis-retinyl acetate) provide a suitable bioavailable form to restore chromophore levels while reducing risk associated 10 with retinoid toxicity. [01441 The previous examples are provided to illustrate but not to limit the scope of the claimed inventions. Other variants of the inventions will be readily apparent to those of ordinary skill in the art and encompassed by the appended claims. All publications, 15 patents, patent applications and other references cited herein are hereby incorporated by reference. 36

Claims (84)

1. A retinyl ester selected from the group consisting of a 9-cis-retinyl ester and an 11-cis-retinyl ester, wherein the ester substituent comprises a carboxylate radical of a C 3 to C 2 2 polycarboxylic acid, with the proviso that the ester substituent is not tartarate.

2. The retinyl ester of claim 1, which is a 9-cis-retinyl ester of a C 3 to C 2 2 polycarboxylate.

3. The retinyl ester of claim 1, which is a 9-cis-retinyl ester of a C 3 to CIO polycarboxylate.

4. The retinyl ester of claim 3, wherein the 9-cis-retinyl ester is 9-cis retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9 cis-retinyl malate or 9-cis-retinyl oxaloacetate.

5. The retinyl ester of claim 1, which is an 11 -cis-retinyl ester of a C 3 to C 2 2 polycarboxylate.

6. The retinyl ester of claim 1, which is an 11 -cis-retinyl ester of a C 3 to CIO carboxylate.

7. The retinyl ester of claim 6, wherein the 1 1-cis-retinyl ester is 11 cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis-retinyl ketoglutarate, 11 -cis-retinyl fumarate, 11 -cis-retinyl malate or 11 -cis-retinyl oxaloacetate.

8. A pharmaceutical composition comprising the retinyl ester of claim 1 and a pharmaceutically acceptable vehicle.

9. A pharmaceutical composition of claim 8, compounded as an opthalmological composition in an opthalmologically acceptable vehicle for administration to the eye topically or by intra-ocular injection.

10. A method of restoring photoreceptor function in a mammal, comprising administering to a mammalian subject having an endogenous retinoid deficiency an effective amount of a synthetic retinal derivative, wherein the synthetic 37 retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, wherein the synthetic retinal derivative is a 9-cis-retinyl ester, an 11 -cis retinyl ester, or a combination thereof; wherein the ester substituent comprises a carboxylate radical of a Ci-Cio monocarboxylic acid or a C 2 to C 2 2 polycarboxylic acid.

11. The method of claim 10, wherein the synthetic retinal derivative is 9-cis-retinyl acetate or 11 -cis-retinyl acetate.

12. The method of claim 10, wherein the ester substituent comprises a carboxylate radical of a polycarboxylic acid of C 3 to CIO.

13. The method of claim 12, wherein the ester substituent is selected from the group consisting of succinate, citrate, ketoglutarate, fumarate, malate and oxaloacetate.

14. The method of claim 10, wherein the mammalian subject is human.

15. A method of ameliorating loss of photoreceptor function in a mammal, comprising: administering an effective amount of a synthetic retinal derivative to the vertebrate eye, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, wherein the synthetic retinal derivative is a 9-cis-retinyl, an 11 -cis-retinyl ester, or a combination thereof; wherein the ester substituent comprises a carboxylate radical of a CI-C 10 monocarboxylic acid or a C 2 to C 2 2 polycarboxylic acid.

16. The method of claim 15, wherein the synthetic retinal derivative is 9-cis-retinyl acetate or 11 -cis-retinyl acetate.

17. The method of claim 15, wherein the ester substituent comprises a carboxylate radical of a polycarboxylic acid of C 3 to CIO. 38

18. The method of claim 17, wherein the ester substituent is selected from the group consisting of succinate, citrate, ketoglutarate, fumarate, malate and oxaloacetate.

19. A method of restoring photoreceptor function in a vertebrate eye, comprising administering to the vertebrate having an endogenous retinoid deficiency an effective amount of a synthetic retinal derivative, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl Ci to CIO ester, and if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 l-cis-retinyl C 1 to C 1 0 ester.

20. The method of claim 19, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI.

21. The method of claim 19, wherein the synthetic retinal derivative comprises a 9-cis-retinyl ester.

22. The method of claim 21, wherein the synthetic retinal derivative comprises 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

23. The method of claim 19, wherein the endogenous retinoid deficiency is associated with Age-Related Macular Degeneration, Leber Congenital Amaurosis, Retinitis Punctata Albesciens, Congenital Stationary Night Blindness or Fundus Albipunctatus.

24. - The method of claim 19, wherein the synthetic retinal derivative is locally administered to the eye.

25. The method of claim 24, wherein the synthetic retinal derivative is locally administered by eye drops, intraocular injection or periocular injection.

26. The method of claim 19, wherein the synthetic retinal derivative is orally administered to the vertebrate. 39

27. The method of claim 19, wherein the vertebrate is a human.

28. A method of sparing the requirement for endogenous retinoid in a vertebrate eye, comprising: administering to the eye a synthetic retinal derivative, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C 1 to CIO ester, and if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1-cis-retinyl C 1 to C 10 ester.

29. The method of claim 28, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI.

30. The method of claim 28, wherein the synthetic retinal derivative comprises a 9-cis-retinyl ester.

31. The method of claim 30, wherein the synthetic retinal derivative comprises 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate..

32. A method of ameliorating loss of photoreceptor function in a vertebrate eye, comprising: administering an effective amount of a synthetic retinal derivative to the vertebrate eye, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester, it is a 9-cis-retinyl C, to CIO ester comprising a monocarboxylic acid ester substituent, and if the synthetic retinal derivative is an 11 -cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1-cis-retinyl C 1 to C 10 ester.

33. The method of claim 32, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI. 40

34. The method of claim 32, wherein the synthetic retinal derivative is orally administered to a vertebrate comprising the eye.

35. The method of claim 32, wherein the synthetic retinal derivative is locally administered to the vertebrate eye.

36. The method of claim 32, wherein the synthetic retinal derivative is a 9-cis-retinyl ester.

37. The method of claim 36, wherein the 9-cis-retinyl ester is 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

38. A method of selecting a treatment for a subject having diminished visual capacity, comprising: determining whether the subject has a deficient endogenous retinoid level, as compared with a standard subject; and administering to the subject an effective amount of a synthetic retinal derivative, wherein the synthetic retinal derivative is converted into a retinal capable of forming a functional opsin/retinal complex, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl Ci to CIO ester, and if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl C 1 to CIO ester.

39. The method of claim 38, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI.

40. The method of claim 38, wherein the subject has Leber Congenital Amaurosis, Retinitis Punctata Albesciens, Congenital Stationary Night Blindness, Fundus Albipunctatus or Age-Related Macular Degeneration.

41. The method of claim 38, wherein the endogenous retinoid is an 11 cis-retinyl ester. 41

42. The method of claim 38, wherein the 9-cis-retinyl ester is a 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

43. The method of claim 38, wherein the synthetic retinal derivative is orally administered to a vertebrate comprising the eye.

44. The method of claim 38, wherein the synthetic retinal derivative is locally administered to the vertebrate eye.

45. A pharmaceutical composition comprising a synthetic retinal derivative in a pharmaceutically acceptable vehicle, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C, to C 10 ester, and if the synthetic retinal derivative is an 11 -cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis retinyl C, to CIO ester.

46. The composition of claim 45, wherein the synthetic retinal derivative is a 9-cis-retinyl ester.

47. The composition of claim 46, wherein the 9-cis-retinyl ester is 9 cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

48. The composition of claim 45, wherein the pharmaceutical composition is compounded for administration as eye drops, an intraocular injectable solution or a periocular injectable solution.

49. A method of treating Leber Congenital Amaurosis in a human subject, comprising: administering to the subject an effective amount of a synthetic retinal derivative, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C, to CIO ester, 42 and if the synthetic retinal derivative is an 11-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl C, to CIO ester.

50. The method of claim 49, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI.

51. The method of claim 49, wherein the synthetic retinal derivative is a 9-cis-retinyl ester.

52. The method of claim 51, wherein the 9-cis-retinyl ester is 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

53. The method of claim 49, wherein the synthetic retinal derivative is locally administered to the eye.

54. The method of claim 53, wherein the synthetic retinal derivative is locally administered by eye drops, intraocular injection or periocular injection.

55. The method of claim 49, wherein the synthetic retinal derivative is orally administered to the subject.

56. A method of treating Retinitis Punctata Albesciens, Congenital Stationary Night Blindness or Fundus Albipunctatus in a human subject, comprising: administering to the subject an effective amount of a synthetic retinal derivative.

57. The method of claim 56, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C, to CIO ester, and if the synthetic retinal derivative is an 1 1-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl C 1 to C 10 ester.

58. The method of claim 56, wherein the synthetic retinal derivative is a 9-cis-retinyl ester. 43

59. The method of claim 56, wherein the 9-cis-retinyl ester is 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

60. The method of claim 56, wherein the synthetic retinal derivative is locally administered to the eye.

61. The method of claim 60, wherein the synthetic retinal derivative is locally administered by eye drops, intraocular injection or periocular injection.

62. The method of claim 56, wherein the synthetic retinal derivative is orally administered to the subject.

63. A method of treating Age-Related Macular Degeneration in a human subject, comprising: administering to the subject an effective amount of a synthetic retinal derivative.

64. The method of claim 63, wherein the synthetic retinal derivative is selected from Formula 1, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI.

65. The method of claim 63, wherein if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis retinyl CI to C 1 0 ester, and if the synthetic retinal derivative is an 11 -cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 1 1-cis-retinyl C, to CIO ester.

66. The method of claim 63, wherein the synthetic retinal derivative is converted into a synthetic retinal that binds to free opsin in the eye.

67. The method of claim 63, wherein the synthetic retinal derivative is a 9-cis-retinyl ester.

68. The method of claim 67, wherein the 9-cis-retinyl ester is 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate. 44

69. The method of claim 63, wherein the synthetic retinal derivative is locally administered to the eye.

70. The method of claim 69, wherein the synthetic retinal derivative is locally administered by eye drops, intraocular injection or periocular injection.

71. The method of claim 63, wherein the synthetic retinal derivative is orally administered to the subject.

72. A method of treating or preventing loss of night vision or contrast sensitivity in an aging human subject, comprising: administering to the subject in need thereof an effective amount of a synthetic retinal derivative.

73. The method of claim 72, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl C to Cio ester, and if the synthetic retinal derivative is an l l-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an I 1-cis-retinyl Ci to CIO ester.

- 74. The method of claim 72, wherein the synthetic retinal derivative is converted into a retinal that binds to free opsin in the eye.

75. The method of claim 72, wherein the synthetic retinal derivative is a 9-cis-retinyl ester.

76. The method of claim 75, wherein the 9-cis-retinyl ester is 9-cis retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9 cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.

77. The method of claim 72, wherein the synthetic retinal derivative is locally administered to the eye.

78. The method of claim 77, wherein the synthetic retinal derivative is locally administered by eye drops, intraocular injection or periocular injection. 45

79. The method of claim 72, wherein the synthetic retinal derivative is orally administered to the subject.

80. The method of claim 72, wherein the synthetic retinal derivative is administered prophylactically to the subject.

81. The use of a synthetic retinal derivative in the preparation of a medicament for administration to a vertebrate having an endogenous retinoid deficiency in the eye, wherein the synthetic retinal derivative is selected from Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI, with the proviso that if the synthetic retinal derivative is a 9-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is a 9-cis-retinyl Ci to CIO ester, and if the synthetic retinal derivative is an I 1-cis-retinyl ester comprising a monocarboxylic acid ester substituent, it is an 11 -cis retinyl Ci to C 10 ester.

82. The use of claim 81, wherein the synthetic retinal derivative comprises a 9-cis-retinyl ester or an 11 -cis-retinyl ester.

83. The use of claim 82, wherein the synthetic retinal derivative is 9 cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, 11-cis-retinyl acetate, 11 -cis-retinyl succinate, 11 -cis-retinyl citrate, 11 -cis-retinyl ketoglutarate, II -cis retinyl fumarate, 11 -cis-retinyl malate or 11 -cis-retinyl oxaloacetate.

84. The use of claim 82, wherein the synthetic retinal derivative comprises 9-cis-retinyl acetate or 9-cis-retinyl succinate. University of Washington Patent Attorneys for the ApplicantNorminated Person SPRUSON & FERGUSON 46