WO2022226116A1 - Ghrelin treatment of brain dysfunction due to viral infection - Google Patents

Abstract

Disclosed are methods for mitigating one or more debilitating symptoms of sustained brain dysfunction due to viral infection, e.g., SARS-CoV-2. These methods comprise administering an effective amount of ghrelin or a variant thereof.

Description

GHRELIN TREATMENT OF BRAIN DYSFUNCTION DUE TO

VIRAL INFECTION

Cross-Reference To Related Application

[0001] This application claims the benefit of U.S. Provisional Application No. 63/177,527, filed April 21, 2021, which is incorporated herein by reference in its entirety and for all purposes.

Field

[0002] This disclosure is directed to methods for treating sustained brain dysfunction due to SARS-CoV-2, post-recovery from a SARS-CoV-2 infection in a patient, e.g., after recovery from the acute phase. The methods employ an effective amount of a composition comprising ghrelin or a ghrelin variant.

State of the Art

[0003] Fatigue and brain fog are associated with changes in brain chemistry resulting in alteration of neurotransmitters such as serotonin, acetylcholine, norepinephrine, and dopamine. A population of patients previously diagnosed with SARS-CoV-2 (the virus that causes COVID-19) evidence prolonged fatigue and/or “brain fog”

(cognitive impairment, brain dysfunction) weeks to months after they otherwise should have recovered.

Summary

[0004] Without being limited to any theory, the technology described herein is predicated on the basis that SARS-CoV-2 infection induces fatigue and/or brain fog in at least a subset of infected patients, for example by altering the functionality of neurons to communicate with each other either by altering the concentration of neurotransmitters and/or by increasing the energy output of the neural mitochondria to deal with the population of the virus/viral proteins that have crossed the blood brain barrier.

[0005] Many of the acute symptoms of an active SARS-CoV-2 infection are debilitating and most resolve themselves up to 14 days after the initial infection occurred. However, in approximately 25% of cases, some or all of the symptoms are not adequately resolved. As described herein, patients who have not resolved one or more of these debilitating symptoms once the acute phase of a SARS-CoV-2 infection can be classified as experiencing “long COVID”, or “post-acute sequele of COVID- 19”. Long COVID relates to a set of symptoms that continue or develop within 4 to 8 weeks after the initial infection, can persist for several months or longer, and can affect multiple systems of the body at once, including cardiovascular, digestive, excretory, and nervous systems. Symptoms of long COVID include, without limitation, gastrointestinal problems, kidney damage, cardiac inflammation, anxiety, depression, sleep disorders, shortness of breath, fatigue, fevers, memory loss, attention disorders, difficulty in fluency, and brain fog. Not much is known about long COVID, nor how to mitigate the still-lengthening list of symptoms.

[0006] It is still unknown if the SARS-CoV-2 virus can cross the blood brain barrier; however, individual components have been found to have that ability. A recent paper (Rhea, E.M. et al. Nature Neuroscience , 2020) showed that the SI spike protein, the protein which the virus uses to attach to target cells, can readily cross the blood-brain barrier in mice. The SI spike protein is proposed to contribute to the neurological damage seen in both acute and long COVID patients, and the mechanism by which it can inflict neurological damage is an area of intense research.

[0007] Infections by other viruses may cause similar brain dysfunction. For example, ghrelin or ghrelin variant may be administered to a subject who is or was infected by a virus that causes encephalitis (including, without limitation, herpes simplex virus types 1 and 2, varicella zoster virus, enteroviruses, West Nile virus, Powassan virus, La Crosse, St. Louis, western equine and eastern equine encephalitis, measles (rubeola), mumps, and German measles (rubella)). In embodiments, any one or more virus may be expressly excluded.

[0008] We have now discovered that administration of ghrelin, or a ghrelin variant, to patients suffering from long-term brain dysfunction, such as fatigue, brain fatigue and/or brain fog due to a viral infection, e.g., SARS-CoV-2 infection, is effective in resolving such dysfunction. Again, without being limited to any theory, we contemplate that the endogenous concentration of ghrelin, a peptide naturally found in the brain, is insufficient to resolve this dysfunction in a timely manner in at least a subset of patients. Administration of exogenous ghrelin to the patient may act to facilitate recovery of neurons damaged by the infection, thereby restoring normal brain function. [0009] In an aspect, provided herein, is a method of treatment for sustained brain dysfunction due to a viral infection in a subject, wherein the brain dysfunction is treated by administering an effective amount of ghrelin or a variant thereof.

[0010] In an aspect, provided herein, is a method for treating or mitigating fatigue in a subject due to a viral infection by administering to the subject an effective amount of ghrelin or a variant thereof to the subject, thereby treating or mitigating the fatigue. In embodiments, the fatigue is brain fatigue.

[0011] In an aspect, provided herein, is a method for treating or mitigating brain fog in a subject due to infection with a virus by administering to the subject an effective amount of ghrelin or a variant thereof, thereby treating or mitigating the brain fog. [0012] In embodiments, the virus is a coronavirus. In embodiments, the virus is SARS-CoV-2.

[0013] In one embodiment, ghrelin administration is continued until the subject’s symptoms (e.g., brain dysfunction, brain fatigue, and/or brain fog) are resolved. In one embodiment, ghrelin administration is continued until the subject is able to resume normal activities. In one embodiment, ghrelin (or ghrelin variant) administration is continued until the subject is cleared by a clinician to resume normal activities. “Normal activities” may be any activities that were interrupted by the brain dysfunction due to the virus. For example, the subject may have been instructed (e.g., by a clinician) not to perform certain tasks, not to return to work, school, sport activities, or some other activity due to the brain dysfunction due to the virus or symptoms thereof. Alternatively, the subject may have been unable to perform the task, and/or the task may have been uncomfortable or otherwise undesireable, due to the brain dysfunction due to the virus or symptoms thereof.

[0014] In one embodiment, there is provided a method for mitigating one or more debilitating symptoms of brain dysfunction for a patient diagnosed with a sustained brain dysfunction due to a viral infection, e.g., SARS-CoV-2, which method includes administering to the patient an effective amount of ghrelin or a variant thereof over multiple consecutive days after the diagnosis of a sustained brain dysfunction due to the viral infection. The methods can include selection or identification of a patient exhibiting one or more symptoms of a sustained brain dysfunction due to the viral infection.

[0015] In one embodiment, administration of ghrelin or ghrelin variant takes the form of a continuous release patch or transdermal device which is optionally replaced during treatment. In one embodiment, ghrelin or ghrelin variant is administered orally, e.g., sublingually. In one embodiment, ghrelin or ghrelin variant is administered by injection.

[0016] In one embodiment, administration of ghrelin or a variant thereof occurs after a period of at least 7 days post-recovery from the acute part of a SARS-COV-2 infection and after diagnosis of a sustained brain dysfunction due to SAR-COV2. In one embodiment, administration of ghrelin or a variant thereof occurs after a period of at least 15 days post-recovery from a SARS-COV-2 infection and after diagnosis of a sustained brain dysfunction due to SAR-COV2. In one embodiment, administration of ghrelin or a variant thereof occurs after a period of at least 30 days post-recovery from a SARS-COV-2 infection and after diagnosis of a sustained brain dysfunction due to SAR-COV2.

[0017] In one embodiment, ghrelin administration takes the form of one or more administration(s). For example, in some embodiments, the administration can be one or more administrations for 1-2 days. In some embodiments, the administration can be one or more administrations per day for a period of at least 3 days, at least 5 days, or at least 7 days. In an embodiment, only a single administration per day is employed and administration is done on a daily basis. In another embodiment, administration takes the form of a medicament loaded syringe.

[0018] In one embodiment, the concentration for each single dose composition of ghrelin or variant thereof is tapered from an initial dose to a final dose over a period of at least 3 days, at least 5 days, or at least 7 days. In an embodiment, the concentration of ghrelin or variant thereof is reduced from the first dose to the final dose such that the last dose has a ghrelin concentration that is no more than 50% of the initial dose.

[0019] In an aspect, provided herein, is a method for mitigating one or more symptoms of a sustained brain dysfunction due to SARS-CoV-2 including: selecting a subject having sustained brain dysfunction due to a viral infection for at least 7 days after recovery from acute infection by the virus; and administering ghrelin or a variant thereof to the subject for a period of time, wherein ghrelin or the variant thereof is administered at a dose of about 20 pg/kg per day to about 120 pg/kg per day.

[0020] In one embodiment, ghrelin is administered. In one embodiment, a variant of ghrelin is administered. In one embodiment, the ghrelin variant is one or more of RM- 131 (or BIM-28131), Dln-101, Growth hormone (GH) releasing hexapeptide (GHRP)- 6, EP 1572, Ape-Ser(Octyl)-Phe-Leu-aminoethylamide, isolated ghrelin splice variant- like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, LY444711, MK-0677, L-692,429, NNC 26-0703, EP 1572, Capromorelin (CP-424, 391-18, RQ-00000005), L-252,564, NN703, G-7203, S-37435, SM-130868, EX-1314, ulimorelin, macimorelin (acetate), anamorelin, ipamorelin, PF-5190457, AMX-213, tabimorelin, capromorelin, GHRP-6, or a combination thereof.

[0021] In one embodiment, the effective amount of ghrelin or variant thereof is about 20 pg/kg per day to about 120 pg/kg per day. In one embodiment, the effective amount of ghrelin or variant thereof is about 80 pg/kg. In one embodiment, the ghrelin or variant thereof is administered twice a day, e.g., as about 40 pg/kg twice per day.

[0022] In one embodiment, the ghrelin or variant thereof is administered for at least 7 days. In one embodiment, the ghrelin or variant thereof is administered for at least 15 days. In one embodiment, the ghrelin or variant thereof is administered for at least 30 days.

[0023] In one embodiment, the ghrelin or variant thereof is administered for up to about 14 days. In one embodiment, the ghrelin or variant thereof is administered for up to 3 days. In one embodiment, the ghrelin or variant thereof is administered for up to 4 days. In one embodiment, the ghrelin or variant thereof is administered for up to 5 days. In one embodiment, the ghrelin or variant thereof is administered for up to 6 days. In one embodiment, the ghrelin or variant thereof is administered for up to 7 days. In one embodiment, the ghrelin or variant thereof is administered for up to 8 days. In one embodiment, the ghrelin or variant thereof is administered for up to 9 days. In one embodiment, the ghrelin or variant thereof is administered for up to 10 days. In one embodiment, the ghrelin or variant thereof is administered for up to 11 days. In one embodiment, the ghrelin or variant thereof is administered for up to 12 days. In one embodiment, the ghrelin or variant thereof is administered for up to 13 days. In one embodiment, the ghrelin or variant thereof is administered for up to 14 days. In one embodiment, the ghrelin or variant thereof is administered for more than 14 days. Detailed Description

[0024] Disclosed are methods for treating brain dysfunction, brain fog, and/or fatigue due to viral infection. However, prior to providing further details, the following terms will be defined. If not defined, terms used herein have their generally accepted scientific meaning. [0025] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0026] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0027] The term “about” when used before a numerical designation, e.g ., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 10%, 5%, 1%, or any subrange or subvalue there between. Preferably, the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%.

[0028] “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others.

[0029] “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.

[0030] “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0031] As used herein, the term "amino acid residue" refers to an amino acid formed upon chemical digestion (hydrolysis) of a polypeptide at its peptide linkages. Unless otherwise specified, the amino acid encompasses L-amino acid, including both natural amino acid and synthetic amino acid or the like as long as the desired functional property is retained by the polypeptide. NH2 refers to the free amino group present at the amino terminus of a polypeptide. COOH refers to the free carboxy group present at the carboxy terminus of a polypeptide. Standard polypeptide abbreviations for amino acid residues are as follows: A (Ala or Alanine); C (Cys or Cysteine); D (Asp or Aspartic Acid); E (Glu or Glutamic Acid); F (Phe or Phenylalanine); G (Gly or Glycine); H (His or Histidine); I (He or Isoleucine); K (Lys or Lysine); L (Leu or Leucine); M (Met or Methionine); N (Asn or Asparagine); P (Pro or Proline); Q (Gin or Glutamine); R (Arg or Arginine); S (Ser or Serine); T (Thr or Threonine); V (Val or Valine); W (Trp or Tryptophan); X (Xaa or Unknown or Other); Y (Tyr or Tyrosine); and Z (Glx/Gln/Glu or Glutamic Acid/Glutamine); and Dpr (2,3-diaminopropionic acid). All amino acid residue sequences represented herein by formula have a left-to- right orientation in the conventional direction of amino terminus to carboxy terminus. The phrase "amino acid residue" is broadly defined to include the naturally occurring and modified and non-naturally occurring amino acids. A dash at the beginning or end of an amino acid residue sequence indicates a peptide bond to a further sequence of one or more amino acid residues or a covalent bond to an amino-terminal group such as H2 or acetyl or to a carboxy -terminal group such as COOH.

[0032] As used herein, the term "amino acid derivatives" include, for example, alkyl- substituted tryptophan, b-naphthylalanine, naphthylalanine, 3,4-dihydrophenylalanine, and methylvaline. The amino acids and amino acid derivatives include both of L forms and D-forms.

[0033] The term "amino acid side chain" refers to any one of the twenty groups attached to the a-carbon in naturally occurring amino acids. For example, the amino acid side chain for alanine is methyl, the amino acid side chain for phenylalanine is phenylmethyl, the amino acid side chain for cysteine is thiomethyl, the amino acid side chain for aspartate is carboxymethyl, the amino acid side chain for tyrosine is 4- hydroxyphenylmethyl, etc.

[0034] As used herein, the term "ghrelin" is a polypeptide having 28 amino acid sequence as set forth in SEQ ID NO. 1, and can include the octanoyl acylation as described above. Human ghrelin is a polypeptide having the amino acid sequence as set forth in GenBank® Accession No. NP 057446 or Swiss-Prot Identifier GHRL HUMAN. Human ghrelin preprotein has 117 amino acids. This preprotein undergoes the following post-translational processing. The signal peptide (amino acids 1-23) is removed and the remaining 94 amino acids are cleaved by a protease to provide a mature 28 amino acid ghrelin (amino acids 24-51) or a mature 27 amino acid ghrelin (amino acids 24-50) and a mature 23 amino acid obestatin (amino acids 76-98). The 28 amino acid mature ghrelin peptide can be further modified at the serine at position 26 in the preprotein by either an O-octanoyl group or an O-decanoyl group. The obestatin mature peptide can be further modified at the lysine at position 98 of the preprotein by an amide group. An additional ghrelin preprotein is known, which lacks the glutamine at position 37 of the preprotein. [0035] As used herein, the term "ghrelin variant" refers to any compound (e.g., peptides, small molecule drugs) having at least about 50% of a functional activity of ghrelin. The functional activity includes, without limitation, feeding regulation, nutrient absorption, gastrointestinal motility, energy homeostasis, anti-inflammatory regulation, suppression of inflammatory cytokines, activation of Gq/Gl 1, accumulation of inositol phosphate, mobilization of calcium from intracellular stores, activation or deactivation of MAP kinases, FKB translocation, CRE driven gene transcription, reduction in reactive oxygen species (ROS), NAMPT enzyme activation, and/or binding of arrestin to ghrelin receptor. A ghrelin variant refers to any compound as described in U.S. Patent Application Publication No. 2017/0281732, which is incorporated herein by reference in its entirety, including for all compositions, formulations, and methods taught therein. Examples of ghrelin variants are provided herein. The terms “ghrelin variant”, “ghrelin analog” or “ghrelin agonist” may be used interchangeably herein.

[0036] The term “administration” refers to dosing a patient with an effective amount of a composition comprising ghrelin (or variant) wherein the dosing can be a single administration, continuous or intermittent or by several subdoses that in the aggregate provide for a single dose. For example, dosing may be continued throughout the course of treatment that may be as short as 1-2 days, 3 days or as long as 7 or more days such as 10 days, 12 days or 14 days, or longer. The route of administration is selected by the attending clinician and is based on factors such as the age, weight and general health of the patient as well as the severity of the condition. Suitable routes include, without limitation, parenteral, intravenous, transdermal, vaginal, nasal, sublingual, pulmonary, and the like.

[0037] The term “asymptomatic” means that the patient reports that s/he has no remaining debilitating symptoms of the viral infection. While some mild symptoms may persist, debilitating symptoms such as, by way of example only and without limitation, brain fog, fatigue, brain fatigue, headache, and/or trouble sleeping have abated. In some cases, the patients is able to resume most if not all of his/her day-to- day or normal activities.

[0038] As used herein, the term "brain dysfunction due to SARS-CoV-2" includes long term fatigue, brain fatigue, and/or brain fog. [0039] As used herein, the term "brain fog" refers to cognitive dysfunction including decrease in memory, concentration and executive function (e.g., planning, reasoning, problem solving, attention, and the like).

[0040] As used herein, “recovery from acute infection” or “post-recovery from acute infection” refers to the end of acute symptoms of the virus. In some embodiments, recovery from acute infection may be based on a negative test for the virus. “Post- recovery’ also can be defined as when the patient no longer is affected by the viral component of the infection but nevertheless is still suffering from the symptoms associated with the infection. In some embodiments, recovery from acute infection may be based on abatement of most or all symptoms of the virus. In some embodiments, recovery from acute infection may be based on a time from initial symptoms or diagnosis within which most patients with infection by the virus have recovered. For example, for SARS-CoV-2, a time from initial symptoms or diagnosis within which most patients with infection by the virus have recovered may be about 7 to about 20 days, or about 10 to about 14 days, or any value or subrange within the given ranges, including endpoints.

[0041] As used herein, an “effective amount” refers to an amount of ghrelin or ghrelin variant sufficient to treat, prevent, mitigate, or ameliorate one or more relevant symptoms.

Methods

[0042] The methods described herein treat patients who are diagnosed as having a sustained brain dysfunction due to SARS-CoV-2. Such a diagnosis and selection or identification of such patients may be made based on the continuation of debilitating symptoms for brain dysfunction due to SARS-CoV-2, for example at least 7 days after recovery from the acute phase of infection with the SARS-CoV-2 virus.

[0043] Patients suffering from a sustained brain dysfunction due to SARS-CoV-2 experience changes in brain chemistry resulting in alteration of neurotransmitters such as serotonin. Patients suffering from brain dysfunction due to SARS-CoV-2 often experience inflammation in the brain due, for example, to metabolic derangement, neuronal damage, or inflammation associated with overproduction of reactive oxygen species (ROS). This disclosure addresses the need to both mitigate the patient’s debilitating symptoms while addressing these unabated adverse events. [0044] The methods described herein further relate to treatment of patients having brain dysfunction due to viral infection, e.g., SARS-CoV-2, with ghrelin or variant thereof by administering multiple doses (administrations) and/or for multiple days.

[0045] In the methods described herein, ghrelin or a variant thereof is administered as a one day treatment, and/or daily ghrelin administration for multiple consecutive days after diagnosis.

[0046] In embodiments, treatment with ghrelin or variant is initiated at least 7 days after the initial (acute) viral infection. In embodiments, treatment is initiated at least 8 days after the initial viral infection. In embodiments, treatment is initiated at least 9 days after the initial viral infection. In embodiments, treatment is initiated at least 10 days after the initial viral infection. In embodiments, treatment with ghrelin or variant is initiated at least 14 days after the initial viral infection. In embodiments, treatment with ghrelin or variant is initiated at least 30 after the initial viral infection. In embodiments, treatment with ghrelin or variant is initiated between about 7 days and about 30 days after the initial viral infection. In embodiments, treatment with ghrelin or variant is initiated between about 8 days and about 30 days after the initial SARS- CoV-2 infection. In embodiments, treatment with ghrelin or variant is initiated between about 9 days and about 30 days after the initial SARS-CoV-2 infection. In embodiments, treatment with ghrelin or variant is initiated between about 10 days and about 30 days after the initial SARS-CoV-2 infection. In embodiments, treatment with ghrelin or variant is initiated between about 14 days and about 30 days after the initial SARS-CoV-2 infection. In embodiments, treatment with ghrelin or variant is initiated between about 7 days and about 14 days after the initial SARS-CoV-2 infection. The number of days may be any value or subrange within the recited ranges, including endpoints.

[0047] In embodiments, ghrelin or a composition comprising ghrelin is administered. In embodiments, a ghrelin variant or a composition comprising a ghrelin variant is administered.

[0048] Ghrelin or a variant can be administered in single adminstration or multiple administrations for a day or for multiple days. In one embodiment, the ghrelin or variant can be administered each day for at least 1 day. In one embodiment, the ghrelin or variant can be administered each day for at least 2 days. In one embodiment, the ghrelin or variant can be administered each day for at least 3 days. In one embodiment, the ghrelin or variant can be administered each day for at least 4 days. In one embodiment, the ghrelin or variant can be administered each day for at least 5 days. In one embodiment, the ghrelin or variant can be administered each day for at least 6 days. In one embodiment, the ghrelin or variant can be administered each day for at least 7 days. In one embodiment, the ghrelin or variant can be administered each day for at least 8 days. In one embodiment, the ghrelin or variant can be administered each day for at least 9 days. In one embodiment, the ghrelin or variant can be administered each day for at least 10 days. In one embodiment, the ghrelin or variant can be administered each day for at least 11 days. In one embodiment, the ghrelin or variant can be administered each day for at least 12 days. In one embodiment, the ghrelin or variant can be administered each day for at least 13 days. In one embodiment, the ghrelin or variant can be administered each day for at least 14 days. In some cases, daily ghrelin or variant administration is continued up to 14 days. In an embodiment, ghrelin or variant can be administered daily for between 1 and 14 days. In an embodiment, ghrelin or variant can be administered for more than 14 days. In an embodiment, ghrelin or variant can be administered until one or more symptoms of the brain dysfunction due to SARS-CoV-2 is resolved. In an embodiment, the ghrelin or variant can be administered continuously (e.g., using a transdermal patch) for between 1 and 14 days or more. The length of treatment may be any value or subrange within the recited ranges, including endpoints.

[0049] In one embodiment, ghrelin or variant can be administered at least once per day. In one embodiment, ghrelin or variant can be administered at least twice per day. In one embodiment, ghrelin or variant can be administered at least 3 times per day. In one embodiment, ghrelin or variant can be administered at least 4 times per day. In one embodiment, ghrelin or variant can be administered at least 5 times per day. In one embodiment, ghrelin or variant can be administered once per day. In one embodiment, ghrelin or variant can be administered twice per day. In one embodiment, ghrelin or variant can be administered 3 times per day. In one embodiment, ghrelin or variant can be administered 4 times per day. In one embodiment, ghrelin or variant can be administered 5 times per day.

[0050] In one embodiment, the ghrelin concentration changes at least twice during the treatment period. Example ghrelin concentration changes are provided in Table 1. Table 1

[0051] In one embodiment, a subject administered ghrelin or variant as described herein may show improvement on one or more assessment tools, when evaluated before, during, and/or after the administration. Any suitable tool may be used, as would be recognized by one of skill in the art. The number of symptoms and severity at any time before, during, and/or after treatment may be measures of interest.

[0052] In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 10%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 15%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 20%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 25%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 30%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 35%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 40%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 45%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 50%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 60%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 70%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 80%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 90%. In one embodiment, the subject shows improvement in any one or more of the assessments of up to about 100%. The improvement may be between any two time points, e.g., before, during, and/or after administration of ghrelin or variant.

Ghrelin and Ghrelin Variants

[0053] Ghrelin is a neuroendocrine hormone that acts as an endogenous ligand for growth hormone secretagogue receptor. It is a 28-amino acid and an endogenously produced peptide predominantly secreted by gastric mucosa. It has been referred to as the "hunger hormone," due to its well-studied effects on appetite, but it also is believed to play a significant role in regulating the distribution and rate of use of energy.

[0054] Ghrelin and ghrelin variants are described, for example, in U.S. Patent No. 9,119,832; and PCT Patent Publication Nos. WO 2015/120203; WO 2016/028826; WO 2016/048488; WO 2016/144978; and WO 2017/075535, each of which is incorporated herein by reference in its entirety.

[0055] In some embodiments, the ghrelin variants can be a sequence that includes any of a number of modifications to the wild type ghrelin sequence, which comprises a polypeptide having an amino acid sequence of Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu- His-Gln-Arg-Val-Gln-Gln- Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro- Arg (SEQ ID NO. 1). Non-limiting examples of potential modifications include modifying the length (shorter or longer) of the sequences, modifying the chemistry of the amino acids, substituting one or more of the amino acids with another amino acid, a synthetic amino acid or otherwise rare or non-naturally occurring amino acid, introducing protecting groups at the N and/or C termini, etc. In some embodiments, the polypeptide is modified with one or more fatty acids. In some embodiments, the fatty acid is an octanoic acid. In some embodiments, the polypeptide is modified at serine at amino acid position 2 and/or serine at amino acid position 3 of SEQ ID NO.

1

[0056] For example, in some embodiments, ghrelin or the ghrelin variants include C1-C20 acylation of the carboxyl group of one or both of the glutamic acid residues or of the C-terminus arginine group. In other embodiments, ghrelin or ghrelin variants include C1-C20 acylation of one or more of the hydroxyl groups of the serine residues. Yet, in other embodiments, ghrelin or ghrelin variants include replacing one or more of the L-amino acids with a D-amino acid. Every amino acid with the exception of glycine can occur in two isomeric forms, which are called L- and D- forms, analogous to left-handed and right-handed configurations. L-amino acids are the form commonly manufactured in cells and incorporated into proteins. As mentioned above, some ghrelin variants can have one or more of L-amino acids substituted with D-amino acids. In some embodiments, one or more of the ghrelin variants listed above, can be specifically excluded.

[0057] In some embodiments, the ghrelin variant comprises or consists of a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO. 1 provided that in some embodiments such variants retain at least 50% of the activity of native ghrelin.

[0058] In some embodiments, the ghrelin variant is a ghrelin mimetic such as a compound which is one or more of RM-131 (Rhythm Pharmaceuticals, Boston, MA) (or BIM-28131 (Ipsen Group), Dln-101 (DiaLean Ltd., Israel), Growth hormone (GH) releasing hexapeptide (GHRP)- 6, EP 1572, Ape-Ser(Octyl)-Phe-Leu- aminoethylamide, isolated ghrelin splice variant-like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, and a combination thereof. In some embodiments, one or more of the ghrelin variants listed above can be specifically excluded. In some embodiments, those ghrelin variants which are a polypeptide have at least 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of one or more of the compounds described in the present disclosure. In some embodiments, ghrelin variants, which comprise short amino acid sequences, such as the RM-131 pentapeptide molecule, can have a substitution of one of its amino acids, for example, a conservative or other type of substitution as described herein with a natural or non natural amino acids, as well as isomers of the same. Other chemical modifications also are contemplated, such as those described elsewhere herein (e.g., protecting groups, octanoylation, acylation, etc.). In some embodiments, one or more of the substitution listed above, can be specifically excluded.

[0059] In some embodiments, the ghrelin variant is one or more of RM-131 (or BIM- 28131), Dln-101, Growth hormone (GH) releasing hexapeptide (GHRP)-6, EP 1572, Ape-Ser(Octyl)- Phe-Leu-aminoethylamide, isolated ghrelin splice variant-like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, LY444711, LY426410, hexarelin/examorelin, growth hormone releasing hexapeptide- 1 (GHRP-I), GHRP-2, GHRP-6 (SK&F- 110679), ipamorelin, MK-0677, NN703, capromorelin, CP 464709, pralmorelin, macimorelin (acetate), anamorelin, relamorelin, ulimorelin, ipamorelin, tabimorelin, ibutamoren, G7039, G7134, G7203, G-7203, G7502, SM-130686, RC-1291, L-692429, L-692587, L-739943, L-163255, L- 163540, L-163833, L-166446, CP-424391, EP-51389, NNC-26-0235, NNC-26- 0323, NNC-26-0610, NNC 26-0703, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26- 1137, NNC-26-1187, NNC-26-1291, MK-0677, L-692,429, EP 1572, L- 252,564, NN703, S- 37435, EX-1314, PF-5190457, AMX-213, and a combination thereof. In some embodiments, one or more of the ghrelin variants listed above, can be specifically excluded.

[0060] In some embodiments, the ghrelin variant comprises a polypeptide comprising the sequence of Gly Ser Ser Phe Leu Ser Pro Glu His Gin Arg Val Gin Val Arg Pro Pro Lys Ala Pro His Val Val (SEQ ID NO. 2). In some embodiments, the ghrelin variant comprises a polypeptide comprising the sequence of Gly Ser Xaa Phe Leu Ser Pro Glu His Gin Arg Val Gin Val Arg Pro Pro His Lys Ala Pro His Val Val (SEQ ID NO. 3), wherein the third position is a 2,3- diaminopropionic acid (Dpr), with the Dpr in the third position being optionally octanoylated. In some embodiments, the ghrelin variant comprises a polypeptide comprising the sequence of Gly Xaa Xaa Phe Leu Ser Pro Glu His Gin Arg Val Gin Val Arg Pro Pro His Lys Ala Pro His Val Val (SEQ ID NO. 4), wherein the second and third position are 2,3 -diaminopropionic acid (Dpr) residues, with the Dpr in the third position being optionally octanoylated. In some embodiments, the ghrelin variant comprises a polypeptide comprising the sequence of Gly Ser Ser Phe Leu Ser Pro Glu His Gin Arg Val Gin Val Arg Pro Pro His Lys Ala Pro His Val Val Pro Ala Leu Pro (SEQ ID NO. 5). In some embodiments, the ghrelin variant comprises a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%), 96%), 97%), 98%), or 99% sequence identity to the amino acid sequence of one or more of the compounds described in the present paragraph. In some embodiments, the ghrelin variant comprises a polypeptide comprising the sequence of Inp-D-2Nal-D-T -Thr-Lys-NH2 (SEQ ID NO. 6). In some embodiments, one or more of the ghrelin variants listed above, can be specifically excluded.

[0061] In some embodiments, the ghrelin variant is one or more of LY444711 (2(R)- (2- Amino-2-methylpropanamido)-N-[ 1 -[ 1 (R)-(4-methoxyphenyl)- 1 -methyl -2- oxo-2-( 1 - pyrrolidinyl)ethyl]-lH-imidazol-4-yl]-5-phenylpentanamide dihydrochloride, C32H44CI2N604; Ely Lilly), MK-0677 (2-Amino-N-[2-benzyloxy- (lR)-[l-(methanesulfonyl)spiro[indoline-3,4'- piperidinJ-G- ylcarbonyl]ethyl]isobutyramide methanesulfonate, C28H40N4O8S2; Merck & Co., Inc.), L-692,429 (Merck Research Laboratories), Tabimorelin (NNC 26-0703,

NN703; N-[5- Amino-5-methyl-2(E)-hexenoyl]-N-methyl-3-(2-naphthyl)-D-alanyl- N-methyl-D-phenylalanine methylamide, C32H40N4O3; Novo Nordisk), Capromorelin (CP-424,391-18; RQ-00000005; CP- 424391; 2-Amino-N-[2-[3a(R)- benzyl-2-methyl-3-oxo-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3- c]pyridin-5-yl]- l(R)-(benzyloxymethyl)-2-oxoethyl]isobutyramide, C28H35N504; Pfizer and RaQualia, Japan), L-252,564 (Merck), G-7203, S-37435 (N-[l(R)-[N-(3-Amino-2- hydroxypropyl)carbamoyl]-2-naphthylethyl]-4-(4-oxo-2,3,4,5-tetrahydro-l,5- benzothiazepin-5- yl)butyramide hydrochloride, C29H35CIN404S; Kaken/Molecular Research Institute), SM-130868 ((+)-(35)-3-(2-chlorophenyl)-l-[2- (diethylamino)ethyl]-3-hydroxo-2-oxo-4- (trifluoromethyl)indoline-6-carboxamide, C22H23CIF3N303; Sumitomo), EX-1314 (Carbamic acid, (2-amino-2- oxoethyl)methyl-, (3-((l S)-l-((2-amino-2-methyl-l-oxopropyl)amino)-2- (phenylmethoxy)ethyl)-l,2,4-triazolo(4,3-a)pyridin-5-yl)methyl ester, monohydrochloride, C24H31N705 HC1; Elixir Pharmaceuticals), ulimorelin((2R,5S,8R,l lR)-5-Cyclopropyl-l l-(4- fluorobenzyl)-2, 7, 8-trimethyl - 4,5,7,8,10,11, 13,14, 15,16-decahydro-2H-l,4,7, 10, 13- benzoxatetraazacyclooctadecine-6,9, 12(3H)-trione, C30H39FN4O4; Tranzyme Pharma, Inc., Ocera Therapeutics, Lyric Pharmaceuticals, Inc.), macimorelin (acetate) (EP 1572; 2-Amino-N-[(2R)-l- [[(lR)-l-formamido-2-(lH-indol-3-yl)ethyl]amino]-3- lH-indol-3-yl)-l-oxopropan-2-yl]-2- methylpropanamide, C26H30N6O3; Sterna Zentaris Inc.), anamorelin (HC1) ( 2-amino-N-((R)-l- ((R)-3-benzyl-3-(l,2,2- trimethylhydrazinecarbonyl)piperidin-l-yl)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)-2- methylpropanamide hydrochloride, C31H43CIN603; Helsinn Group), ipamorelin (2- Methylalanyl-L-histidyl-3-(2-naphthyl)-D-alanyl-D-phenylalanyl-L- lysinamide,C38H49N905;), PF-5190457, GHRP-6 (L-histidyl-D-tryptophyl-L-alanyl- L- tryptophyl-D-phenylalanyl-L-Lysinamide), AMX-213 (Ammunix), and a combination thereof. In some embodiments, one or more of the ghrelin variants listed above, can be specifically excluded.

[0062] In some embodiments, the ghrelin variant is one or more of LY426410 (2- Methylalanyl-N-[ 1 -[ 1 (R)-(4-methoxyphenyl)-2-(4-methyl- 1 -piperidinyl)-2- oxoethyl]- 1H- imidazol-4-yl]-0-benzyl-D-serinamide; 2- Amino-N-[ 1 (R)- (benzyloxymethyl)-2-[ 1 -[ 1 (R)-(4- methoxyphenyl)-2-(4-methyl-l-piperidinyl)-2- oxoethyl]-lH-imidazol-4-ylamino]-2-oxoe), hexarelin/examorelin ((2S)-6-amino-2- [[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3- (lH-imidazol-5- yl)propanoyl]amino]-3-(2 -methyl- lH-indol-3- yl)propanoyl]amino]propanoyl]amino]-3-(lH-indol-3-yl)propanoyl]amino]-3- phenylpropanoyl]amino]hexanamide), growth hormone releasing hexapeptide-1 (GHRP-I), GHRP-2, GHRP-6 (SK&F-l 10679), CP 464709 (2-amino-N-[(2R)-l- [(3aR)-3-oxo-3a-(pyridin- 2-ylmethyl)-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]-3-[(2,4- difluorophenyl)methoxy]-l-oxopropan-2-yl]-2- methylpropanamide), pralmorelin ((2S)-6-amino- 2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)- 2-[[(2R)-2-aminopropanoyl]amino]-3-naphthalen-2- ylpropanoyl]amino]propanoyl]amino]-3-(lH-indol-3-yl)propanoyl]amino]-3- phenylpropanoyl]amino]hexanamide), relamorelin (4-[[(2S)-2-[[(2R)-2-[[(2R)-3-(l- benzothiophen-3-yl)-2-(piperidine-3-carbonylamino)propanoyl]amino]-3-(lH-indol-3- yl)propanoyl]amino]-3-phenylpropanoyl]amino]piperidine-4-carboxamide), ulimorelin, ((7R, 1 OR, 13 S, 16R)- 13 -cyclopropyl -7-[(4-fluorophenyl)methyl]- 10,11, 16-trimethyl- 17-oxa- 5,8,1 1, 14-tetrazabicyclo[16.4.0]docosa-l(22),18,20- triene-6,9,12-trione), tabimorelin (N-[(2E)- 5-amino-5-methylhex-enoyl]-N-methyl-3- (2-naphthyl)alanyl-N,Na-dimethyl-D- phenylalaninamide; NN703; NNC 26-0703), ibutamoren (2-amino-2-methyl-N-[(2R)-l-(l- methylsulfonylspiro[2H-indole-3,4'- piperidine]- -yl)-l-oxo-3-phenylmethoxypropan-2- yljpropanamide), G7039 (Genentech), G7134 (Genentech), G7502 ([[5-(2-amino-6-oxo-3H- purin-9-yl)-3,4- dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [3,4,5-trihydroxy-6- (hydroxymethyl)oxan-2-yl] hydrogen phosphate), Anamorelin/RC-1291 (2-amino-N- [(2R)-1- [(3R)-3-benzyl-3-[dimethylamino(methyl)carbamoyl]piperidin-l-yl]-3-(lH- indol-3-yl)-l- oxopropan-2-yl]-2-methylpropanamide), L-692429 (3 -amino-3 -methyl- N-[(3R)-2-oxo-l-[[4-[2- (2H-tetrazol-5-yl)phenyl]phenyl]methyl]-4,5-dihydro-3H-l- benzazepin-3-yl]butanamide), Pexiganan [INNJ/L-692587 (Glycyl-L-isoleucylglycyl- L-lysyl-L-phenylalanyl-L-leucyl-L-lysyl- L-lysyl-L-alanyl-L-lysyl-L-lysyl-L- phenylalanylglycyl-L-lysyl-L-alanyl-L-phenylalanyl-L-valyl- L-lysyl-L-isoleucyl-L- leucyl-L-lysyl-L-lysinamide) (SEQ ID NO: 7), CHEMBL291200/L- 739943 (3- amino-3-methyl-N-[(3R)-l-[[4-[2-

[(methylcarbamoylamino)methyl]phenyl]phenyl]methyl]-2-oxo-4,5-dihydro-3H-l- benzazepin-3- yljbutanamide), L-163255 (2-amino-2-methyl-N-[(2R)-l-(l- methylsulfonylspiro[2H-indole-3,4'- piperidine]- -yl)-l-oxo-5-phenylpentan-2- yljpropanamide), L- 163, 540 (l-[2(R)-(2-amino-2- methylpropionylamino)-3-(lH- indol-3-yl)propionyl]- 3-benzylpiperidine-3(S)-carboxylic acid ethyl ester), L- 163833, L- 166446, EP-51389, NNC-26-0235 (3-(aminomethyl)benzoyl-2- naphthylalanyl-N-methylphenylalanyl-lysinamide,3-(aminomethyl)benzoyl-2Nal-N- Me-Phe- Lys-NH2, NNC-26-0235), NNC-26-0323 (3-(aminomethyl)benzoyl-D-2Nal- N-Me-D-Phe-Lys- NH2), NNC-26-0610 (Novo Nordisk), NNC-26-0722, NNC-26- 1089, NNC-26-1136, NNC-26- 1137, NNC-26-1187, NNC-26-1291, EP 1572 (Aib- DTrp-DgTrp-CHO), S-37435 (N-[(2R)-1- [(3-amino-2-hydroxypropyl)amino]-3- naphthalen-2-yl-l-oxopropan-2-yl]-4-(l,l,4-trioxo-2,3- dihydro-1 {6}, 5- benzothiazepin-5-yl)butanamide), and a combination thereof.

[0063] In some embodiments, the ghrelin variant is one or more of RM-131 (or BIM- 28131), Dln-101, Growth hormone (GH) releasing hexapeptide (GHRP)-6, EP 1572, Ape-Ser(Octyl)-Phe-Leu-aminoethylamide, isolated ghrelin splice variant-like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, LY444711, MK-0677, L-692,429, NNC 26-0703, EP 1572, Capromorelin (CP-424, 391-18, RQ-00000005), L-252,564, NN703, G-7203, S-37435, SM-130868, EX-1314, ulimorelin, macimorelin (acetate), anamorelin, ipamorelin, PF-5190457, AMX-213, tabimorelin, capromorelin, GHRP-6, or a combination thereof.

[0064] In some embodiments, one or more of the ghrelin variants listed herein may be specifically excluded.

Pharmaceutical Compositions

[0065] Ghrelin or a variant thereof will be administered in a therapeutically effective amount by any of the accepted modes of administration suitable for delivery of a peptide. The actual amount of ghrelin or a variant thereof is dependent upon numerous factors such as the severity of the symptoms to be treated, the age and otherwise relative health of the subject, the route and form of administration, and other factors well-known to the skilled artisan.

[0066] An effective amount or a therapeutically effective amount or dose of ghrelin or a variant thereof refers to that amount that results in amelioration of one or more symptoms in a patient. Specific dosages may vary within a range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject’s condition. [0067] In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 10 ng/kg to about 10 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 1 pg/kg to about 10 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 1 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 10 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 20 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 30 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 40 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 50 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 60 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 70 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 80 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 90 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 100 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 10 pg/kg to about 0.1 mg/kg per day. The effective amount may be any value or subrange within the recited ranges, including endpoints.

[0068] This ghrelin or ghrelin variant is not limited to any particular composition or pharmaceutical carrier, as such may vary. In general, ghrelin or a variant thereof will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In embodiments, administration is parenteral using a dosage regimen that can be adjusted as provided above. Other pharmaceutical compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. [0069] Pharmaceutical dosage forms of ghrelin or ghrelin variant may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano-/micro-) encapsulating, entrapping, or lyophilization processes. The compositions can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0070] One pharmaceutical composition for use in the methods described herein is a sterile, aqueous composition such as those suitable for intravenous or intramuscular injection. In one embodiment, such compositions are preloaded into syringes for use by the clinician or the patient. Preferably, the syringes are loaded into a container and are labeled, marked or otherwise identified as for use on a given day. For example, in a 7 day treatment regimen, the identication for each syringe will indicate that it is for day 1, or day 2 and so on.

[0071] Alternatively, the pharmaceutical composition can take the form of a transdermal patch that provides for continuous release of ghrelin or a variant thereof in amounts such that the aggregate delivered in a given day is an effective amount as provided above. Given that ghrelin has a serum half-life of about 30 minutes, continuous release allows for continuous presence in the serum as well as in the brain.

[0072] When administration of ghrelin is via a transdermal patch, a single or multiple number of patches can be used. In a preferred embodiment, the multiple number of patches are used where each patch is identified for use in a given day of treatment. Each patch can contain the same dosing of ghrelin or a variant thereof or the dosing can be tapered as provide previously.

[0073] When a single patch is used, the patch can be formulated to provide the same dose per day of ghrelin or a variant thereof. Alternatively, the patch can be formulated so as to provide for a tapering of the dosing of ghrelin or variant thereof over the treatment period.

Example

Example 1: Treatment of sustained brain dysfunction due to SARS-CoV-2 using ghrelin

[0074] This example illustrates how a patient suffering from brain dysfunction after the acute phase of SARS-CoV-2 infection is resolved can be treated.

[0075] The drug product is supplied in a 5 mL clear, borosilicate glass vial with a butyl-rubber closure (fluoro-resin film laminated), as a sterile lyophilized white powder or cake equivalent to 14 mg of ghrelin as the active ingredient and sucrose (inactive ingredient).

[0076] Ghrelin (drug product) and diluent are stored refrigerated between 2°C to 8°C (35.6°F to 46.4°F). Reconstituted ghrelin for SC administration 14 mg (in 5 mL multi use vials) is stable for up to 14 days at 10°C or for up to 3 days when stored at 25°C/1000 Lux. Upon reconstitution, the drug composition (drug product plus diluent) is stored refrigerated at 2°C to 8°C (35.6°F to 46.4°F).

[0077] A patient suffering from brain dysfunction due to SARS-CoV-2 is treated about 2 weeks post the acute phase of the infection with the drug composition. Specifically, the treatment protocol is set per Example C of Table 1 above. At the completion of the treatment protocol, the patient is reexamined and evaluated for recovery from brain dysfunction. In one embodiment, the patient is evaluated during the initial visit for one or more of the following components: level of fatigue, ability to work or attend school, ability to focus (concentrate), level of social interaction, and the like. Each component may be measured on a scale, e.g., 0 to 5 (worst to best), and the patient may self-evaluate each component. At the completion of the therapy, the patient self-evaluates against the same criteria. This protocol is contemplated to provide significant improvement from the brain dysfunction in the patient. Using the example above, where there is a maximum of 20 points, a patient is deemed to have a positive result if his/her score increases by at least 10%. In embodiments, a positive result is an increase of at least 20%. In embodiments, a positive result is an increase of at least 30%. In embodiments, a positive result is an increase of at least 40%. In embodiments, a positive result is an increase of at least 50% or higher.

Claims

WHAT IS CLAIMED IS:

1. A method for mitigating one or more symptoms of brain dysfunction due to viral infection, the method comprising administering to the patient an effective amount of ghrelin or a variant thereof, thereby mitigating the one or more symptoms.

2. A method for treating or mitigating fatigue in a subject due to a viral infection, the method comprising administering to the subject an effective amount of ghrelin or a variant thereof, thereby treating or mitigating the fatigue.

3. A method for treating or mitigating brain fog in a subject due to infection with a virus, the method comprising administering to the subject an effective amount of ghrelin or a variant thereof, thereby treating or mitigating the brain fog.

4. The method of any one of claims 1 to 3, wherein the viral infection was due to a coronavirus.

5. The method of claim 4, wherein the viral infection was due to SARS-Co-V2.

6. The method of any one of claims 1 to 5, wherein ghrelin is administered.

7. The method of any one of claims 1 to 5, wherein a ghrelin variant is administered.

8. The method of claim 7, wherein the ghrelin variant is one or more of RM-131 (or BIM-28131), Dln-101, Growth hormone (GH) releasing hexapeptide (GHRP)-6, EP 1572, Ape-Ser(Octyl)-Phe-Leu-aminoethylamide, isolated ghrelin splice variant-like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, LY444711, MK-0677, L-692,429, NNC 26-0703, EP 1572, Capromorelin (CP-424, 391-18, RQ-00000005), L- 252,564, NN703, G-7203, S-37435, SM-130868, EX-1314, ulimorelin, macimorelin (acetate), anamorelin, ipamorelin, PF-5190457, AMX-213, tabimorelin, capromorelin, GHRP-6, or a combination thereof.

9. The method of any one of claims 1 to 8, wherein administration of ghrelin or the variant thereof is continued until the symptoms, fatigue, and/or brain fog is treated or attenuated.

10. The method of any one of claims 1 to 9, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

11. The method of claim 10, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

12. The method of claim 11, wherein the ghrelin or variant is administered by subcutaneous injection.

13. The method of claim 10, wherein the pharmaceutical composition is a transdermal patch.

14. The method of any one of claims 1 to 13, wherein the administration of ghrelin or variant thereof is maintained for a period of at least 7 days.

15. The method of any one of claims 1 to 14, wherein the administration of ghrelin or variant thereof is maintained for a period of at least 15 days.

16. The method of any one of claims 1 to 15, wherein the administration of ghrelin or variant thereof is maintained for a period of at least 30 days.

17. The method of any one of claims 1 to 16, wherein a single dose of ghrelin or a variant thereof is administered per day.

18. The method of any one of the above claims, wherein ghrelin administration is continued until the subject is able to resume normal activities.

19. The method of any one of the above claims, wherein ghrelin administration is continued until one or more symptoms of braain dysfunction, fatigue, or brain fog is treated or attenuated.

20. A method for mitigating one or more symptoms of a sustained brain dysfunction due to SARS-CoV-2 comprising: a. selecting a subject having sustained brain dysfunction due to a viral infection for at least 7 days after recovery from acute infection by the virus; and b. administering ghrelin or a variant thereof to the subject for a period of time, wherein ghrelin or the variant thereof is administered at a dose of about 20 pg/kg per day to about 120 pg/kg per day.

21. The method of claim 20, wherein the viral infection is due to coronavirus.

22. The method of claim 21, wherein the viral infection is due to SARS-CoV-2.

23. The method of any one of claims 20 to 22, wherein ghrelin is administered.

24. The method of any one of claims 20 to 22, wherein a ghrelin variant is administered.

25. The method of claim 24, wherein the ghrelin variant is one or more of RM- 131 (or BIM-28131), Dln-101, Growth hormone (GH) releasing hexapeptide (GHRP)-6, EP 1572, Ape-Ser(Octyl)-Phe-Leu-aminoethylamide, isolated ghrelin splice variant-like compound, ghrelin splice variant, growth hormone secretagogue receptor GHS-R la ligand, LY444711, MK-0677, L-692,429, NNC 26-0703, EP 1572, Capromorelin (CP-424, 391-18, RQ-00000005), L- 252,564, NN703, G-7203, S-37435, SM-130868, EX-1314, ulimorelin, macimorelin (acetate), anamorelin, ipamorelin, PF-5190457, AMX-213, tabimorelin, capromorelin, GHRP-6, or a combination thereof.

26. The method of any one of claims 20 to 25, wherein the ghrelin or variant thereof is administered twice per day.

27. The method of any one of claims 20 to 26, wherein the ghrelin or variant thereof is administered at a dose of about 80 pg/kg per day.

28. The method of claim 27, wherein the ghrelin or variant thereof is administered as about 40 pg/kg twice per day.

29. The method of any one of claims 20 to 28, wherein the period of time is up to about 14 days.

30. The method of claim 29, wherein the period of time is about 14 days.

31. The method of any one of claims 20 to 30, wherein the patient is evaluated for the one or more symptoms of sustained brain dysfunction due to viral infection on scheduled basis.

32. The method of any one of claims 20 to 31, wherein the patient is evaluated for the one or more symptoms of sustained brain dysfunction due to viral infection prior to administration of ghrelin or variant thereof.

33. The method of any one of claims 20 to 32, wherein the patient is evaluated for the one or more symptoms of sustained brain dysfunction due to viral infection during the period of time of administration of ghrelin or variant thereof.

34. The method of any one of claims 20 to 33, wherein the patient is evaluated for the one or more symptoms of sustained brain dysfunction due to viral infection at about 7 days, 10 days, 14 days, 20 days, and/or 30 days after initiation of administration of ghrelin or variant thereof.