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WO2020000641A1 - Acide nucléique pour le codage de la protéine nadh déshydrogénase à sous-unité sigma humaine et son application - Google Patents

Acide nucléique pour le codage de la protéine nadh déshydrogénase à sous-unité sigma humaine et son application Download PDF

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Publication number
WO2020000641A1
WO2020000641A1 PCT/CN2018/103937 CN2018103937W WO2020000641A1 WO 2020000641 A1 WO2020000641 A1 WO 2020000641A1 CN 2018103937 W CN2018103937 W CN 2018103937W WO 2020000641 A1 WO2020000641 A1 WO 2020000641A1
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WIPO (PCT)
Prior art keywords
sequence
protein
nucleic acid
seq
cells
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Application number
PCT/CN2018/103937
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English (en)
Chinese (zh)
Inventor
李斌
Original Assignee
武汉纽福斯生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201810702492.7A external-priority patent/CN110656117A/zh
Priority claimed from CN201810703168.7A external-priority patent/CN110724695A/zh
Application filed by 武汉纽福斯生物科技有限公司 filed Critical 武汉纽福斯生物科技有限公司
Priority to CA3103740A priority Critical patent/CA3103740A1/fr
Priority to SG11202012044QA priority patent/SG11202012044QA/en
Priority to BR112020026361-3A priority patent/BR112020026361A2/pt
Priority to KR1020217001385A priority patent/KR102627561B1/ko
Priority to MX2020013772A priority patent/MX2020013772A/es
Priority to EP19826653.8A priority patent/EP3814492A4/fr
Priority to KR1020247001775A priority patent/KR20240014102A/ko
Priority to PCT/CN2019/094136 priority patent/WO2020001657A1/fr
Priority to JP2021521870A priority patent/JP2021529001A/ja
Priority to CN201980003485.0A priority patent/CN110876269B/zh
Priority to AU2019296451A priority patent/AU2019296451B2/en
Priority to CN202110786630.6A priority patent/CN113476484A/zh
Priority to CN202110786772.2A priority patent/CN113528510A/zh
Priority to CA3109432A priority patent/CA3109432A1/fr
Priority to AU2019323434A priority patent/AU2019323434A1/en
Priority to SG11202101032VA priority patent/SG11202101032VA/en
Priority to CN201980054770.5A priority patent/CN112584874A/zh
Priority to PCT/CN2019/101538 priority patent/WO2020038352A1/fr
Priority to JP2021509893A priority patent/JP7403852B2/ja
Priority to EP19853225.1A priority patent/EP3840785A4/fr
Priority to KR1020217007727A priority patent/KR20210068014A/ko
Publication of WO2020000641A1 publication Critical patent/WO2020000641A1/fr
Priority to US16/836,644 priority patent/US11034954B2/en
Priority to US17/181,849 priority patent/US11352645B2/en
Priority to US17/317,295 priority patent/US20220340895A1/en
Priority to US17/320,388 priority patent/US11332741B1/en
Priority to AU2021204690A priority patent/AU2021204690A1/en
Priority to US17/726,833 priority patent/US20220259619A1/en
Priority to JP2023029170A priority patent/JP2023078173A/ja
Priority to JP2023205807A priority patent/JP2024028861A/ja
Priority to AU2023285773A priority patent/AU2023285773A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins

Definitions

  • the invention relates to the technical field of genetic engineering, in particular to a nucleic acid encoding a human NADH dehydrogenase subunit protein and application thereof.
  • Leber's hereditary optic neuroneopathy is a mitochondrial hereditary disease that mainly affects the macular papillary bundle fibers and causes degeneration of the optic nerve.
  • the disease is prevalent in young and middle-aged men, and the clinical manifestations are simultaneous or successive acute or subacute painless vision loss in both eyes, and may be accompanied by central visual field defect and color vision disorder.
  • the coding sequence of OPA1 has the sequence shown in SEQ ID NO.:7.
  • the fusion nucleic acid has the structure of Formula I from the 5 'end to the 3' end:
  • Z2 is a nucleotide sequence according to the first aspect of the invention.
  • the Z1 is a COX10 coding sequence or an OPA1 coding sequence.
  • Bits 610-2034 are 3'-UTR sequences.
  • the vector is an AAV vector containing or inserted with the nucleotide sequence according to the first aspect of the present invention or the fusion nucleic acid according to the second aspect of the present invention; preferably the AAV vector plasmid pSNaV .
  • a host cell containing the vector according to the third aspect of the present invention, or the genome of which the exogenous nucleotide sequence of the first aspect of the present invention is integrated Or the fusion nucleic acid according to the second aspect of the present invention.
  • Figure 5 shows the fundus photographs of rabbit eyes under glass microscope, where A is the rAAV2 / 2-optimized ND6 group (experimental group A1), B is the rAAV2 / 2-ND6 group (experimental group B1), and C is rAAV2- EGFP group (control group C1).
  • NADH dehydrogenase subunit 1 protein used interchangeably.
  • human NADH dehydrogenase subunit 1 protein used interchangeably.
  • ND1 (protein) used interchangeably.
  • AAV vectors can be prepared using standard methods in the art. Any serotype of adeno-associated virus is suitable. Methods for purifying vectors can be found in, for example, U.S. Patent Nos. 6566118, 6989264, and 6995006, the disclosures of which are incorporated herein by reference in their entirety. The preparation of hybrid vectors is described, for example, in PCT Application No. PCT / US2005 / 027091, the disclosure of which is incorporated herein by reference in its entirety. The use of AAV-derived vectors for in vitro and in vivo transport of genes has been described (see, for example, International Patent Application Publication Nos. WO91 / 18088 and WO93 / 09239; U.S. Patent Nos.
  • the present invention provides a coding sequence of NADH dehydrogenase subunit 1 protein and application thereof. It has been found through research that the optimized ND1 coding sequence of the present invention makes the expression of ND1 protein more efficient, and more ND1 protein plays a physiological role in the patient's optic ganglion cells.
  • the nucleic acid encoding the human NADH dehydrogenase subunit 1 protein according to the present invention has a nucleotide sequence as shown in SEQ ID NO :: 3 or 4, and has a full length of 951 bp.
  • sequence fragments that affect gene expression and protein localization.
  • sequence fragments include, but are not limited to, codon usage preferences, eliminate secondary structures (such as hairpin structures) that are not conducive to expression, and change GC content. CpG dinucleotide content, mRNA secondary structure, concealed splice sites, early polyadenylation sites, internal ribosome entry sites and binding sites, negative CpG islands, RNA unstable regions, repeating sequences ( Direct repeats, inverted repeats, etc.) and restriction sites that may affect cloning.
  • SEQ ID NO.:4 a specially optimized DNA coding sequence as shown in SEQ ID NO.:4 is finally obtained. This sequence is specially optimized, and the expression of ND1 is significantly increased.
  • fusion nucleic acid refers to a nucleic acid formed by joining two or more nucleotide sequences from different sources, or two or more nucleosides from the same source but whose natural positions are not linked to each other. Nucleic acid formed by linking acid sequences.
  • the protein encoded by the fusion nucleic acid of the present invention is called a fusion protein, and in the present invention, it is an ND6 fusion protein or an ND1 fusion protein.
  • the coding sequence of the mitochondrial targeting peptide is the COX10 gene as shown in SEQ ID NO: 5 or 6.
  • the COX10 sequence shown in SEQ ID NO.:5 is the original COX10 coding sequence
  • the COX10 sequence shown in SEQ ID NO.:6 is the COX10 coding sequence obtained after targeted optimization.
  • the sequence of the fusion nucleic acid is shown as SEQ ID NO .: 9 or 10.
  • the COX10 gene is a mitochondrial targeting sequence that guides the ND6 protein into the mitochondria and exerts its physiological functions.
  • the 3'UTR is a non-coding sequence designed behind the ND6 protein. Its role is to stabilize the expression of the COX10 gene mitochondrial targeting sequence and the ND6 sequence. .
  • the sequence of the fusion nucleic acid is shown as SEQ ID NO .: 11 or 12.
  • the COX10 gene is a mitochondrial targeting sequence, which guides the ND1 protein into the mitochondria and exerts its physiological functions.
  • the 3'UTR (Untranslated Region) is a non-coding region and is designed behind the ND1 protein to stabilize the expression of mitochondrial targeting sequences and ND1 .
  • a nucleic acid sequence encoding a ND6 or ND1 protein is provided as a vector, preferably an expression vector is provided.
  • an expression vector is provided.
  • it is provided as a gene therapy vector that is preferably suitable for transduction and expression in retinal target cells.
  • the vector can be viral or non-viral (e.g., a plasmid).
  • Viral vectors include those derived from: adenovirus, adeno-associated virus (AAV) including mutant forms, retroviruses, lentivirus, herpes virus, vaccinia virus, MMLV, GaLV, simian immunodeficiency virus (SIV) , HIV, pox virus, and SV40.
  • the viral vector is replication-defective, although it is envisaged that it may be replication-deficient, capable of replication or conditionally replicating.
  • Viral vectors can often maintain an extrachromosomal state without integrating into the genome of target retinal cells.
  • a preferred viral vector for introducing a nucleic acid sequence encoding an ND6 or ND1 protein to a retinal target cell is an AAV vector, such as a self-complementary adeno-associated virus (scAAV).
  • scAAV self-complementary adeno-associated virus
  • Selective targeting can be achieved using specific AAV serotypes (AAV serotype 2 to AAV serotype 12) or modified versions of any of these serotypes (including AAV 4YF and AAV 7m8 vectors).
  • Viral vectors can be modified to delete any non-essential sequences.
  • the virus in AAV, can be modified to delete all or part of the IX gene, Ela, and / or Elb gene.
  • helper virus such as adenovirus
  • replication is very inefficient.
  • the replication gene and the capsid gene are provided in trans (in the pRep / Cap plasmid), and only the 2ITR of the AAV genome is retained and packaged into the virion, while the adenovirus gene is required Provided by adenovirus or another plasmid. Similar modifications can also be made to lentiviral vectors.
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence.
  • the promoter sequence is a strongly constitutive promoter sequence capable of driving high-level expression of any polynucleotide sequence operably linked thereto.
  • Another example of a suitable promoter is elongation growth factor-1 ⁇ (EF-1 ⁇ ).
  • constitutive promoter sequences can also be used, including but not limited to the simian virus 40 (SV40) early promoter, mouse breast cancer virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, avian leukemia virus promoter, Epstein-Barr virus immediate early promoter, Russ sarcoma virus promoter, and human gene promoters such as, but not limited to, the actin promoter , Myosin promoter, heme promoter, and creatine kinase promoter.
  • the present invention should not be limited to the application of a constitutive promoter. Inducible promoters are also considered as part of the invention.
  • the invention also provides a host cell for expressing ND6 or ND1 protein.
  • the host cell is a mammalian cell (preferably a human, more preferably a human optic nerve cell or a photoreceptor cell), which increases the expression of the ND6 or ND1 protein.
  • the optimized nucleic acid encoding human ND6 or ND1 protein has a higher expression level, which translates more ND6 or ND1 fusion proteins, while the COX10 sequence can accurately locate the ND6 or ND1 fusion protein on the mitochondrial inner membrane, so there are more Many ND6 or ND1 proteins are transfected into mitochondria.
  • the agent for fusion nucleic acid of the present invention is injected into the vitreous cavity of a rabbit eye, and the agent maintains viability in the vitreous cavity and is transfected into optic nerve cells.
  • Optimized ND6 or ND1 nucleic acid encodes more ND6 or ND1 protein than the prior art, which has higher transfection efficiency and can better treat Leber hereditary optic neuropathy.
  • the optimized COX10 sequence or OPA1 sequence of the present invention can accurately locate the ND6 or ND1 fusion protein on the mitochondrial inner membrane, so more ND6 or ND1 proteins are transfected into the mitochondria.
  • rabbits were divided into 3 groups: experimental group 1-1, experimental group 1-2 and control group.
  • the cells are lysed after the lysate has been in contact with the cells for 1-2 seconds.
  • agarose gel electrophoresis (as shown in Figure 9) found that the ND1 target band was around 950bp, indicating that the selected plasmid was the target plasmid.
  • Real-time PCR was performed on a Real-time PCR Detection System instrument.
  • a Real-time PCR Detection System instrument In a 0.2 mL PCR reaction tube, 12.5 ⁇ L of SYBR Green mix, 8 ⁇ L of ddH 2 O, 1 ⁇ L of each primer, 2.5 ⁇ L of cDNA sample, and 25 ⁇ L of the total system were added.
  • Each sample was used to amplify both the target gene and the internal reference gene rabbit ⁇ -actin.
  • Each gene was amplified in triplicate.
  • the reagents common to each PCR reaction tube can be added together and then aliquoted. After loading, perform Real-time PCR.
  • a melting curve analysis of 94 ° C to 55 ° C was performed.
  • the relative quantitative method was used to study the difference in gene expression. This method does not need to make a standard curve.
  • the housekeeping gene rabbit ⁇ -actin is used as the internal reference gene.
  • the analysis software that comes with the instrument can automatically generate expression values.
  • the coding sequence of ND1 (SEQ ID No .: 3) of Example 7 is specially optimized, and the optimized ND1 coding sequence (SEQ ID No .: 4) is obtained, and the 5 'of the gene is optimized at ND1.
  • the optimized mitochondrial coding sequence of COX10 (as shown in SEQ ID NO.:6) is ligated to the end, and the UTR sequence of 3 'end of ND1 optimized gene is shown (shown as SEQ ID NO.:8).
  • the sequence of the gene (or fusion nucleic acid) is shown in SEQ ID NO.:12. All gene sequences were synthesized by Chengdu Qingke Zixi Biotechnology Co., Ltd.
  • the homology between the specially optimized coding sequence shown in SEQ ID No.:12 and SEQ ID No.:11 at position 1-1035 (that is, the COX10-ND1 coding sequence) is only 77.68% (804/1035). ).
  • mice taken 24 rabbits divided into 3 groups, 3mm away from the limbal puncture pars into the vitreous cavity, for intravitreal injection, were divided into experimental groups A3 (injected 10 10 vg / 50ul rAAV2 / 2- optimization ND1 ), Experimental group B3 (injected 10 10 vg / 50ul rAAV2 / 2-ND1) and control group C3 (injected 10 10 vg / 50ul rAAV2-EGFP).
  • experimental groups A3 injected 10 10 vg / 50ul rAAV2 / 2- optimization ND1
  • Experimental group B3 injected 10 10 vg / 50ul rAAV2 / 2-ND1
  • control group C3 injected 10 10 vg / 50ul rAAV2-EGFP
  • ND1-R TTTTAGGGGCTCTTTGGTGAA (SEQ ID NO.:30)

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Abstract

L'invention concerne un acide nucléique pour le codage d'une protéine NADH déshydrogénase à sous-unité sigma humaine, un acide nucléique de fusion comprenant une séquence de codage de peptides de ciblage mitochondrial, un vecteur et une cellule hôte comprenant l'acide nucléique ou l'acide nucléique de fusion, un procédé de préparation d'une protéine recombinée ou de la protéine de fusion, une préparation pharmaceutique et l'utilisation du vecteur ou de la préparation pharmaceutique dans le traitement de la neuropathie optique héréditaire. L'acide nucléique pour le codage de la protéine NADH déshydrogénase à sous-unité sigma humaine est un acide nucléique servant au codage d'une protéine NADH déshydrogénase à sous-unité sigma 6 humaine comportant une séquence nucléotidique telle que représentée dans SEQ ID No : 1 ou 2, ou présentant une homologie supérieure ou égale à 95 % avec SEQ ID No : 1 ou 2, ou un acide nucléique codant pour une protéine NADH déshydrogénase à sous-unité sigma 1 humaine comportant une séquence nucléotidique telle que représentée dans SEQ ID No : 3 ou 4, ou présentant une homologie supérieure ou égale à 95 % avec SEQ ID No : 3 ou 4.
PCT/CN2018/103937 2018-06-29 2018-09-04 Acide nucléique pour le codage de la protéine nadh déshydrogénase à sous-unité sigma humaine et son application WO2020000641A1 (fr)

Priority Applications (30)

Application Number Priority Date Filing Date Title
CN202110786772.2A CN113528510A (zh) 2018-06-29 2019-07-01 治疗遗传性视神经病变的组合物和方法
CN202110786630.6A CN113476484A (zh) 2018-06-29 2019-07-01 治疗遗传性视神经病变的组合物和方法
EP19826653.8A EP3814492A4 (fr) 2018-06-29 2019-07-01 Compositions et méthodes de traitement de la neuropathie optique héréditaire de leber
SG11202012044QA SG11202012044QA (en) 2018-06-29 2019-07-01 Compositions and methods for treating leber's hereditary optic neuropathy
BR112020026361-3A BR112020026361A2 (pt) 2018-06-29 2019-07-01 Composições e métodos para tratar neuropatia óptica hereditária de leber
KR1020217001385A KR102627561B1 (ko) 2018-06-29 2019-07-01 레버 유전성 시신경병증의 치료를 위한 조성물 및 방법
MX2020013772A MX2020013772A (es) 2018-06-29 2019-07-01 Composiciones y métodos para el tratamiento de la neuropatía óptica hereditaria de leber.
CA3103740A CA3103740A1 (fr) 2018-06-29 2019-07-01 Compositions et methodes de traitement de la neuropathie optique hereditaire de leber
KR1020247001775A KR20240014102A (ko) 2018-06-29 2019-07-01 레버 유전성 시신경병증의 치료를 위한 조성물 및 방법
PCT/CN2019/094136 WO2020001657A1 (fr) 2018-06-29 2019-07-01 Compositions et méthodes de traitement de la neuropathie optique héréditaire de leber
JP2021521870A JP2021529001A (ja) 2018-06-29 2019-07-01 レーベル遺伝性視神経症を治療するための組成物及び方法
CN201980003485.0A CN110876269B (zh) 2018-06-29 2019-07-01 治疗遗传性视神经病变的组合物和方法
AU2019296451A AU2019296451B2 (en) 2018-06-29 2019-07-01 Compositions and methods for treating leber's hereditary optic neuropathy
EP19853225.1A EP3840785A4 (fr) 2018-08-20 2019-08-20 Compositions et méthodes de traitement de la neuropathie optique héréditaire de leber
KR1020217007727A KR20210068014A (ko) 2018-08-20 2019-08-20 레버 유전성 시신경병증의 치료를 위한 조성물 및 방법
CA3109432A CA3109432A1 (fr) 2018-08-20 2019-08-20 Compositions et methodes de traitement de la neuropathie optique hereditaire de leber
JP2021509893A JP7403852B2 (ja) 2018-08-20 2019-08-20 レーベル遺伝性視神経症を治療するための組成物及び方法
AU2019323434A AU2019323434A1 (en) 2018-08-20 2019-08-20 Compositions and methods for treating leber's hereditary optic neuropathy
SG11202101032VA SG11202101032VA (en) 2018-08-20 2019-08-20 Compositions and methods for treating leber's hereditary optic neuropathy
CN201980054770.5A CN112584874A (zh) 2018-08-20 2019-08-20 用于治疗莱伯氏遗传性视神经病变的组合物和方法
PCT/CN2019/101538 WO2020038352A1 (fr) 2018-08-20 2019-08-20 Compositions et méthodes de traitement de la neuropathie optique héréditaire de leber
US16/836,644 US11034954B2 (en) 2018-06-29 2020-03-31 Compositions and methods for treating leber's hereditary optic neuropathy
US17/181,849 US11352645B2 (en) 2018-08-20 2021-02-22 Compositions and methods for treating Leber's hereditary optic neuropathy
US17/317,295 US20220340895A1 (en) 2018-06-29 2021-05-11 Compositions and methods for treating leber's hereditary optic neuropathy
US17/320,388 US11332741B1 (en) 2018-06-29 2021-05-14 Compositions and methods for treating leber's hereditary optic neuropathy
AU2021204690A AU2021204690A1 (en) 2018-06-29 2021-07-05 Compositions and methods for treating Leber's hereditary optic neuropathy
US17/726,833 US20220259619A1 (en) 2018-08-20 2022-04-22 Compositions and methods for treating leber's hereditary optic neuropathy
JP2023029170A JP2023078173A (ja) 2018-06-29 2023-02-28 レーベル遺伝性視神経症を治療するための組成物及び方法
JP2023205807A JP2024028861A (ja) 2018-08-20 2023-12-06 レーベル遺伝性視神経症を治療するための組成物及び方法
AU2023285773A AU2023285773A1 (en) 2018-06-29 2023-12-20 Compositions and methods for treating Leber's hereditary optic neuropathy

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810702492.7 2018-06-29
CN201810702492.7A CN110656117A (zh) 2018-06-29 2018-06-29 一种编码人nadh脱氢酶亚单位6蛋白的核酸及其应用
CN201810703168.7 2018-06-29
CN201810703168.7A CN110724695A (zh) 2018-06-29 2018-06-29 一种编码人nadh脱氢酶亚单位1蛋白的核酸及其应用

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US11352645B2 (en) 2018-08-20 2022-06-07 Wuhan Neurophth Biotechnology Limited Company Compositions and methods for treating Leber's hereditary optic neuropathy
US11357869B2 (en) 2019-12-09 2022-06-14 Wuhan Neurophth Biotechnology Limited Company Compositions and methods for treating leber's hereditary optic neuropathy with NADH dehydrogenase proteins

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US11352645B2 (en) 2018-08-20 2022-06-07 Wuhan Neurophth Biotechnology Limited Company Compositions and methods for treating Leber's hereditary optic neuropathy
US11357869B2 (en) 2019-12-09 2022-06-14 Wuhan Neurophth Biotechnology Limited Company Compositions and methods for treating leber's hereditary optic neuropathy with NADH dehydrogenase proteins

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