WO2007001010A1 - Produit pharmaceutique pour le traitement de la maladie de parkinson - Google Patents

Produit pharmaceutique pour le traitement de la maladie de parkinson Download PDF

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Publication number
WO2007001010A1
WO2007001010A1 PCT/JP2006/312854 JP2006312854W WO2007001010A1 WO 2007001010 A1 WO2007001010 A1 WO 2007001010A1 JP 2006312854 W JP2006312854 W JP 2006312854W WO 2007001010 A1 WO2007001010 A1 WO 2007001010A1
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Prior art keywords
mediatophore
gene encoding
vector
disease
parkinson
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PCT/JP2006/312854
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English (en)
Japanese (ja)
Inventor
Haruhiro Higashida
Shigeru Yokoyama
Taku Kin
Shoji Ohkuma
Nobuaki Shimizu
Hirokazu Hirai
Shinichi Muramatsu
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National University Corporation Kanazawa University
Jichi Medical University
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Priority to JP2007523965A priority Critical patent/JPWO2007001010A1/ja
Publication of WO2007001010A1 publication Critical patent/WO2007001010A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C12N9/0073—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14) with NADH or NADPH as one donor, and incorporation of one atom of oxygen 1.14.13
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/88—Lyases (4.)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron
    • C12N2840/203—Vectors comprising a special translation-regulating system translation of more than one cistron having an IRES

Definitions

  • the present invention relates to a medicament for the treatment of Parkinson's disease.
  • Parkinson's disease is a disease in which neurons in the substantia nigra below the central part of the brain cause degeneration and die. Since the midbrain substantia nigra produces dopamine, a neurotransmitter in the brain, in Parkinson's disease, there is a shortage of donomin in the brain, and the suppression of nerves in the suppressor system by donomin decreases, and the acetylcholine-promoting system Nerve nerves become dominant, and the action of the basal ganglia appears strongly, causing extrapyramidal symptoms such as limb tremors, muscle rigidity, peristalsis and postural disturbance.
  • Drug therapy for Parkinson's disease includes the ability to administer anticholinergic agents to suppress facilitating nerves in the early stages. L-Dopa, a minagonist and dopamine precursor, is administered. In some cases, amantadine or the like is administered as a drug having a dopamine release promoting action.
  • a gene that expresses tyrosine hydroxylase (TH) that converts L-tyrosin to L-dopa or aromatic amino acid decarboxylase (AADC) that converts L-dopa to dopamine A method has been proposed in which adeno-associated virus is introduced into the brain using an adeno-associated virus as a vector.
  • GDNF glial cell line-derived neurotrophic factor
  • acetylcholine which is one of the neurotransmitters, in addition to the mechanism by which acetylcholine stored in vesicles is released, it is called 16,000 dal called mediatophore. Ton protein lipid pentamers have been reported to release (FEBS LETT ERS, 261, pp. 303-306, 1990; Life Science, 72, pp. 2029-2038, 2003). Previously, this mediatophore has been reported to be one of a group of APTases! / (J. Biochem, 112, pp. 212-219, 1992), but it is involved in the release of dopamine. There are no reports of this.
  • Non-Patent Document 1 FEBS LETTERS, 261, pp.303-306, 1990
  • Non-Patent Document 2 Life Science, 72, pp.2029-2038, 2003
  • Non-Patent Document 3 J. Biochem, 112, pp.212-219, 1992
  • An object of the present invention is to provide an effective therapeutic means for Parkinson's disease. More specifically, it is an object of the present invention to provide a drug for gene therapy that can effectively treat Parkinson's disease by promoting the release of donomin in the brain.
  • the present inventors have introduced a vector incorporating a gene encoding mediatophore into the brain to express the mediatophore in the brain.
  • the inventors have found that the amount of released dopamine is remarkably increased and that Parkinson's disease can be effectively treated by using this recombinant vector as a drug for gene therapy.
  • the present invention has been completed based on the above findings.
  • a medicament for treating Parkinson's disease which comprises a vector incorporating a gene encoding a mediatophore and can express the mediatophore in the brain.
  • the present invention also provides a medicament for treating Parkinson's disease, which comprises a vector incorporating a gene encoding mediatophore and can promote the release of dominin in the brain.
  • the aforementioned pharmaceutical comprising a vector incorporating a gene encoding a mediatophore and a gene encoding an aromatic amino acid decarboxylase and a gene encoding Z or tyrosine hydroxylase.
  • the vector there is provided a medicament as described above, wherein one is an adeno-associated virus (AAV) vector.
  • a medicament comprising a combination of the above medicament with dopamine and / or L-dopa is also provided by the present invention.
  • a method for treating Parkinson's disease comprising administering to a patient a vector incorporating a gene encoding mediatophore and expressing the mediatophore in the brain.
  • a method for treating Parkinson's disease comprising administering to a patient a vector incorporating a gene encoding mediatophore to promote dopamine release in the brain.
  • a method for treating Parkinson's disease is provided to a patient with a vector that incorporates a gene encoding a mediatophore, a gene encoding an aromatic amino acid decarboxylase, and a gene encoding a Z or tyrosine hydroxylase enzyme.
  • a method comprising: administering and expressing mediatophore and aromatic amino acid decarboxylase and Z or tyrosine hydroxylase in the brain; and administering donomin and Z or L-dopa to the patient. Is done.
  • the present invention also provides the use of a gene encoding a mediatophore for the manufacture of the above medicament.
  • the medicament of the present invention has high effectiveness as a medicament for gene therapy of Parkinson's disease.
  • FIG. 1 is a diagram showing the results of measuring the amount of dopamine released into the striatum by administration of the medicament of the present invention.
  • the medicament of the present invention is a medicament for treating Parkinson's disease, comprising a vector incorporating a gene encoding mediatophore, and capable of expressing the mediatophore in the brain. ! /
  • the sequence of a gene encoding a mammalian mediatophore is known, and for example, the gene sequence encoding a rat-derived mediatophore has already been reported as Accession No. D10874 in the GenBank database. Therefore, the person skilled in the art It is possible to easily obtain a gene encoding a mammalian mediatophore.
  • cDNA encoding mediatophore can be easily obtained from the cerebrum of mammals according to the method specifically described in the examples of the present specification.
  • the medicine of the present invention can be applied as a medicine for mammals including humans In order to treat human Parkinson's disease, it is desirable to use a gene encoding a human-derived mediatophore.
  • the gene used for the medicament of the present invention may be any gene that can express a mediatophore that functions in the living body of a mammal.
  • Mediatophores include natural mediatophores derived from mammals, and modified mediatops containing several amino acid substitutions, insertions, and Z or deletions in the amino acid sequence of natural mediatophores. There may be.
  • a gene used in the medicament of the present invention a gene having any nucleic acid sequence encoding the above-mentioned natural type or modified mediatophore can be used.
  • the medicament of the present invention can be prepared using a vector so that the gene encoding mediatophore can be expressed in the brain.
  • a vector capable of directly introducing a gene into the brain in vivo can be used, and either a viral vector or a non-viral vector may be used. Of these, it is preferable to use a viral vector.
  • a viral vector an adeno-associated virus (AAV) vector, a lentivirus vector, a herpes virus vector and the like are available. Of these, an AAV vector is preferable.
  • AAV adeno-associated virus
  • a lentivirus vector a lentivirus vector
  • herpes virus vector a herpes virus vector and the like
  • an AAV vector is preferable.
  • a gene therapy drug for Parkinson's disease for example, a drug using an AAV vector has been developed (Avigen).
  • AAV betater is particularly preferably used for the medicine of the present invention because it can be expected to have relatively long gene expression with high safety.
  • Adeno-associated viruses include type 1 AAV virus (AAV 1), type 2 AAV virus (AAV2), type 3 AAV virus (AAV3), type 4 AAV virus (AAV4), and type 5 AAV virus (AAV5).
  • AAV3 is registered with Gene Bank (NC_001729) and described in the literature (Virology, 221, pp.208-217, 1996).
  • NC_001729 Gene Bank
  • Human Gene Therapy 13, pp. 345-354, 2002 can be referred to.
  • the method for producing the medicament of the present invention is not particularly limited.
  • a recombinant vector can be prepared according to the following method.
  • the mediatophore gene is inserted between the cytoguchi megalovirus (CMV) promoter region and the SV40 polyA region and incorporated into the plasmid along with inverted terminal repeat (ITR) sequences present at both ends of the type 3 AAV (AAV3) virus genome.
  • CMV cytoguchi megalovirus
  • ITR inverted terminal repeat
  • a vector plasmid is prepared by The above vector plasmids, knocking plasmids (plasmids for expressing AAV nonstructural protein Rep and cabsid protein VP), and helper plasmids (adenovirus-derived nucleotide sequences E2A, E4, and VA)
  • AAV vector containing the mediatophore gene can be prepared by transfecting three types of plasmids (including the region) into HE K293 cells derived from human kidney.
  • the drug of the present invention may incorporate a gene encoding tyrosine hydroxylase (TH) and Z or aromatic amino acid decarboxylase (AADC).
  • a vector incorporating a gene encoding mediatophore and a gene encoding tyrosine hydroxylase (TH) and Z or aromatic amino acid decarboxylase (AADC) are combined. It is also possible to use a medicine that can be combined with the inserted vector.
  • AAV vectors allow multiple types of vectors to infect a single cell, so AAV vectors containing mediatophore genes, AAB vectors containing tyrosine hydroxylase (TH), and Z or aromatic amino acids AAV vectors containing decarboxylase (AADC) can be simultaneously administered into the brain to simultaneously express these genes.
  • a vector incorporating a gene encoding a mediatophore and a gene encoding a neurotrophic factor such as DGNF
  • a mediatophore may be used as a medicament of the present invention. It is also possible to use a combination of a vector incorporating a gene coding for and a vector incorporating a neurotrophic factor.
  • Gene therapy for Parkinson's disease using an AAV vector includes, for example, neural progression Ayumi, 45, pp.92-103, 2001, or experimental medicine, 20, pp.1296-1300, 2002, etc., and these publications or references cited in these publications.
  • the mediatophore can be expressed in the cells by directly administering the medicament of the present invention to the striatal cells in the brain.
  • the expression of mediatophore in striatal cells promotes the release of dopamine, thereby improving the symptoms of Parkinson's disease.
  • the dosage of the medicament of the present invention is not particularly limited, but it is desirable to adjust the dosage so that the mediatophore is fully expressed in the striatum cells and the amount of released domino is increased.
  • Such a dose can be appropriately determined by conducting, for example, a model animal experiment specifically described in the examples of the present specification.
  • a pharmaceutical of the present invention comprising a gene encoding an aromatic amino acid decarboxylase (AADC) together with a gene encoding a mediatophore to a striatal cell
  • the mediatophore is sometimes used.
  • AADC aromatic amino acid decarboxylase
  • a donomin precursor is used.
  • Administration of certain L-dopa can enhance the release of donomin from striatal cells.
  • PCR polymerase chain reaction
  • the obtained PCR product was incorporated into a plasmid (pCR2.1-TOPO; Invitrogen) by the TA cloning method and named pCRMP.
  • pCRMP plasmid
  • the nucleotide sequence of the PCR product was determined and compared with the sequence already reported as Accession No. D10874 in the GenBank database, there was one mismatch between the protein coding region and the 3 'untranslated region. (D1 0874 422th A is C, 566-569 TTTT is TTTTT), it was confirmed that the deduced amino acid sequence was completely matched.
  • CMV cytomegalovirus
  • IRES green fluorescent protein
  • pAAV-MP The nucleotide sequences of cytomegalovirus (CMV) promoter, ribosome internal recognition site (IRES), and green fluorescent protein (EGFP) are excised from the commercially available plasmid (pIRES2-EGFP, Clontech) with restriction enzyme Notl and adeno-associated.
  • the plasmid containing the viral (AAV) DNA sequence was inserted between the hairpin DNA sequences called inverted terminal repeats (ITR) of pAAV. Thereafter, the cDNA fragment of the mediatophore excised from the above pCRMP with the restriction enzyme EcoRI was inserted between the CMV promoter and the IRES sequence (pAAV-MP).
  • HEK293 cells 1.5 ⁇ 10 6 HEK293 cells were seeded in a 225 cm 2 flask and cultured in 10% FCS-DMEM / F12 medium at 5% CO 2 and 37 ° C.
  • Transfusion was performed by the calcium phosphate method. After mixing 3 types of plasmids (pAAV-RC, p Helper, pAAV MP, 25 ⁇ g each) with 0.3 ⁇ CaCl, 2 X HBS (80 mM NaCl,
  • the culture solution in the flask was replaced with a medium supplemented with DNA-calcium phosphate, and the medium was changed after culturing for several hours.
  • Recombinant virus (rAAV-MP) was collected. Remove 0.5M EDTA and remove cells TB It was suspended in S (100 mM Tris HC1, pH 8.0, 150 mM NaCl). Freeze-Z thawing was repeated three times using dry ice ethanol and 37 ° C water nose. After centrifuging at 10,000 Xg for 10 minutes, the supernatant was collected to remove coarse cell debris.
  • RAAV-MP was purified by ultracentrifugation with a density gradient of cesium chloride CsCl. A density gradient was created by superimposing 4 M and 2.2 M CsCl in an ultracentrifugation tube. The cell disruption solution containing rAAV-MP was overlaid, and then ultracentrifuged (25,000 rpm, 3 hours). Refractive index was measured, and fractions containing rAAV-MP with RI: 1.365-1.380 were collected. This fraction was layered again on the CsCl solution and ultracentrifuged (38,000 rpm, 2 hours) to obtain a fraction containing rAAV-MP.
  • mice were anesthetized with Nembutal (200 1 intraperitoneal administration per 30 g body weight) and fixed using a small animal fixation device.
  • body temperature controller the body temperature of the mouse was maintained at 37 ° C., the hair on the head was shaved, and then the skin was incised with nasal force applied to the back of the head.
  • a hole 2 to 3 mm in diameter was drilled using a microdrill on the skull, 2.0 mm outside the Bregma (depending on the age of the mouse) and 2.0 mm outside the midline.
  • the dura mater and the arachnoid under the bone were punctured with a needle.
  • Virus was filled in a flexfill microsyringe (manufactured by WPI, 10 ⁇ 1 volume), and the flexfil microsyringe was set in an ultra micropump 2 (manufactured by WPI) attached to a micromanipulator. A microsyringe needle tip was inserted about 2 mm from this hole. The virus was injected at a rate of 100 nl / min for 10 minutes for a total of 11 using a digital controller Micro4 (manufactured by WPI) dedicated to Ultra Micropump 2. The incised skin is sutured with an ophthalmic microneedle with sutures, the fixing device force is removed, and the mouse is removed until anesthesia awakens. Observation was made in a cage (in a safety cabinet) placed on a single pad. The mouse cage was then returned to the infected animal rack.
  • the measurement of dopamine was carried out by brain microphone dialysis using unanesthetized mice (body weight 26-30 g, male).
  • the surgical procedure was basically the same as in the case of AAV inoculation into the cerebellar subarachnoid space.
  • the mouse was anesthetized with Nembutal (15.5 mg intraperitoneally administered per 30 g body weight), and after anesthesia, the hair of the head was shaved and fixed to a small animal stereotaxic apparatus.
  • the body temperature was maintained at 37 ° C with a body temperature controller.
  • a midline incision was made in the scalp, and a hole with a diameter of 2-3 mm was drilled using a micro drill into the skull 0.4 mm caudal to Bregma and 2.0 mm outside the midline under a stereomicroscope.
  • the dura mater and arachnoid membrane under the skull were carefully dissected at the tip of the needle.
  • a micro screw was attached to the skull as an anchor.
  • the tip of the guide force-Yule fixed to the electrode holder of the stereotaxic device was inserted 0.4 mm tail side from Bregma, 2.0 mm outside the midline, and 1.7 mm deep from the brain surface. Thereafter, the guide force-Yule was fixed to the skull with dental cement. After confirming that the dental cement was completely solidified, a dummy force-yure was inserted into the guide force-yure and fixed with a cap nut. The mouse was removed from the fixation device and observed on a heating pad until it awakened from anesthesia. Mice were returned to their cages after waking up completely from anesthesia.
  • the experiment for measuring dopamine was performed under conditions of no anesthesia and no restraint after the mice had completely recovered the invasive power by surgery (about 5 to 7 days).
  • the mouse was fully adapted to a measuring box with a diameter of 40 cm and a height of 50 cm.
  • the cerebral striatum where the tip of the dialysis probe was located was perfused with dialysate using a syringe pump (flow rate, 1 ⁇ L / min).
  • the time course of the dopamine concentration in the dialysate collected from the striatum was analyzed using a high-performance liquid chromatograph.
  • An online analysis system with an electrochemical detector manufactured by Aicom Co., Ltd.
  • the retention time of donomin is about 8.5 minutes. It was.
  • the experiment was started after confirming that the peak of dopamine in the recovered solution was constant and stable.
  • NaH PO ⁇ 2 ⁇ O 15.6g was dissolved in ultrapure water to make 1L.
  • Na HPO-12H 0 35.8g was dissolved in ultrapure water to make 1L.
  • the dialysate is composed of NaCl (146 mM) KCl (2.7 mM) CaCl (1.2 mM) MgCl (1.0 mM)
  • a mouse that had been stained with the substantia nigra by connecting the forward and reverse mediatophore cDNA to a viral expression vector was used.
  • the amount of overflowing dopamine was measured by refluxing with the potassium salt of potassium salt at the concentration indicated on the striatum. The results are shown in FIG. It was shown that the amount of dopamine released was increased by medium-at-four.

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Abstract

Cette invention concerne un produit pharmaceutique destiné à être utilisé dans le traitement de la maladie de Parkinson comprenant un vecteur dans lequel est intégré un gène codant pour le médiatophore et qui peut exprimer le médiatophore dans le cerveau.
PCT/JP2006/312854 2005-06-29 2006-06-28 Produit pharmaceutique pour le traitement de la maladie de parkinson WO2007001010A1 (fr)

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JP2007523965A JPWO2007001010A1 (ja) 2005-06-29 2006-06-28 パーキンソン病の治療のための医薬

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Cited By (6)

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WO2012057363A1 (fr) 2010-10-27 2012-05-03 学校法人自治医科大学 Virions de virus adéno-associé pour le transfert de gènes dans des cellules neuronales
WO2018131551A1 (fr) 2017-01-13 2018-07-19 学校法人自治医科大学 Vecteur aav pour la disruption du gène du facteur lié à la coagulation sur le génome du foie
WO2019146745A1 (fr) 2018-01-26 2019-08-01 国立大学法人徳島大学 Nouveau virion de virus adéno-associé pour traiter la maladie de tay-sachs et la maladie de sandhoff
WO2020026968A1 (fr) 2018-07-30 2020-02-06 株式会社遺伝子治療研究所 Méthode pour améliorer l'expression génique par un vecteur aav
WO2021009805A1 (fr) 2019-07-12 2021-01-21 株式会社遺伝子治療研究所 Virion de virus adéno-associé pour transfert de gènes vers le foie humain
WO2022224372A1 (fr) 2021-04-21 2022-10-27 学校法人自治医科大学 Virion de virus adéno-associé pour le traitement d'une déficience en ornithine transcarbamylase

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