WO2019132624A1 - 하이브리드 hgf 유전자가 도입된 aav(아데노-연관 바이러스) 벡터 - Google Patents
하이브리드 hgf 유전자가 도입된 aav(아데노-연관 바이러스) 벡터 Download PDFInfo
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- WO2019132624A1 WO2019132624A1 PCT/KR2018/016937 KR2018016937W WO2019132624A1 WO 2019132624 A1 WO2019132624 A1 WO 2019132624A1 KR 2018016937 W KR2018016937 W KR 2018016937W WO 2019132624 A1 WO2019132624 A1 WO 2019132624A1
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- 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
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- A61K48/0075—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 delivery route, e.g. oral, subcutaneous
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C—CHEMISTRY; METALLURGY
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- C07K14/475—Growth factors; Growth regulators
- C07K14/4753—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
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Definitions
- the present invention relates to an AAV vector comprising a predetermined hybrid HGF gene sequence.
- Gene therapy uses genetic recombination technology to deliver therapeutic genes into the cells of a patient to induce genetic modification of target cells or to express specific proteins to treat genetic diseases and incurable diseases.
- the substance that transmits the gene in vivo is called a carrier or a vector, and the vector is classified into a viral vector and a non-viral vector.
- viral vectors include retroviruses and adenoviruses.
- Non-viral vectors include naked DNA, liposomes, and the like.
- Hepatocyte growth factor is one of the growth factors, and various functions are under study. Examples include: (1) treatment of heart disease with HGF using liposomes as carriers (Aoki et al., Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infracted myocardium: up-regulation of essential transcription factor for angiogenesis , et al., Gene Therapy 7: 417-427, 2000), (2) treatment of liver disease with HGF using AAV as a carrier (Suzumura et al., Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice . Hepatol Int 2:..
- the present inventors have made intensive studies to develop a gene delivery vehicle with enhanced efficiency of hybrid HGF gene expressing simultaneous expression of HGF (Hepatocyte Growth Factor) including flHGF and dHGF. As a result, the inventors of the present invention have completed the present invention by confirming that the gene transfer efficiency can be significantly improved when a descending mutant of a known hybrid HGF gene and an adenovirus-associated virus (AAV) as a gene carrier are used.
- HGF Hepatocyte Growth Factor
- AAV adenovirus-associated virus
- an object of the present invention is to provide an AAV (Adeno-Associated Virus) vector into which foreign nucleic acid sequences of a predetermined nucleotide sequence are introduced.
- AAV Ado-Associated Virus
- DPN diabetic peripheral neuropathy
- ALS amyotrophic lateral sclerosis
- an Adeno-Associated Virus (AAV) vector into which a foreign nucleic acid sequence consisting of the nucleotide sequence of SEQ ID NO: 5 is introduced.
- AAV Adeno-Associated Virus
- the present inventors have made intensive studies to develop a gene delivery vehicle with enhanced efficiency of hybrid HGF gene expressing simultaneous expression of HGF (Hepatocyte Growth Factor) including flHGF and dHGF. As a result, it has been found that the gene transfer efficiency can be significantly improved by using a downsampling variant of a known hybrid HGF gene and an adenovirus-associated virus (AAV) as a gene carrier.
- HGF Hepatocyte Growth Factor
- AAV adenovirus-associated virus
- hybrid HGF gene refers to a gene sequence that coexpresses two or more HGF variants by selective splicing. More specifically, the two or more HGF variants described above include at least full length HGF (flHGF) variants and deleted variant HGF (dHGF) variants.
- the hybrid HGF gene of the present invention can be used within a range that does not change the amino acid sequence of the protein expressed from the coding region due to codon degeneracy or considering the codons preferred in the organism to which the HGF and dHGF gene are to be expressed Various modifications can be made in the coding region and various modifications or modifications can be made within a range not affecting the expression of the gene even in the portion excluding the coding region, and such modified genes are also included in the scope of the present invention. Accordingly, the present invention also includes a polynucleotide having a base sequence substantially the same as the hybrid HGF gene of SEQ ID NO: 5 and a fragment of the gene. By substantially the same polynucleotide is meant those having a sequence homology of 80% or more, preferably 90% or more, and most preferably 95% or more.
- the above-mentioned hybrid HGF gene may include the cDNA corresponding to exons 1 to 18 of the human HGF gene and the intron 4 or fragment thereof of the human HGF gene inserted between the exons 4 and 5 of the cDNA.
- the HGF-X7 sequence consisting of the nucleotide sequence of SEQ ID NO: 6 is conventionally known (see KR2017-0024614 (June 7, 2017)).
- the above-mentioned nucleotide sequence of SEQ ID NO: 6 has a limitation due to its size in the insertion into an AAV vector.
- the nucleotide sequence of SEQ ID NO: 5 of the present invention corresponds to a sequence having a significantly increased gene transfer efficiency in the down-sequence sequence by removing a part of the sequence corresponding to the intron 4 fragment of the nucleotide sequence of SEQ ID NO: 6.
- HGF-X8 of the known sequence No. 7 is significantly increased Gene transfer efficiency and expression efficiency.
- a polynucleotide can be transported to a subject in the naked DNA state or contained in a gene carrier, and a plasmid or a viral vector can be used as a gene carrier.
- a plasmid or a viral vector can be used as a gene carrier.
- an adeno-associated virus (AAV) vector is used as a gene carrier.
- AAV vectors can infect non-dividing cells and can infect a wide variety of cells.
- a detailed description of the preparation and use of AAV vectors is disclosed in detail in U.S. Patent Nos. 5,139,941 and 4,797,368.
- a study of AAV as a gene delivery system is described in LaFace et al, Virology, 162: 483486 (1988), Zhou et al., Exp. Hematol. (NY), 21: 928-933 (1993), Walsh et al, J. Clin. Invest., 94: 1440-1448 (1994) and Flotte et al., Gene Therapy, 2: 29-37 (1995).
- the AAV virus is a plasmid (McLaughlin et al., J. Virol., 62: 1963-1973 (1988); and Samulski et al., Supra) containing a gene sequence of interest in which two AAV terminal repeats are located next to each other. , J. Virol., 63: 3822-3828 (1989)) and expression plasmids containing wild-type AAV coding sequences without terminal repeats, and plasmids containing the helper gene of adenovirus (McCarty et al., J Virol., 65: 2936-2945 (1991)).
- the AAV vector of the present invention can be used to carry the foreign gene sequence into cells according to various virus infection methods known in the art, and the method is not particularly limited.
- the AAV vector of the present invention has an AAV serotype selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15 and AAV16.
- the present invention provides a transformant transformed by the AAV vector described above.
- the AAV vector of the present invention can be introduced into an appropriate host cell, for example, a mammalian cell such as 293T or an insect cell, and the transformed host cell can be used to transform the gene of the present invention It can replicate large amounts of DNA or mass-produce proteins.
- an appropriate host cell for example, a mammalian cell such as 293T or an insect cell
- the transformed host cell can be used to transform the gene of the present invention It can replicate large amounts of DNA or mass-produce proteins.
- composition for preventing or treating diabetic peripheral neuropathy (DPN) or amyotrophic lateral sclerosis (ALS) comprising the AAV vector described above .
- prophylactic refers to any act that inhibits diabetic neuropathy or amyotrophic lateral sclerosis by administration of the compositions of the present invention.
- treatment refers to (a) delay or inhibit progression / development of diabetic neuropathy or amyotrophic lateral sclerosis; (b) relief of diabetic neuropathy or amyotrophic lateral sclerosis; And (c) removal of diabetic neuropathy or amyotrophic lateral sclerosis.
- composition of the present invention may comprise a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carriers to be included in the composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate , Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, no.
- the pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
- the pharmaceutical composition of the present invention is preferably parenterally administered and can be administered orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, intracranially, intracerebroventricular injection, intracerebral injection, Administration.
- the pharmaceutical composition of the present invention can be formulated and administered by injection.
- the appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, the administration method, the age, body weight, sex, disease symptom, administration time, administration route, excretion rate and responsiveness of the patient, Usually, a skilled physician can easily determine and prescribe dosages effective for the desired treatment.
- the AAV vector of the present invention is administered at a dose of 1 ⁇ 10 8 to 1 ⁇ 10 12 GC / site.
- the pharmaceutical composition of the present invention may be formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container.
- the formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
- the diabetic neuropathy described above is polyneuropathy or focal neuropathy.
- the multiple peripheral neuropathy described above is selected from the group consisting of hyperglycemic neuropathy, distal symmetric polyneuropathy, autonomic neuropathy, acute neuropathy, sensory neuropathy, acute painful sensory neuropathy, and chronic sensorimotor neuropathy. < Desc / Clms Page number 2 > More specifically, the focal peripheral neuropathy described above includes at least one of cranial neuropathy, truncal neuropathy, limb neuropathy, thoracolumbar radiculoneuropathy, and lumbosacral myelopathy radiculoplexus neuropathy). < / RTI >
- the present invention provides an Adeno-Associated Virus (AAV) vector into which an exogenous nucleic acid sequence composed of a predetermined nucleotide sequence is introduced.
- AAV Adeno-Associated Virus
- the present invention provides a transformant transformed with the AAV vector described above.
- the present invention provides a composition for preventing or treating diabetic peripheral neuropathy (DPN) or amyotrophic lateral sclerosis (ALS) comprising the above-described AAV vector.
- DPN diabetic peripheral neuropathy
- ALS amyotrophic lateral sclerosis
- the hybrid HGF gene can be delivered to the subject with high transfer efficiency.
- Figure 1 is a schematic diagram showing a method for producing down-sizing variants of HGF-X7 from pCK-HGF-X7.
- Figure 2 is a schematic diagram showing a method for cloning DownSing variants of HGF-X7 into a pCA vector.
- FIG. 3 is a graph showing the expression levels of HGF protein in C2C12 cells infected with AAV-pCA-HGF-X7-d3 and AAV-pCA-HGF-X7-d4, respectively.
- FIG. 4 is a graph showing the expression levels of HGF protein in C2C12 cells infected with AAV2-pCA-HGF-X7-d4 and AAV2-pCA-HGF-X8, respectively.
- FIG. 5 is a graph showing that the progression of the disease is delayed after muscle administration of AAV6-pCA-HGF-X7-d4 in ALS mice.
- FIG. 6 is a graph showing the degree of improvement in survival rate after muscle administration of AAV6-pCA-HGF-X7-d4 in ALS mice.
- FIG. 7 is a graph showing the degree of slowing of weight loss after muscle administration of AAV6-pCA-HGF-X7-d4 in ALS mice.
- FIG. 8 is a graph showing survival rate and behavioral analysis results of AAV1-pCA-HGF-X7-d4 in ALS mice after intrathecal administration.
- Colonies containing pCK-HGF-X7-d1, pCK-HGF-X7-d2, pCK-HGF-X7-d3 and pCK-HGF-X7-d4 in the colonies resulting from transferring the PCR products to C cells were selected From this, plasmid DNA was extracted (see Fig. 1).
- pCA vector was treated with ClaI and SalI restriction enzymes and ligated together with four fragments of HGF-X7-d1, HGF-X7-d2, HGF-X7-d3 and HGF-X7- -X7-d1, pCA-HGF-X7-d2, pCA-HGF-X7-d3 and pCA-HGF-X7-d4.
- AAV was prepared using each plasmid DNA prepared in Experimental Example 2.
- 293T cells ATCC
- the plasmid DNA prepared in Experimental Example 2 and pHelper and pAAV-RC AAV Helper-Free System, Agilent, USA
- AAV was collected.
- the collected AAV was measured using a titration kit (AAVpro Titration Kit, Takara, JP).
- AAV was produced using four serotypes (AAV1, AAV2, AAV5 and AAV6).
- C2C12 cells (ATCC) were plated on a 12 well plate at 8 ⁇ 10 4 cells / well and the cells were stabilized for 24 hours.
- the C2C12 cells were infected with AAV2-pCA-HGF-X7-d3 and AAV2-pCA-HGF-X7-d4, respectively, with the same amount of titer.
- Two days after infection the supernatant was collected and analyzed by HGF ELISA (R & D systems, US) for the amount of HGF protein.
- the expression amount of HGF by AAV2-pCA-HGF-X7-d4 was higher than that of AAV2-pCA-HGF-X7-d3 (see FIG.
- C2C12 cells (ATCC) were plated on a 12 well plate at 8 ⁇ 10 4 cells / well and the cells were stabilized for 24 hours.
- the C2C12 cells were infected with AAV2-pCA-HGF-X7-d4 and AAV2-pCA-HGF-X8, each of which had an equal amount of titer.
- HGF ELISA R & D systems, US
- the hSOD1-G93A model widely used as an ALS model, was used.
- ALS mouse Jackson Laboratory, US
- Tg-AAV6-MCS 8, Tg-AAV6-pCA-HGF-X7-d4: 7
- Non-Tg individuals were picked and used as negative controls (non-Tg: 5).
- the AAV was administered at 1 ⁇ 10 8 GC / site to the thigh muscle, the tibialis muscle and the calf muscle of the mice that were 90 days old, respectively, and a total of 3 ⁇ 10 8 GC / head was administered.
- ALS disease eventually leads to death as disease progresses, the above three indicators are the most widely used analytical criteria in ALS animal experiments.
- the rate of disease progression was quantified by the following criteria.
- ALS mice In ALS mice (AAV6-MCS-treated group), it was confirmed that the disease became worse over time. However, when AAV6-pCA-HGF-X7-d4 was administered, it was confirmed that the progression was delayed.
- the mean value of the symptom score of ALS mice in the experimental period was 2.36 and the value of AAV6-pCA-HGF-X7-d4 was 2.88 in comparison with that of ALS mice (AAV6-MCS group) (See Fig. 5).
- AAV6-pCA-HGF-X7-d4 when administered, it was confirmed that the survival rate was remarkably improved.
- the survival rate of the group receiving AAV6-MCS was found to be 139 days, while that of AAV6-pCA-HGF-X7-d4 was increased to about 147 days (about 8 days) 6).
- the hSOD1-G93A model widely used as an ALS model, was used.
- ALS mouse Jackson Laboratory, US
- Tg was confirmed by genotyping. Individuals having a certain level of mutation gene were selected and used in the experiment.
- negative controls 13 animals were set.
- Tg individuals were grouped into Tg-AAV1-MCS and Tg-AAV1-pCA-HGF-X7-d4 groups of 14 and 16, respectively.
- AAV was administered once at 5 x 10 9 GC / site into the spinal canal of mice 60 days old.
- the survival rate the most important index of ALS disease.
- a rotarod and hanging wire survey were conducted to examine the motility of the subject in the ALS disease situation.
- grip strength was measured to examine the strength of muscle function.
- the accerating method is used to measure the time it takes to place the mouse on a rotating rod and then move on a long rotating rod. In particular, the speed of the rotating rod is accelerated over time.
- Grip strength is measured by measuring the muscle strength after placing the forefoot and hind legs of the mouse on each instrument for measuring strength.
- AAV1-pCA-HGF-X7-d4 shows a therapeutic effect when administered intrathecally. Survival rates were significantly higher in AAV1-pCA-HGF-X7-d4 treated group than in AAV1-MCS treated group. The average lifespan of the mice treated with AAV1-MCS was 144 days, while the average of the mice treated with AAV1-pCA-HGF-X7-d4 was increased to about 160 days by about 16 days.
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Abstract
Description
d1 | forward(SEQ ID NO: 8) | TCTCGGTATTTGTGGATCCTATTATGATCTTTTGTGTAAA |
reverse(SEQ ID NO: 9) | TTTACACAAAAGATCATAATAGGATCCACAAATACCGAGA | |
d2 | forward(SEQ ID NO: 10) | TCTCGGTATTTGTGGATCCTTTACTATTATAAACCAAAAC |
reverse(SEQ ID NO: 11) | GTTTTGGTTTATAATAGTAAAGGATCCACAAATACCGAGA | |
d3 | forward(SEQ ID NO: 12) | TCTCGGTATTTGTGGATCCTAAGGTGTAAGATGTTAAAGG |
reverse(SEQ ID NO: 13) | CCTTTAACATCTTACACCTTAGGATCCACAAATACCGAGA | |
d4 | forward(SEQ ID NO: 14) | TCTCGGTATTTGTGGATCCTTATAAGAAAAGCAATAAACA |
reverse(SEQ ID NO: 15) | TGTTTATTGCTTTTCTTATAAGGATCCACAAATACCGAGA |
Claims (4)
- 서열번호 5의 뉴클레오타이드 서열로 이루어진 외래 핵산서열이 도입된 AAV(Adeno-Associated Virus) 벡터.
- 제 1 항에 따른 AAV 벡터에 의해 형질전환된 형질전환체.
- 제 1 항에 따른 AAV 벡터를 포함하는 근위축성측삭경화증(amyotrophic lateral sclerosis, ALS) 또는 당뇨병성 신경병증(diabetic peripheral neuropathy, DPN) 예방 또는 치료용 조성물.
- 제 3 항에 있어서, 상기 당뇨병성 신경병증은 다발성 말초신경병증 (polyneuropathy) 또는 국소성 말초신경병증(focal neuropathy)인 것을 특징으로 하는 조성물.
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US16/956,926 US11634728B2 (en) | 2017-12-29 | 2018-12-28 | Adeno-associated virus (AAV) vector having hybrid HGF gene introduced thereto |
JP2020532995A JP7140353B2 (ja) | 2017-12-29 | 2018-12-28 | ハイブリッドhgf遺伝子が導入されたaav(アデノ-関連ウイルス)ベクター |
CN201880085076.5A CN111542613B (zh) | 2017-12-29 | 2018-12-28 | 导入有杂交的肝细胞生长因子的腺相关病毒载体 |
CA3086046A CA3086046C (en) | 2017-12-29 | 2018-12-28 | Adeno-associated virus (aav) vector having hybrid hgf gene introduced thereto |
AU2018395121A AU2018395121B2 (en) | 2017-12-29 | 2018-12-28 | Adeno-associated virus (AAV) vector having hybrid HGF gene introduced thereto |
EP18894300.5A EP3733855A4 (en) | 2017-12-29 | 2018-12-28 | ADENO-ASSOCIATED VIRUS (AAV) VECTOR INCLUDING A HYBRID HGF GENE INTRODUCED INTO ITS BREAST |
SG11202006169PA SG11202006169PA (en) | 2017-12-29 | 2018-12-28 | Adeno-associated virus (aav) vector having hybrid hgf gene introduced thereto |
RU2020121178A RU2762367C1 (ru) | 2017-12-29 | 2018-12-28 | Вектор на основе аденоассоциированного вируса (aav), имеющий гибридный ген hgf, введенный в него |
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KR20230152503A (ko) | 2022-04-27 | 2023-11-03 | 주식회사 헬릭스미스 | 척수강 내 투여에 최적화 된 간세포 성장인자 유전자가 도입된 aav 벡터 |
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Also Published As
Publication number | Publication date |
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EP3733855A4 (en) | 2021-03-03 |
US20210071199A1 (en) | 2021-03-11 |
CN111542613B (zh) | 2023-11-21 |
CN111542613A (zh) | 2020-08-14 |
CA3086046C (en) | 2023-02-21 |
KR102112476B1 (ko) | 2020-05-19 |
US11634728B2 (en) | 2023-04-25 |
AU2018395121B2 (en) | 2022-10-06 |
SG11202006169PA (en) | 2020-07-29 |
JP7140353B2 (ja) | 2022-09-22 |
RU2762367C1 (ru) | 2021-12-20 |
AU2018395121A1 (en) | 2020-07-30 |
CA3086046A1 (en) | 2019-07-04 |
JP2021506283A (ja) | 2021-02-22 |
EP3733855A1 (en) | 2020-11-04 |
KR20190082139A (ko) | 2019-07-09 |
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