AAV1-FS344(AAV1-FS344) - 药物靶点：FST x MSTN_在研适应症：杜氏肌营养不良症，包涵体肌炎_专利_临床

概要

基本信息

药物类型

腺相关病毒基因治疗

别名

AAV1 vectored follistatin gene therapy - Milo Biotechnology、AAV1-Follistatin、rAAV1 CMV huFollistatin 344

+ [2]

靶点

FST x MSTN

作用机制

FST inhibitors(Follistatin inhibitors)、MSTN 抑制剂(生长分化因子-8 抑制剂)

治疗领域

神经系统疾病遗传病与畸形皮肤和肌肉骨骼疾病+ [1]

在研适应症

杜氏肌营养不良症包涵体肌炎

非在研适应症

贝克型肌营养不良

原研机构

Nationwide Children's Hospital

在研机构

Nationwide Children's Hospital

Milo Biotechnology LLC

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

2

项与 AAV1-FS344 相关的临床试验

NCT02354781

/ Completed临床1/2期IIT

Phase I/II Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy

The proposed clinical trial is an outgrowth of the safety record and functional improvement seen in the BMD follistatin gene therapy trial. In this study the investigators propose to inject AAV1.CMV.huFS344 at a total dose of 2.4E12 vg/kg to six DMD patients. This dose will be divided between gluteal muscles, quadriceps and tibialis anterior. This is a wider distribution of vector than given to BMD patients, who overall improved the distance walked on the 6MWT without adverse events related to viral transduction into a single muscle.

开始日期2015-01-01

申办/合作机构

Nationwide Children's Hospital

[+1]

NCT01519349

/ Completed临床1期IIT

Phase I Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis.

The investigators are performing a gene therapy clinical trial in Becker muscular dystrophy (BMD) and sporadic inclusion body myositis (sIBM) patients. Both of these conditions have an important common feature: loss of ability to walk because of weakness of the thigh muscles. The investigators plan to do a gene therapy trial to deliver a gene to muscle called follistatin (FS344) that can build muscle size and strength. If successful, the investigators can increase the size of the thigh muscle and potentially prolong a patient's ability to walk. The gene will be carried into the muscle by a virus called adeno-associated virus (AAV). This virus occurs naturally in muscle and does not cause any human disease, setting the stage for its safe use in a clinical trial.
Presently there is no treatment that can reverse Becker muscular dystrophy or sporadic inclusion body myositis. Only supportive care is currently possible.
In this study, subjects with either of these diseases will have shots of the follistatin gene injected directly into thigh muscle on one (first cohort) or both legs (2nd and 3rd cohort). One hundred and eighty days following the gene delivery, the muscle will undergo biopsy to look closely at the muscle to see if the muscle fibers are bigger. Between the time of the gene transfer and the muscle biopsy, patients will be carefully monitored for any side effects of the treatment. This will include an MRI of the thigh muscle before treatment and at day 180 following treatment. Blood and urine tests, as well as physical examination will be done on the subjects during the screening visit and on days 0, 1, 2, 7, 14, 30, 60, 90, and 180 to make sure that there are no side effects from the gene injections. Sutures will be removed 2 weeks post-biopsy.
Additional blood samples will be collected at 9, 12, 18, and 24 months. Patients will be seen at the end of 1st and 2nd years for a physical exam, assessment of muscle strength and appropriate blood tests.

开始日期2012-01-01

申办/合作机构

Nationwide Children's Hospital

[+1]

100 项与 AAV1-FS344 相关的临床结果

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100 项与 AAV1-FS344 相关的转化医学

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100 项与 AAV1-FS344 相关的专利（医药）

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50

项与 AAV1-FS344 相关的文献（医药）

2024-09-10·Genes

Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy.

Article

作者: Gallagher, Thomas ; Flotte, Terence R ; Tang, Qiushi ; Reil, Darcy ; Benson, Janet ; Fu, Dongtao ; Pires-Ferreira, Debora ; Lindborg, Jane A ; Blackwood, Meghan ; Keeler, Allison M ; Vyhnal, Kristin K ; Gruntman, Alisha M ; Chichester, Jessica A

BACKGROUND/OBJECTIVESα-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species.METHODSIn this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 10¹² to 1.3 × 10¹³ vg/kg, bracketing those used in our clinical trials.RESULTSWe found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels.CONCLUSIONSOur results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 10¹³-1 × 10¹⁴ vg/kg, which is within the dose range used for approved rAAV gene therapies. Muscle-targeting strategies could be incorporated when delivering systemic administration of high-dose rAAV gene therapies to increase transduction of muscle tissues and reduce the burden on the liver, especially in diseases that can present with hepatotoxicity such as AAT deficiency.

2022-02-01·Human Gene Therapy2区 · 医学

Short-Term Steroid Treatment of Rhesus Macaque Increases Transduction

2区 · 医学

Article

作者: Guggino, William B. ; Yanda, Murali K. ; Tomar, Vartika ; Cebotaru, Cristina Valeria ; Cebotaru, Liudmila

Repeat dosing poses a major hurdle for the development of an adeno-associated virus (AAV)-based gene therapy for cystic fibrosis, in part because of the potential for development of an immune reaction to the AAV1 capsid proteins. Here, to dampen the immune response to AAV1, we treated Rhesus monkeys with methylprednisolone before and after the instillation of two doses of AAV1Δ27-264-CFTR into their airways at 0 and 30 days, followed by a single dose of AAV1-GFP on day 60. Animals were euthanized on day 90, except for one monkey that was sacrificed at 1 year. No adverse events occurred, indicating that the two AAV1 vectors are safe. rAAV1-CFTR and AAV1-GFP vector genomes and mRNA transcripts were detectable in all lung sections and in the liver and pancreas at day 90 and after 1 year at levels comparable with animals necropsied at 90 days. The numbers of vector genomes for cystic fibrosis transmembrane regulator (CFTR) and green fluorescent protein (GFP) detected here were higher than those found in the monkeys infected without methylprednisolone treatment that we tested previously.¹ Also, lung surface and keratin 5-positive basal cells showed higher CFTR and GFP staining than did the cells from the uninfected monkey control. Positive immunostaining, also detected in the liver and pancreas, remained stable for at least a year. All animals seroconverted for anticapsid antibodies by 90 days post-treatment. The neutralizing antibody titer declined in the animal necropsied at 1 year. Conclusion: AAV1 safely and effectively transduces monkey airway and basal cells. Both the presence of vector genomes and transduction from AAV1-CFTR and AAV1-GFP virus seen in the monkeys 4 months to 1 year after the first instillation suggest that repeat dosing with AAV1-based vectors is achievable, particularly after methylprednisolone treatment.

2019-12-01·Acta Neuropathologica Communications2区 · 医学

Intrathecal delivery of recombinant AAV1 encoding hepatocyte growth factor improves motor functions and protects neuromuscular system in the nerve crush and SOD1-G93A transgenic mouse models

2区 · 医学

ArticleOA

作者: Kim, Jin Hong ; Kim, Subin ; Lee, Junghun ; Yu, Seung Shin ; Lee, Nayeon ; Lee, Sang Hwan ; Kim, Sunyoung

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease resulting from motor neuron degeneration that causes muscle weakness, paralysis, and eventually respiratory failure. We investigated whether recombinant adeno-associated virus encoding human hepatocyte growth factor (rAAV-HGF) could generate beneficial effects in two mouse models with neuromuscular problems when intrathecally delivered to the subarachnoid space. We chose AAV serotype 1 (rAAV1) based on the expression levels and distribution of HGF protein in the lumbar spinal cord (LSC). After a single intrathecal (IT) injection of rAAV1-HGF, the protein level of HGF in the LSC peaked on day 14 and thereafter gradually decreased over the next 14 weeks. rAAV1-HGF was initially tested in the mouse nerve crush model. IT injection of rAAV1-HGF improved mouse hindlimb strength and rotarod performance, while histological analyses showed that the length of regenerated axons was increased and the structure of the neuromuscular junction (NMJ) was restored. rAAV1-HGF was also evaluated in the SOD1-G93A transgenic (TG) mouse model. Again, rAAV1-HGF not only improved motor performance but also increased the survival rate. Moreover, the number and diameter of spinal motor neurons (SMNs) were increased, and the shape of the NMJs restored. Data from in vitro motor cortical culture experiments indicated that treatment with recombinant HGF protein (rHGF) increased the axon length of corticospinal motor neurons (CSMNs). When cultures were treated with an ERK inhibitor, the effects of HGF on axon elongation, protein aggregation, and oxidative stress were suppressed, indicating that ERK phosphorylation played an important role(s). Taken together, our results suggested that HGF might play an important role(s) in delaying disease progression in the SOD1-G93A TG mouse model by reducing oxidative stress through the control of ERK phosphorylation.

100 项与 AAV1-FS344 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
杜氏肌营养不良症	临床2期	-	Milo Biotechnology LLC	-
杜氏肌营养不良症	临床2期	-	Nationwide Children's Hospital	-
包涵体肌炎	临床2期	-	Nationwide Children's Hospital	-
包涵体肌炎	临床2期	-	Milo Biotechnology LLC	-
贝克型肌营养不良	临床1期	美国	Nationwide Children's Hospital	2012-01-01
包涵体肌炎	临床1期	美国	-	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02354781 (CTgov)	临床1/2期	杜氏肌营养不良症	3	rAAV1.CMV.huFollistatin344 (2.4E12 vg/kg CMV.huFollistatin344)	窪襯獵遞構選齋窪鏇願(鏇鹽窪積膚觸廠鹽襯壓) = 窪構願憲繭壓襯築網遞窪餘鏇鹹願範範憲壓糧 (鹹積壓糧窪鹹鑰觸繭鏇, 窪糧網醖鏇夢醖餘簾壓 ~ 糧鹽繭觸鑰夢築憲壓憲) 更多	-	2020-04-15
				rAAV1.CMV.huFollistatin344 (2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344)	鏇構衊築淵鏇積鬱願鬱(願壓壓網積網遞簾齋膚) = 顧顧積餘窪鹽製糧淵鑰觸鑰築醖廠壓範膚艱膚 (範壓膚壓壓繭膚鬱壓廠, 醖觸顧襯網膚憲艱網鹽 ~ 淵積餘蓋獵觸獵範鬱範) 更多
Pubmed \| Mol Ther 人工标引	临床1期	包涵体肌炎	14	AAV1-FS344	(窪壓遞蓋製壓糧淵蓋顧) = 艱齋簾觸窪醖醖夢憲築遞鹹簾獵鏇蓋淵選網醖 (鬱衊糧襯鑰範構製選網 )	积极	2017-04-05
				untreated	(窪壓遞蓋製壓糧淵蓋顧) = 範築襯齋蓋窪鏇構鑰獵遞鹹簾獵鏇蓋淵選網醖 (鬱衊糧襯鑰範構製選網 )