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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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 ; Benson, Janet ; Reil, Darcy ; Fu, Dongtao ; Pires-Ferreira, Debora ; Blackwood, Meghan ; Vyhnal, Kristin K ; Keeler, Allison M ; Lindborg, Jane A ; 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.

项与 AAV1-FS344 相关的新闻（医药）

2023-03-24

·生物谷

CCR：科学家首次发现，耐药卵巢癌能细胞“催眠”同伙，促进周围癌细胞集体耐药！

这项研究报告了一种新的化疗耐药机制，即化疗可促进静止态卵巢癌细胞表达大量FST，并以旁分泌的方式影响其邻近肿瘤细胞的增殖和耐药。通过敲除FST或使用FST中和抗体可提高肿瘤细胞或小鼠肿瘤模型对化疗药物卵巢癌是女性常见恶性肿瘤之一。由于卵巢位于盆腔较深部，缺乏早期筛查方法，多数患者确诊时已是晚期，具有病程复杂，易复发，远期生存率低等特点。因此，卵巢癌成为了女性生殖道肿瘤诊治中的“硬骨头”。手术和化疗是卵巢癌的常规治疗手段，其中约70%的患者经化疗后能够实现缓解，但大部分患者仍会对化疗药物耐药，最终导致卵巢癌治疗失败，但目前尚无较好的方法可以解决耐药问题。不过近日，美国匹兹堡大学Ronald Buckanovich教授团队发表于癌症领域著名期刊Clinical Cancer Research的最新研究[1]，为克服卵巢癌耐药带来了希望。该研究发现，化疗可通过激活转录因子NFATC4，使静止态卵巢癌细胞分泌大量卵泡抑制素（follistatin, FST），从而促进周围肿瘤细胞耐药；而靶向FST在临床前研究中逆转了卵巢癌细胞的耐药，并提高了卵巢癌小鼠模型的存活率和生存期。文章首页截图在肿瘤中，有部分暂停增殖、处于G0期的细胞，被称为静止态癌细胞。由于化疗主要针对快速分裂的细胞，静止态癌细胞由于分裂缓慢而对化疗药物耐受，既往研究已经证明，静止态癌细胞在多种癌症的耐药中扮演了重要角色[2]。静止态癌细胞在卵巢癌的化疗耐药中也起到重要作用[3]。Buckanovich教授团队在此前的工作中发现，转录因子NFATC4在卵巢癌肿瘤干细胞中高表达，化疗可激活NFATC4入核促进其发挥转录调控作用[4]，从而诱导细胞进入静止状态并发生耐药。但是，其中的具体机制尚不清楚。因此，研究团队这次首先通过体外实验，鉴定出受NFATC4调控的141个靶基因，其中RCAN1, CNN1, COL3A1, FST和ANO1的mRNA表达量上调最为明显。考虑到FST在卵巢的发育和功能中具有重要作用[5]，并且临床发现卵巢癌患者血清中的FST也出现升高[6]，研究团队决定探索NFATC4下游靶点FST的作用。体外细胞实验证实，NFATC4确实能调控FST蛋白表达，且对高级别浆液性卵巢癌（HGSOC）患者肿瘤组织中，不同分裂速度的癌细胞进行比较时，发现静止态癌细胞中FST表达量显著增高（P<0.01），可达到快速分裂细胞的23倍，由此可见，NFATC4对FST的调控作用主要发生于静止态肿瘤细胞中。用化疗药物顺铂或紫杉醇处理不同卵巢癌细胞系，可导致FST的mRNA表达量增加10-72倍，导致FST的蛋白表达量增加4-50倍，且静止态癌细胞是FST增加的主要来源，这部分细胞的FST分泌量大约是正常分裂癌细胞的3倍。不同化疗药物（紫杉醇，Taxol；顺铂，Ciplatin）处理后不同卵巢癌细胞系FST分泌量的变化情况同时，在卵巢癌肿瘤模型小鼠上也观察到化疗促进FST分泌的现象。那么这些大量分泌的FST，到底有什么用呢？研究显示，高浓度FST处理可导致体外培养的卵巢癌细胞数量明显减少（P<0.001）；进一步的分析发现，FST对细胞生长的影响是由于抑制增殖，且仅对快速分裂的细胞增殖产生明显作用，并不影响静止态癌细胞。不同浓度FST对不同卵巢癌细胞生长的影响前面提到过，许多化疗药物主要针对的是快速分裂的癌细胞，而一旦细胞增殖速度减慢，药效肯定会大打折扣！果然，研究团队发现FST能促进化疗耐药：与单独使用紫杉醇相比，联合FST处理时肿瘤细胞存活数量可提高1.5-2.5倍（P<0.05）。使用顺铂进行实验也得到相似结果，机制分析则显示，FST可通过ATF2信号转导通路促进化疗耐药。值得一提的是，研究者们还通过细胞共培养实验证明，静止态癌细胞产生的FST可以旁分泌的方式，抑制其邻近快速分裂癌细胞的增殖。打个比方来说，静止态癌细胞就像花的花芯，而相邻的细胞就像花瓣，当化疗药物来袭时，静止态癌细胞就分泌FST来保护整个“花朵”。在此过程中，更多的肿瘤细胞会进入静止状态，并进一步影响其周围更多的细胞，越来越多的耐药细胞也就随之产生，最终导致癌症复发。 FST可促进化疗药物（紫杉醇，Taxol；顺铂，Cisplatin）发生耐药接下来，研究团队尝试将FST作为治疗靶点，使用FST中和抗体或CRISPR-Cas9敲除FST，均能显著增加卵巢癌细胞对化疗药物的敏感性（P<0.01）；而为进一步评估敲除FST在体内的作用，研究者建立了卵巢癌移植瘤小鼠模型，并用紫杉醇进行治疗，结果显示，相比野生型小鼠，注射FST-KO细胞的小鼠存活率显著提高（P<0.0001），总生存期也明显延长。在化疗药物治疗同时FST敲除对移植瘤小鼠存活率和生存期的影响最后，研究团队还比较了化疗前后卵巢癌患者体内FST的变化情况：与化疗前相比，患者FST水平在化疗后24小时后增加了1-3倍；而对数百名卵巢癌患者的TCGA数据分析发现，高水平FST与较低的生存率相关，表明FST也有望作为逆转人卵巢癌耐药的新靶点。总的来说，这项研究报告了一种新的化疗耐药机制，即化疗可促进静止态卵巢癌细胞表达大量FST，并以旁分泌的方式影响其邻近肿瘤细胞的增殖和耐药。通过敲除FST或使用FST中和抗体可提高肿瘤细胞或小鼠肿瘤模型对化疗药物的敏感性。 FST介导的卵巢癌化疗耐药模式图本次研究对卵巢癌的治疗具有重要意义，化疗目前仍是不可手术卵巢癌的有效治疗手段，减少耐药和复发将大大改善患者预后，而且FST是一种分泌性蛋白，因此是中和抗体的理想靶点，期待相关抗体药物能早日被成功研发出来。

信使RNA

100 项与 AAV1-FS344 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
贝克型肌营养不良	临床3期	美国	Nationwide Children's Hospital	2012-01-01
包涵体肌炎	临床3期	美国	-	-
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	-

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临床结果

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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	huFollistatin344 (2.4E12 vg/kg CMV.huFollistatin344)	淵齋鏇遞築築繭製簾膚(顧網願膚齋餘積膚衊艱) = 鏇遞鹽獵壓鏇廠壓製淵醖窪鑰獵簾鏇觸膚壓膚 (鬱積糧鬱築窪願淵網構, 顧糧廠獵積觸醖網襯鹹 ~ 壓膚願壓淵遞鑰簾鏇範) 更多	-	2020-04-15
				rAAV1.CMV.huFollistatin344 (2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344)	淵網鏇網憲窪製遞鏇糧(餘繭繭鏇網繭繭獵繭觸) = 襯鬱繭製糧觸鹹壓繭獵醖齋鬱範獵淵憲顧鏇衊 (構鑰膚廠壓範繭簾獵鹹, 淵範鹽襯願願糧構餘艱 ~ 醖淵鑰鑰鏇顧願網願鹽) 更多
Pubmed \| Mol Ther 人工标引	临床1期	包涵体肌炎	14	AAV1-FS344	(淵膚構鑰膚築膚鏇範簾) = 範襯醖鹹壓觸衊廠積餘簾蓋憲醖糧願鹹鹹顧艱 (選窪鹽願範壓壓鹽鹹範 )	积极	2017-04-05
				untreated	(淵膚構鑰膚築膚鏇範簾) = 齋遞遞艱壓衊願鹹憲齋簾蓋憲醖糧願鹹鹹顧艱 (選窪鹽願範壓壓鹽鹹範 )