(Galgt2 gene therapy (Nationwide Childrens Hospital)) - 药物靶点：GALGT2_在研适应症：杜氏肌营养不良症_专利_临床

概要

基本信息

药物类型

基因疗法

别名

GalNAc tranferase gene therapies、Galgt2 gene therapy

+ [1]

靶点

GALGT2

作用机制

B4GALNT2基因刺激剂(人1,4N乙酰氨基半乳糖转移酶2基因刺激剂)、基因转移

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

在研适应症

杜氏肌营养不良症

非在研适应症-

原研机构

Nationwide Children's Hospital

在研机构

Sarepta Therapeutics, Inc.

Nationwide Children's Hospital

Myonexus Therapeutics, Inc.初创企业

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-

关联

2

项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 相关的临床试验

NCT03333590 / Active, not recruiting临床1/2期IIT

Phase I/IIa Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients. There will be a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver vector to each whole lower limb of DMD subjects via a major lower limb artery.

开始日期2017-11-06

申办/合作机构

Nationwide Children's Hospital

NCT02704325 / Withdrawn临床1/2期IIT

Phase I Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients that will involve direct intramuscular injection to the extensor digitorum brevis muscle (EDB).

开始日期2016-04-01

申办/合作机构

Nationwide Children's Hospital

100 项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 相关的临床结果

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100 项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 相关的转化医学

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100 项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 相关的专利（医药）

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4

项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 相关的文献（医药）

2019-03-01·Molecular Therapy1区 · 医学

rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart

1区 · 医学

Article

作者: Rui Xu ; Deborah A. Zygmunt ; Ying Jia ; Paul T. Martin

Dilated cardiomyopathy is a common cause of death in patients with Duchenne muscular dystrophy (DMD). Gene therapies for DMD must, therefore, have a therapeutic impact in cardiac as well as skeletal muscles. Our previous studies have shown that GALGT2 overexpression in mdx skeletal muscles can prevent muscle damage. Here we have tested whether rAAVrh74.MCK.GALGT2 gene therapy in mdx cardiac muscle can prevent the loss of heart function. Treatment of mdx hearts with rAAVrh74.MCK.GALGT2 1 day after birth did not negatively alter hemodynamic function, tested at 3 months of age, and it prevented early left ventricular remodeling and expression of fibrotic gene markers. Intravenous treatment of mdx mice with rAAVrh74.MCK.GALGT2 at 2 months of age significantly improved stroke volume and cardiac output compared to mock-treated mice analyzed at 17 months, both at rest and after stimulation with dobutamine. rAAVrh74.MCK.GALGT2 treatment of mdx heart correlated with increased glycosylation of α-dystroglycan with the CT glycan and increased utrophin protein expression. These data provide the first demonstration that GALGT2 overexpression can inhibit the loss of cardiac function in the dystrophin-deficient heart and, thus, may benefit both cardiac and skeletal muscles in DMD patients.

2018-09-01·Molecular Therapy - Methods & Clinical Development2区 · 医学

An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.GALGT2 to Leg Skeletal Muscles in the Rhesus Macaque

2区 · 医学

ArticleOA

作者: Shao, Guohong ; Hood, Benjamin C ; Chicoine, Louis G ; Cheatham, Sharon L ; Guggenheim, Haley N ; Jia, Ying ; Peterson, Ellyn ; Rodino-Klapac, Louise R ; Cheatham, John P ; Crowe, Kelly E ; Griffin, Danielle A ; Maki, Agatha E ; Cramer, Megan L ; Flanigan, Kevin M ; Bolon, Brad ; Martin, Paul T ; Xu, Rui ; Zygmunt, Deborah A

Recombinant adeno-associated virus (rAAV)rh74.MCK.GALGT2 is a muscle-specific gene therapy that is being developed to treat forms of muscular dystrophy. Here we report on an isolated limb infusion technique in a non-human primate model, where hindlimb blood flow is transiently isolated using balloon catheters to concentrate vector in targeted leg muscles. A bilateral dose of 2.5 × 10¹³ vector genomes (vg)/kg/limb was sufficient to induce GALGT2-induced glycosylation in 10%-60% of skeletal myofibers in all leg muscles examined. There was a 19-fold ± 6-fold average limb-wide increase in vector genomes per microgram genomic DNA at a bilateral dose of 2.5 × 10¹³ vg/kg/limb compared with a bilateral dose of 6 × 10¹² vg/kg/limb. A unilateral dose of 6 × 10¹³ vg/kg/limb showed a 12- ± 3-fold increase in treated limb muscles compared to contralateral untreated limb muscles, which received vector only after release into the systemic circulation from the treated limb. Variability in AAV biodistribution between different segments of the same muscle was 125% ± 18% for any given dose, while variability between the same muscle for any given treatment dose was 45% ± 7%. These experiments demonstrate that treatment of muscles throughout the leg with rAAVrh74.MCK.GALGT2 can be accomplished safely using an isolated limb infusion technique, where balloon catheters transiently isolate the limb vasculature, but that intra- and inter-muscle transduction variability is a significant issue.

2017-06-01·Human Gene Therapy2区 · 医学

Induction of T-Cell Infiltration and Programmed Death Ligand 2 Expression by Adeno-Associated Virus in Rhesus Macaque Skeletal Muscle and Modulation by Prednisone

2区 · 医学

Article

作者: Chicoine, Louis G. ; Rodino-Klapac, Louise R. ; Martin, Paul T. ; Cramer, Megan L. ; Shao, Guohong

Use of adeno-associated virus (AAV) to transduce genes into skeletal muscles can be associated with T-cell responses to viral capsid and/or to transgenic protein. Intramuscular mononuclear cell infiltrates primarily consisting of CD8+ T cells and also containing FOXP3+ regulatory T cells were present in rhesus macaque skeletal muscle treated with rAAVrh74.MCK.GALGT2 by vascular delivery. Administration of oral prednisone prior to AAV gene delivery and throughout the study reduced such infiltrates by 60% at 24 weeks post AAV delivery compared with AAV-treated animals not receiving prednisone, regardless of the presence of pre-existing AAV serum antibodies at the time of treatment. The majority of CD8+ T cells in AAV-treated muscles expressed activated caspase 3 and programmed cell death protein 1 (PD1), suggesting ongoing programmed cell death. AAV-transduced skeletal muscles also had elevated expression of programmed death ligand 2 (PDL2) on skeletal myofibers, and this increase in expression extended to muscles where transgene was not overexpressed. These data demonstrate that prednisone can reduce the extent of intramuscular T-cell infiltrates in AAV-treated muscles, which may aid in achieving long-term transgene expression, as may the induction of PDL2 expression on skeletal myofibers to promote PD1-mediated programmed T-cell death.

100 项与 Galgt2 gene therapy (Nationwide Childrens Hospital) 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
杜氏肌营养不良症	临床2期	-	Nationwide Children's Hospital	-
杜氏肌营养不良症	临床2期	-	Sarepta Therapeutics, Inc.	-

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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


NCT03333590 (CTgov)	临床1/2期	杜氏肌营养不良症	2	rAAVrh74.MCK.GALGT2	積顧憲製鑰糧蓋繭夢艱(鑰齋窪艱壓蓋壓淵蓋醖) = 淵鏇顧憲鑰構築齋顧選鑰廠網繭衊夢範廠製糧 (淵選夢製鏇鹹遞蓋遞獵, 範築艱鹹觸製簾構窪鏇 ~ 糧蓋艱糧遞廠鏇鬱鬱壓) 更多	-	2022-04-25