Delving into the Latest Updates on Galgt2 gene therapy (Nationwide Childrens Hospital) with Synapse

Overview

Basic Info

Drug Type

Gene therapy

Synonyms

GalNAc tranferase gene therapies, Galgt2 gene therapy

+ [1]

Target

GALGT2

Mechanism

B4GALNT2 gene stimulants(Beta-1,4 N-acetylgalactosaminyltransferase 2 gene stimulants), Gene transference

Therapeutic Areas

Nervous System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Muscular Dystrophy, Duchenne

Inactive Indication-

Originator Organization

Nationwide Children's Hospital

Active Organization

Nationwide Children's Hospital

Sarepta Therapeutics, Inc.

Myonexus Therapeutics, Inc.Startup

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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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.

01 Sep 2018·Molecular Therapy - Methods & Clinical DevelopmentQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Shao, Guohong ; Hood, Benjamin C ; Chicoine, Louis G ; Cheatham, Sharon L ; Guggenheim, Haley N ; Peterson, Ellyn ; Jia, Ying ; 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.

01 Jun 2017·Human Gene TherapyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with Galgt2 gene therapy (Nationwide Childrens Hospital)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Muscular Dystrophy, Duchenne	Phase 2	-	Sarepta Therapeutics, Inc.	-
Muscular Dystrophy, Duchenne	Phase 2	-	Nationwide Children's Hospital	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03333590 (CTgov)	Phase 1/2	Muscular Dystrophy, Duchenne	2	rAAVrh74.MCK.GALGT2	opkihuvvfv(vhdpnekyuk) = qeprqxzgjz qpfnlwtidi (ildjfrsyyj, fswkmoenqd - xpfxyeytgc) View more	-	25 Apr 2022
ASGCT2021	Phase 1/2	Muscular Dystrophies GALGT2 positive fibers	2	rAAVrh74.MCK. GALGT2	pvljljovzq(vvnxskstvb) = ftgxhumroq ctxewxquto (uciwcmipkn ) View more	Positive	27 Apr 2021
ASGCT2021	Phase 1/2	Muscular Dystrophies GALGT2 positive fibers	2	Placebo	pmkmzlgxrq(gkozdwkojl) = ttyqolyxrn ejyrjoyude (fxnpsjotbq )	Positive	27 Apr 2021