This is an open-label, dose escalation gene transfer therapy study evaluating the safety of SRP-9004 (patidistrogene bexoparvovec) via isolated limb infusion (ILI) administration in approximately 6 participants with LGMD2D.

Start Date01 Feb 2015

Sponsor / Collaborator

Sarepta Therapeutics, Inc.

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100 Clinical Results associated with Patidistrogene bexoparvovec

100 Translational Medicine associated with Patidistrogene bexoparvovec

100 Patents (Medical) associated with Patidistrogene bexoparvovec

Literatures (Medical) associated with Patidistrogene bexoparvovec

01 Apr 2021·Human Gene TherapyQ2 · MEDICINE

Preclinical Systemic Delivery of Adeno-Associated α-Sarcoglycan Gene Transfer for Limb-Girdle Muscular Dystrophy

Q2 · MEDICINE

Article

Author: Rodino-Klapac, Louise R. ; Peterson, Ellyn L. ; Potter, Rachael A. ; Heller, Kristin N. ; Pozsgai, Eric R. ; Griffin, Danielle A.

Limb-girdle muscular dystrophy type 2D/R3 (LGMD2D/R3) is a progressive muscular dystrophy that manifests with muscle weakness, respiratory abnormalities, and in rare cases cardiomyopathy. LGMD2D/R3 is caused by mutations in the SGCA gene resulting in loss of protein and concomitant loss of some or all components of the dystrophin-associated glycoprotein complex. The sgca-null (sgca^-/-) mouse recapitulates the clinical phenotype of patients with LGMD2D/R3, including dystrophic features such as muscle necrosis and fibrosis, elevated serum creatine kinase (CK), and reduction in the generation of absolute muscle force and locomotor activity. Thus, sgca^-/- mice provide a relevant model to test the safety and efficacy of gene transfer. We designed a self-complementary AAVrh74 vector containing a codon-optimized full-length human SGCA (hSGCA) transgene driven by a muscle-specific promoter, shortened muscle creatine kinase (tMCK). In this report, we test the efficacy and safety of scAAVrh74.tMCK.hSGCA in sgca^-/- mice using a dose-escalation design to evaluate a single systemic injection of 1.0 × 10¹², 3.0 × 10¹², and 6.0 × 10¹² vg total dose compared with vehicle-treatment and wild-type mice. In sgca^-/- mice, treatment with scAAVrh74.tMCK.hSGCA resulted in robust expression of α-sarcoglycan protein at the sarcolemma membrane in skeletal muscle at all doses tested. In addition, scAAVrh74.tMCK.hSGCA was effective in improving the histopathology of limb and diaphragm muscle of sgca^-/- mice, as indicated by reductions in fibrosis, central nucleation, and normalization of myofiber size. These molecular changes were concomitant with significant increases in specific force generation in the diaphragm and tibialis anterior muscle, protection against eccentric force loss, and reduction in serum CK. Locomotor activity was improved at all doses of vector-treated compared with vehicle-treated sgca^-/- mice. Lastly, vector toxicity was not detected in a serum chemistry panel and by gross necropsy. Collectively, these findings provide support for a systemic delivery of scAAVrh74.tMCK.hSGCA in a clinical setting for the treatment of LGMD2D/R3.

100 Deals associated with Patidistrogene bexoparvovec

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Indication	Highest Phase	Country/Location	Organization	Date
Muscular Dystrophies, Limb-Girdle	Phase 2	-	Nationwide Children's Hospital	-
Muscular Dystrophies, Limb-Girdle	Phase 2	-	Myonexus Therapeutics, Inc.Startup	-
Sarcoglycanopathies	Preclinical	-	Sarepta Therapeutics, Inc.	01 Feb 2015
Sarcoglycanopathies	Preclinical	-	Nationwide Children's Hospital	01 Feb 2015

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