Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.

• DOI: 10.17615/6ydv-fq39
• Publication Date: 2023-01-04
• Authors: Sharla M. Birch; Michael W. Lawlor; Thomas J. Conlon; Lee-Jae Guo; Julie M. Crudele; Eleanor C. Hawkins; Peter P. Nghiem; Mihye Ahn; Hui Meng; Margaret J. Beatka; Brittany A. Fickau; Juan C. Prieto; Martin A. Styner; Michael J. Struharik; Courtney Shanks; Kristy J. Brown; Diane Golebiowski; Amanda K. Bettis; Cynthia J. Balog-...; Nathalie Clement; Kirsten E. Coleman; Manuela Corti; Xiufang Pan; Stephen D. Hauschka; J. Patrick Gonzalez; Carl A. Morris; Joel S. Schneider; Dongsheng Duan; Jeffrey S. Chambe...; Barry J. Byrne; Joe. N. Kornegay
• Keywords: 0301 basic medicine; Muscles; Infant, Newborn; Heart; Genetic Therapy; Muscular Dystrophy, Animal; 3. Good health; Dystrophin; Muscular Dystrophy, Duchenne; Mice; 03 medical and health sciences; Dogs; Animals; Humans; Muscle, Skeletal

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by theDMDgene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013vector genomes per kilogram (vg/kg), 1 × 1014vg/kg, and 2 × 1014vg/kg;n= 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day −7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.