Neuropediatrics 2021; 52(S 01): S1-S53
DOI: 10.1055/s-0041-1739648
Abstract Salzburg

Safety, β-Sarcoglycan Expression, and Functional Outcomes from Systemic Gene Transfer of rAAVrh74.MHCK7.hSGCB in LGMD2E/R4

L. R. Rodino-Klapac
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
,
E. R. Pozsgai
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
S. Lewis
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
D. A. Griffin
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
A. S. Meadows
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
3   Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States
,
K. J. Lehman
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
K. Church
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
N. F. Reash
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
M. A. Iammarino
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
L. P. Lowes
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
,
E. Koenig
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
,
S. Neuhaus
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
,
X. Li
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
,
A. Mueller-York
1   Sarepta Therapeutics, Inc, Cambridge, Massachusetts, United States
,
J. R. Mendell
2   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
4   The Ohio State University, Columbus, Ohio, United States
› Author Affiliations
› Further Information
 

Background/Purpose: Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by mutations in the β-sarcoglycan gene (SGCB), resulting in loss of SGCB protein and other components of the dystrophin-associated protein complex (DAPC). LGMD2E/R4 manifests as progressive hip/shoulder muscle weakness. This first-in-human, phase 1/2 trial (NCT03652259) evaluated SRP-9003, a self-complementary rAAVrh74.MHCK7.hSGCB construct restoring SGCB.

Methods: Patients aged 4 to 15 years with SGCB mutation (both alleles) received 1 SRP-9003 IV infusion: Cohort 1 (n = 3), 1.85 × 1013 vg/kg; Cohort 2 (n = 3), 7.41 × 1013 vg/kg. Endpoints included safety (primary), SGCB expression (secondary), and function (North Star Assessment for Limb-girdle Type Muscular Dystrophies [NSAD], time to rise, 4-stair climb, 100-meter timed test, 10-meter timed test).

Results: We report Year 2 (Y2; Cohort 1) and Year 1 (Y1; Cohort 2) results. As of January 2021, SRP-9003 was well tolerated with no new safety signals since the previous data cut (July 2020). Immunofluorescence showed robust SGCB expression posttreatment, leading to DAPC reconstitution, maintained to Y2 (Cohort 1). Improvements in NSAD and timed function tests were maintained at Y2 in Cohort 1 and Y1 in Cohort 2. Post hoc analysis showed improved NSAD outcomes versus untreated natural history cohort (9.2-point difference, Y2; 95% CI, 3.2−15.1).

Conclusion: Results suggest long-term efficacy of SRP-9003, supporting advancement of the clinical development program.

Funding

This study was funded by Sarepta Therapeutics, Inc.

Conflict of Interest

L.R.R.-K., E.R.P., S.L., D.A.G., A.S.M., E.K., S.N., X.L., and A.M.-Y. are or have been employees of Sarepta Therapeutics, Inc, and may own stock in the company. L.P.L. received fees from Sarepta Therapeutics, Inc, for licensure of the LGMD natural history data set. J.R.M. received financial support from Sarepta Therapeutics, Inc, for travel to meetings to present any products sponsored by Sarepta. K.J.L., K.C., N.F.R., and M.A.I. have no conflicts to disclose. Product is investigational only.

*Presenting on behalf of the authors.



Publication History

Article published online:
28 October 2021

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