Expression-Functional Correlation and Validation of a Surrogate Marker for DAPC Restoration in a Mouse Model of LGMD2E


Scientific Other

Poster Number: 182


ERIC POZSGAI, Ellyn Peterson, Amber Kempton, Oliver Rogers, YoungEun Seo, Louise Rodino-Klapac, PhD


1. Sarepta Therapeutics, 2. Nationwide Children’s Hospital; Sarepta Therapeutics, Inc., 6. Sarepta Therapeutics

Background: Limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutations in β-sarcoglycan (SGCB) leading to protein deficiency, loss of formation of the sarcoglycan complex, and loss of stabilization of the dystrophin-associated protein complex (DAPC). The sarcoglycans and sarcospan are integral proteins critical for stabilizing the DAPC and providing mechanical support to the sarcolemma. SGCB-/- mice have been shown to concurrently display loss of additional sarcoglycans (α, γ, and δ). Evidence suggests sarcospan may also be lost in the absence of SGCB. Further evaluation of SGCB+/- mice will provide insight into a potential expression-function correlation. Additionally, we hypothesize that other sarcoglycan and sarcospan expression may be able to serve as a surrogate marker for functional restoration of DAPC following SGCB gene transfer.
Objectives: To characterize SGCB+/- mice and assess the ability for SGCB gene transfer to restore sarcoglycan and sarcospan expression in SGCB-/- mice and test their utility as a surrogate marker for DAPC restoration.
Approach: Transcriptional and translational regulation of SGCB along with functional outputs were assessed in SGCB+/- mice. Sarcoglycan and sarcospan protein expression in skeletal and cardiac muscle from untreated and vector-dosed SGCB-/- mice was evaluated by immunofluorescence staining and western blot and compared to functional outputs following gene transfer.
Results: SGCB+/- mice were not found to have any significant dystrophic phenotype and a correlation of expression to function is still being evaluated. Sarcoglycan and sarcospan expression in SGCB-/- was significantly reduced, both of which were restored following SGCB gene transfer.
Conclusions: Preliminary co-localization studies confirmed restoration of the DAPC following SGCB gene therapy. This data suggests the potential for additional sarcoglycans and sarcospan to serve as a surrogate marker for functional restoration of the DAPC.