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Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B
Daniel C. Bittel, … , Jack H. Van der Meulen, Jyoti K. Jaiswal
Daniel C. Bittel, … , Jack H. Van der Meulen, Jyoti K. Jaiswal
Published January 4, 2022
Citation Information: J Clin Invest. 2022;132(1):e141295. https://doi.org/10.1172/JCI141295.
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Research Article Muscle biology Article has an altmetric score of 132

Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B

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Abstract

Efficient sarcolemmal repair is required for muscle cell survival, with deficits in this process leading to muscle degeneration. Lack of the sarcolemmal protein dysferlin impairs sarcolemmal repair by reducing secretion of the enzyme acid sphingomyelinase (ASM), and causes limb girdle muscular dystrophy 2B (LGMD2B). The large size of the dysferlin gene poses a challenge for LGMD2B gene therapy efforts aimed at restoring dysferlin expression in skeletal muscle fibers. Here, we present an alternative gene therapy approach targeting reduced ASM secretion, the consequence of dysferlin deficit. We showed that the bulk endocytic ability is compromised in LGMD2B patient cells, which was addressed by extracellularly treating cells with ASM. Expression of secreted human ASM (hASM) using a liver-specific adeno-associated virus (AAV) vector restored membrane repair capacity of patient cells to healthy levels. A single in vivo dose of hASM-AAV in the LGMD2B mouse model restored myofiber repair capacity, enabling efficient recovery of myofibers from focal or lengthening contraction–induced injury. hASM-AAV treatment was safe, attenuated fibro-fatty muscle degeneration, increased myofiber size, and restored muscle strength, similar to dysferlin gene therapy. These findings elucidate the role of ASM in dysferlin-mediated plasma membrane repair and to our knowledge offer the first non–muscle-targeted gene therapy for LGMD2B.

Authors

Daniel C. Bittel, Sen Chandra Sreetama, Goutam Chandra, Robin Ziegler, Kanneboyina Nagaraju, Jack H. Van der Meulen, Jyoti K. Jaiswal

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Figure 3

hASM rescues bulk endocytosis deficit in the LGMD2B patient cells.

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hASM rescues bulk endocytosis deficit in the LGMD2B patient cells.
(A) S...
(A) Schematic showing the assay used to monitor bulk endocytosis. (1 and 2) The plasma membrane was labeled with fluorescent WGA, and (3) membrane endocytosis was monitored over a 3-minute period by (4) quenching the WGA fluorescence at the cell surface by using bromophenol blue (BPB) at the end of endocytosis period. Punctate fluorescence in the cell, not quenched by BPB, marks the internalized WGA localized in endosomes. (5) Internalized WGA fluorescence was expressed relative to the baseline labeling prior to quenching. (B) Confocal image of mouse myoblast labeled with WGA at baseline and after 3 minutes of endocytosis in untreated and hASM-treated cells. (C) Plot showing the effect of different doses of hASM on bulk membrane endocytosis in mouse myoblasts. (D) Confocal images showing fluorescent WGA–labeled healthy and patient myoblasts at baseline (left panel) and after 3 minutes of endocytosis (right panel). (E) Plot showing quantification of bulk endocytosis by healthy and LGMD2B patient muscle cells and the effect of hASM on patient cell endocytosis (n > 2 experimental repeats per condition). All data are presented as mean ± SEM. *P < 0.05 (vs. untreated cells), assessed via 1-way ANOVA with Tukey’s HSD post hoc test (C and E). Scale bars: 10 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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