Editors' ChoiceGene Therapy

A hop, skip, and a protein away

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Science Translational Medicine  28 Oct 2015:
Vol. 7, Issue 311, pp. 311ec185
DOI: 10.1126/scitranslmed.aad5501

Precision medicine has an ever-growing toolbox to make an immediate impact on monogenic diseases, such as limb girdle muscular dystrophy (LGMD). LGMD is caused by an exon mutation in the gene encoding γ-sarcoglycan protein, a crucial protein in muscle cell membranes. Gao et al. decided to skip right by this mutation using an exon skipping technology, which restored the reading frame and produced an internally truncated protein substitute of γ-sarcoglycan. This so-called “Mini-Gamma” protein—although a little smaller, slightly weaker, and fewer in number—could perform many of γ-sarcoglycan protein's functions. The authors engineered a Drosophila model of muscular dystrophy with a deletion of the γ-sarcoglycan gene. The diseased flies showed improved cardiac function and better motility when Mini-Gamma was expressed, compared with the LGMD mutated γ-sarcoglycan protein. In a human embryonic kidney cells, Mini-Gamma interacted with its appropriate membrane subunits, a vote of confidence that this approach could work in mammals. In vivo in mice, Mini-Gamma localized properly to muscle cell membranes and reduced the thinness of diaphragm muscles, a common symptom of LGMD. The truncated protein even reduced fibrosis and improved cardiac function. To evaluate human relevance, Gao et al. successfully expressed Mini-Gamma in fibroblasts from a LGMD patient.

Sometimes, part of a protein can be enough to reverse disease symptoms. Compared with conventional gene therapy that ultimately expresses a native, whole protein, exon skipping's targeted nature creates a functional, truncated protein. This technique could transform LGMD into the milder Becker form of muscular dystrophy, extending patients' walking time and maintaining muscle strength. However, exon skipping only partially restored the phenotype in prior clinical trials, owing to a lower production level of the truncated protein. Therefore, exon skipping may not be a cure for muscular dystrophy; it's a potential amelioration, and one that still awaits human testing. There is also the challenge to deliver the therapy effectively to several muscle beds to make an impact. Still, a partial correction from a partial protein can make a whole world of difference for LGMD patients.

Q. Q. Gao et al., Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J. Clin. Invest.10.1172/JCI82768 (2015). [Full Text]

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