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Micro-dystrophin gene constructs for repairing heart and muscle function in rats: the smaller is enough?

Gene Therapy volume 29, pages 477–478 (2022)Cite this article

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Duchenne muscular dystrophy (DMD) is the most common and most severe form of muscular dystrophies and it is associated with progressive skeletal muscle degeneration, cardiac arrhythmias and dilated cardiomyopathy with concomitant progressive cardiac fibrosis [1]. Unfortunately, DMD is a lethal disease and patients die in their second or third decade mainly due to cardiac complications [2, 3]. Current medications for DMD is involving corticosteroids which can delay the disease progression but they also cause several adverse effects and other drugs such as RAAS inhibitors and β-blockers are used for delay the progression of cardiac contractile dysfunction [4]. However, DMD is still incurable therefore there is an urgent need for evidence-based therapies to treat and repair skeletal and cardiovascular complications.

DMD is caused by a gene mutation resulting in the total lack of a sub-sarcolemmal protein, called dystrophin. Being a single-gene mutation disease, DMD seemed to be a perfect candidate for gene therapy. However, several obstacles emerged, such as the size of the dystrophin gene resulting in packaging problems and the delivery and administration to target widespread muscles. Nevertheless, the micro-dystrophin (MD) gene constructs of dystrophin and systemic AAV delivery are developed and at least partially restore the gain of function in the animal model of DMD [5]. Furthermore, other novel gene editing technology, namely CRISPR-Cas9 in combination with AAV vector [6, 7] may bring a hope to restore the expression and function of dystrophin protein in DMD patients. Moreover, based on the recent clinical trial, MD constructs of dystrophin even without the carboxy-terminal (CT) domain may be sufficient for restoring the function of dystrophin [8] but as we all know, the devil is in the details.

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  1. Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Vienna, Austria

    Petra Lujza Szabo & Attila Kiss

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  1. Petra Lujza Szabo
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  2. Attila Kiss
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Conceptualisation: PLS and AK; writing, review editing: PLS and AK. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Attila Kiss.

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Szabo, P.L., Kiss, A. Micro-dystrophin gene constructs for repairing heart and muscle function in rats: the smaller is enough?. Gene Ther 29, 477–478 (2022). https://doi.org/10.1038/s41434-022-00337-2

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