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  1. Evaluation Summary:

    This paper bears on cardiac pro-arrhythmic findings reported on Duchenne Muscular Dystrophy. iPSC-CMs reprogrammed from cardiomyopathic DMD patients showed a dysfunctional NaV1.5-Kir2.1 channelosome relatable to reduced cardiac excitability and conduction. These findings suggests a possible clinical rescue of this phenotype by introducing the scaffolding protein α1-syntrophin.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  2. Reviewer #3 (Public Review):

    Patient with DMD can have severe arrhythmias. The authors explored the expression of cardiac ion channels and modelled arrhythmogenic behavior in stem cell derived cardiomyocytes from DMD patients. Of particular focus was the Nav1.5-Kir2.1 channelosome. Of three samples (two male, one female) all had reduced sodium current (Ina) and two of three had reduced potassium current (Ik1). In the one stem cell line attempted, transfecting alpha1-syntrophin rescued channel expression and cellular electrophysiological profile.

    The work successfully identifies, for three DMD patients, reduction in two cardiac ion channels previously known to cluster in a channelosome, with particular emphasis on reduced Ina current. The rescue by alpha1-syntrophin supports the mechanism of the putative arrhythmogenic ion channel deficiencies and provides a potential therapeutic pathway. The study is limited by a small samples size of three patients and is confined to the traditional limitations of stem cell derived cardiomyocytes which have limitations relative to mature adult cardiomyocytes or in vivo studies. However, despite these inherent limitations, the findings provide important mechanistic details on DMD arrhythmogenesis and provide a crucial lead for investigators interested in developed therapeutic solutions for a devastatingly lethal disease.

  3. Reviewer #2 (Public Review):

    In the manuscript "SNTA1 Gene Rescues Ion Channel Function in iPSC-CMs from Muscular Dystrophy Patients with Cardiomyopathy and Arrhythmias", authors used DMD donor iPSC-CM to demonstrate electrophysiological dysfunction, specifically pinpointed to the dislocated Nav1.5-Kir2.1 complex, which can be rescued by scaffolding protein a-syntrophin (SNTA1). This model illustrates a very straightforward mechanism of DMD associate cardiomyopathy and offers a feasible/potential treatment. The iPSC in vitro differentiated CM often present with concerns of not resembling rod-shape mature myocytes. This manuscript did an elegant assay by using matrigel-coated PDMS system, yielding morphologically matured myocytes. Beautiful work.

  4. Reviewer #1 (Public Review):

    The strengths of the paper lie in its novelty in relating cardiac to skeletal muscle phenotypes in muscle dystrophic disease. It addresses a well known but poorly understood clinical finding implicating the associated skeletal muscle SNTA deficiency with a NaV1.5-Kir2.1 and consequent cardiac arrhythmic phenotype.

    The study was based on iPSCs from a restricted number of clinical patients. Future studies will need to follow these up using genetically modified animals to determine phenotypes and the whole organ and animal levels.

    This is a well written paper on work of high and interesting quality.