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1. It is not clear why the patient with Becker MD is included in Figure 2. However now that it is included it should be pointed out the band is quite faint in Panel 2a and, given the amount of cTnT in that lane, the relative intensity is extremely low. Why is the Becker patient not included in Figure 2b?
1. SNTA1 appears to restore membrane-localization of Nav1.5/Kir2.1 and partially restore AP, INa and Ik1 flow, and other EP parameters. How is contractility and arrhythmia in rescued DMD-iCM? Arrythmia is mentioned in the title but is not shown in the data? 2. iPS-CMs from the female patient had the highest max among the positive patients, yet the lowest CV and lowest Ina,peak . This result is counterintuitive.
These are very important and relevant questions which have led us to conduct new optical mapping experiments. To address the issue of lack of arrhythmia data, we determined whether by rescuing the defective Nagene expression also prevents arrhythmias. These data are presented as new Figure 8 demonstrating that SNTA1 improves conduction velocity toward control , shortens the optical action potential duration.
We agree with the reviewer that the iPSC-CM data derived from the female patient are not as conclusive as we have liked. The results were unexpected even to us, and we recognize that the small number of patients may be a limitation. However, as discussed in the manuscript, one possible explanation is that heterozygous females may have a mosaic of two or more cell types with dramatically different levels of dystrophin expression due to random inactivation of one of the X chromosomes.
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