We thank María Sabater Molina and Juan Ramón Gimeno Blanes for the interesting Letter and the opportunity to expand some important points regarding LMNA-cardiomyopathy, MYBPC3 hypertrophic cardiomyopathy, and gene therapy approaches.1

The Letter underscored and clarified the importance of Dr Francis Mojica's contribution to the discovery of CRISPR. It was not our intention to misattribute the discovery of CRISPR but rather to emphasize the first use of the CRISPR/Cas9 complex as a genome editing tool.

Pathogenic variants in the LMNA gene may give rise to several phenotypes, including muscular dystrophy, lipodystrophy, and acrogeria. The cardiomyopathy spectrum encompasses approximately 7% of cases of genetic dilated cardiomyopathy, characterized by atrioventricular block, atrial arrhythmias, left ventricular dysfunction, and ventricular arrhythmias, with a mean age of onset of 40 years.2 In LMNA-H222P iPSC-cardiomyocytes, LMNA shRNA silencing both endogenous alleles and LMNA cDNA and a lentiviral vector normalized the proportion of abnormal nuclei. In a mouse model (KI-LMNAdelK32), systemic administration of AAV2/9 vectors containing human mature lamin A alone or in combination with shRNA targeting p.K32del LMNA mRNA increased maximal survival and lamin A/C protein levels.3

An MYBPC3 gene replacement approach has been developed (TN-201). Preliminary data in Mybpc3-/- mice show that TN-201 improved left ventricular hypertrophy, cardiac function, and lifespan relative to vehicle-treated Mybpc3-/- mice.4 In October 2023, the first patient participating in the Phase 1b trial evaluating the safety of an intravenous infusion of TN-201 was dosed.

We would like to thank the authors and editors again for the opportunity to clarify these important aspects, and eagerly anticipate the emergence of new gene therapy approaches.