Gene therapy for neonatal sarcomeric cardiomyopathies: towards first-in-patient

Homozygous or compound heterozygous truncating mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP?C) cause neonatal cardiomyopathy, which rapidly evolves into systolic heart failure and death within the first year of life. We recently provided evidence of longterm disease prevention by Mybpc3 gene therapy in homozygous Mybpc3?targeted knock?in mice, which genetically mimic human neonatal cardiomyopathies. In the absence of alternative treatment options except heart transplantation, gene therapy is a realistic treatment option for this subset of infants with severe and fatal neonatal cardiomyopathy. Our main objective towards clinical application is to reproduce our mouse findings in a larger animal model. Our gene therapy medicinal product is a recombinant adeno?associated virus serotype 9, which contains the human MYBPC3 cDNA under the control of human cardiac troponin T promoter. The project aims at the generation of a pig model of neonatal cardiomyopathy carrying bi?allelic truncating MYBPC3 mutations with the combination of CRISPR/Cas9 RNA?guide nuclease, somatic cell nuclear transfer and embryo transfer. We expect to produce bi?allelic truncating mutations that will result in a severe, fatal neonatal cardiomyopathy in pigs.