Efficient LAMA1 Gene Activation by Epigenome Editing as a Therapeutic Approach for LAMA2-CMD.

Abstract

Epigenome editing technology holds great promise for treating diverse genetic disorders. In this study, we demonstrate epigenetic activation of thegene for the treatment of-CMD, a severe congenital muscle dystrophy (CMD) caused by biallelic mutations in thegene.is a sister homolog that is known to compensate for the function of. However, supplementingorgene via viral platform is not feasible due to the large size of their coding sequences. Through a single administration of our adeno-associated virus (AAV) vector encoding all the necessary elements for epigenetic activation, we observed significantgene upregulation and phenotype improvements in mouse disease models. The muscle-tropic AAV capsid exhibited desired vector biodistribution and promising pharmacodynamics with good safety profiles in 2-year-old juvenile nonhuman primates (NHPs). Moreover, administration to 8-month-old infant NHPs demonstrated superior pharmacodynamics compared with 2-year-old juveniles, even at half the dose. Our approach holds broad applicability for a range of loss-of-function genetic disorders and could offer a therapeutic breakthrough where active epigenome offers clinical benefit.