Therapeutic upregulation of gene expression in inherited cardiomyopathies from current approaches to future directions

Abstract

A substantial proportion of inherited cardiomyopathy cases are driven by mechanisms of haploinsufficiency, where a loss-of-function variant in one allele leads to insufficient protein expression, resulting in loss of normal cardiac function. Current therapies treat symptoms or mitigate risk of complications and do not prevent disease onset or progression. Recently, substantial advances have been made in gene therapies for cardiomyopathies in both preclinical and clinical settings, particularly using viral delivery of whole genes and gene-editing approaches. Alongside these is an emerging area of therapies that aim to upregulate endogenous gene expression. This encompasses a broad array of strategies that may act by removing gene repression or directly enhancing expression, can enhance transcription or translation and may use a variety of modalities such as gene editing or oligonucleotides. Here, we review the mechanisms and current uses of gene upregulation strategies and critically evaluate their advantages and limitations as therapies for inherited cardiomyopathies. Inherited cardiomyopathies caused by haploinsufficiency are promising targets for therapies that restore endogenous gene expression. In this Review, Kirk et al. discuss emerging gene upregulation strategies, evaluate their mechanisms, therapeutic potential and challenges for preventing disease progression.