Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model

Abstract

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

“…Gene replacement strategies using adeno-associated virus (AAV) to deliver a packageable form of dystrophin, called micro-dystrophin, are in numerous clinical trials following decades of preclinical studies demonstrating efficacy in skeletal muscles ( Gregorevic et al, 2004 ; Gregorevic et al, 2008 ; Duan, 2018 ; Crudele and Chamberlain, 2019 ; Ramos et al, 2019 ). AAV-micro-dystrophin also successfully transduces cardiac muscle and improves function in a DMD heart failure mouse model ( Gregorevic et al, 2004 ; Howard et al, 2021a ). However, genetic therapies will not restore normal levels of full-length dystrophin, leaving at least residual inflammation that must be targeted to prevent exacerbation of disease pathology ( Angelini et al, 2022 ).…”

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

“…The absence of an animal model that closely resembles the severity of DMD cardiomyopathy has hindered large-scale and reliable studies of potential therapeutic strategies aimed at ameliorating the dystrophic heart phenotype. Previous studies have described different mouse models displaying worsened heart pathology that were generated by additional genetic manipulations [ 8 ], such as deletion of utrophin in the double mutant mdx /utrn−/− [ 13 , 14 ], which was recently further manipulated to resemble human heart pathology in the Fiona/dko mouse model [ 15 ]. Another strategy was to eliminate or humanize the telomerase gene in mdx mice, as in the mdx/mTR model [ 16 ].…”

Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy

“…The existing animal models for DMD are not appropriate for such a study because they die before the disease progression into cardiopathy. To address this gap, Howard et al ( 143 ) recently developed a dystrophic dko mouse model with transgenic correction of skeletal muscles that progresses into late-stage heart failure over 12 months in a series of steps similar to human DMD cardiomyopathy. Authors showed for the first time that micro-dystrophin effectively prevents cardiac failure in mouse.…”