Curing genetic heart muscle disease (CureHeart)

Cardiomyopathies are among the most common severe genetic diseases, occurring with a prevalence of 1 in 250 across all populations. They are the leading cause of sudden death in the young and account for about half of all cardiac transplants.

The large majority are autosomal dominant, with childhood or adult onset; the underlying genetics are now well understood.

Genetic testing has been widely adopted, resulting in identification of large numbers of pre-symptomatic mutation carriers.

Current therapies reduce symptoms, and internal cardiac defibrillators abort fatal arrhythmias, but do not protect from heart failure, the major cause of death. There are no disease modifying therapies.

The fundamental disease-initiation mechanisms, either dominant negative or haploinsufficient, are well worked out for the large majority of cardiomyopathies.

We have demonstrated proof-of-concept strategies for selective knockdown of dominant negative alleles, for dealing with the diversity of pathogenic missense alleles, and for editing strategies to either target a haplotype defined by a common variant or to correct the pathogenic variant.

Similarly, for haploinsufficient cardiomyopathies, we have developed proof-of-concept strategies for upregulation of the wild type allele, or restoration of the mutant one.

Our team has contributed significantly to advances in gene editing tools, specifically base and prime editing, and to developing viral vectors and other approaches for cardiac delivery.

We will combine these approaches to develop feasible approaches to halt or reverse established disease and, ultimately, to prevent cardiomyopathy from developing in mutation carriers.

We will develop new strategies to match the right patients and approaches, monitor the effects of therapy, and assess efficacy and safety.

To deliver such transformational advances we have assembled a world-leading multidisciplinary team with exceptional scientists from diverse backgrounds, clinician scientists with expertise in cardiomyopathy, leading industry partners and highly experienced patient advocates and charity representatives.