What we all need to know about the change to come in the way we diagnose, treat and risk stratified patients with cardiomyopathies

This state-of-the-art review by Helms, Thompson and Day is not one to miss. While we have spent the last six decades describing cardiomyopathies by shape, function and the risk associated with their natural history, over the last decade (even more on the last five years) an explosion of data commanded by the advances on genetics and molecular therapeutics is changing way we can treat and will treat cardiomyopathies.

This state-of-the-art paper refers to the three major subtypes of cardiomyopathies, hypertrophic (HCM), dilated (DCM) and arrhythmogenic (ACM).  Emerging therapies are reviewed for novel pharmacological or non-pharmacological approaches targeting specific genetic cardiomyopathies. 

Somatic gene therapy requires the direct delivery of a nucleotide sequence to the target cells.  Modern vectors have overcome issues with efficacy or safety hindering this therapy in the past. Nowadays, retroviral vectors can be used in haematological and immune disorders integrating permanently in the genome. Adeno-associated virus vectors (AAV) are non-integrating and replication deficient and some of the serotypes have a natural heart tropism making them attractive for the development of different gene heart therapies. With Gene replacement therapy (GRT)  the wild-type gene form is transferred by a vector to replace the gene function for  a loss of function gene variant. This mechanism is common for several cardiomyopathy genes, TTN, LMNA, DSP, PKP2, BAG3, FLNC, MYBPC3.  There is currently a GRT clinical trial for LAMP2 truncating variant responsible for Danon disease.

Many problems, limitations, and potential uses of AAV still remain unsolved and the lessons from ongoing trials Duchenne muscular dystrophy (DMD) will shed some light in the near future. Gene silencing therapy (GST) aims to reduce the expression of a mutant gene. It applies mainly to the missense mutations. There are however many biological and technical challenges of GST. The most relevant GST clinical application is in TTR amyloidosis.  Patirisan using silencing RNA therapy is approved for the treatment of TTR amyloid related neuropathy. A trial for the use of this drug for TTR cardiomyopathy (APOLLO-B) is ongoing. Finally direct, genome editing is now conceivable because of CRISP-Cas9 technology. In order to be able to edit the variant without creating another error a replacement strategy needs to be deployed at the same time. This is not yet possible but if overcome could be curative on a single dose. While new vectors are developed, safety and efficacy are improved we are certainly closer to see an increment of the genetic clinical trials for inherited cardiomyopathies with immediate hopes for very severe cases and very rare but high-risk presentations.

Modulators of primary disease response pathway.

This approach investigates the modification of the pathophysiological hallmark of the condition. In HCM, there is a status of hypercontractility while in DCM the opposite happens. Several compounds have been developed to target the contractile status of the cell by modulating the activity of the myosin. Several clinical trials have been or are underway with variable results. Notably, the EXPLORER-HCM trial showed that Mevacamten an allosteric modulator of the cardiac myosin showed compared to placebo a positive effect in the management of LVOTO.

Protein stabilizers or chemical chaperones.

Protein aggregation can result in cardiotoxicity like in cardiac amyloidosis. By using a chemical chaperon several process can be interfered by preventing aggregation, degradation, etc of the proteins.  For example Tafimidis shows efficacy in a phase 3 clinical trial for patients with wyld type and pathogenic variant in TTR.

Protein quality control modulators.

This approach looks to target the cell natural mechanisms for protein homeostasis in order to treat haploinsufficiency. Example of this strategy is the potential use of the HSP70- ubiquitin proteosome dependant pathway to target HCM causes by MYPC3 variants.

Modulation of secondary disease pathways include metabolic modulation, downstream signalling pathways and acting on environmental factors. Diastolic hypertension for example increases the risk of HCM in the presence of a sarcomere mutation or not.

In summary, the treatment of Inherited cardiomyopathies is changing and the potential for new therapies is very promising.