In brief

Treatments targeting the SUN1 gene could help patients with dilated cardiomyopathy (DCM) live longer and slow the formation of heart and skeletal defects.

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Remedy for a fragile heart

27 Sep 2022

Experimental gene therapy promises a new lease of life for patients with genetic heart disease.

Whether relaxing by the pool or sweating on a treadmill, every heartbeat involves a perfectly orchestrated sequence of electrical impulses and cellular activity. A dizzying array of proteins work in unison to initiate contractions, and the functional loss of even one can have devastating consequences.

One example is lamin A, a structural protein found in heart cells. In dilated cardiomyopathy (DCM), mutations in the gene encoding lamin A cause the heart’s chambers to weaken, severely compromising cardiac function. Notably, lamin A is a particularly difficult therapeutic target—over 450 different lamin A-associated gene mutations have been reported in DCM patients.

Colin Stewart, a Research Director at the A*STAR Skin Research Labs (A*SRL), has been studying lamins for over three decades and was among the first to establish the proteins’ role in congenital heart disease. In a recent breakthrough, Stewart’s team found a promising lead for DCM therapy.

Using a genetically engineered mouse model lacking the LMNA gene, the gene that encodes for lamin A protein, the researchers found that the absence of the protein triggered a spike in another structural protein called SUN1. Animals with elevated SUN1 levels died of cardiac failure around a month after birth. The team then developed an experimental gene therapy that suppresses SUN1 and administered it to the mice with unexpected results.

“To our immense surprise, we found that the loss of SUN1 made the mice healthier because they lived much longer. It also took longer for the heart and skeletal defects to develop,” said Stewart. The researchers hypothesised that blocking SUN1, prevents the weakened heart cells from being subjected to mechanical stress as the heart contracts.

“Mice that received the gene therapy lived for over a year, instead of a month, and showed good to normal contractile function and reduced tissue scarring,” said Stewart. These findings put SUN1 in the spotlight as an attractive target for treating DCM patients.

Meanwhile, Stewart helped co-found Nuevocor, a spin-off company that raised US$24 million in funding to bring their DCM gene therapy to the clinic. Stewart says ongoing efforts aim to refine the gene therapy’s viral delivery platform.

“We intend to test these new variants in non-human primate models to ensure the gene therapy is delivered to the heart cells and expressed at sufficient levels to be of therapeutic value,” shared Stewart.

The A*STAR-affiliated researchers contributing to this research are from A*STAR’s Skin Research Labs (A*SRL) and Genome Institute of Singapore (GIS).

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Chai, R.J., Werner, H., Li, P.Y., Lee, Y.L., Stewart, C.L. et al. Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy, Nature Communications 12, 4722 (2021) | article

About the Researcher

Colin Stewart has established an international reputation in stem cells and mouse models of disease. His current research programme is on studying a collection of rare diseases (the laminopathies) that are relevant to understanding and developing new therapies for more common ailments, including heart failure, obesity and ageing. In 2012 he made a key discovery that loss of the protein SUN1 significantly ameliorated many of these diseases including heart failure and atherosclerosis. This has been the basis for him being a co-founder of Nuevocor, a Singapore company that is developing new therapeutics to treat these diseases, including novel forms of gene therapy.

This article was made for A*STAR Research by Wildtype Media Group