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).
