Researchers at The Jackson Laboratory for Genomic Medicine have developed a potential new treatment for dilated cardiomyopathy (DCM), a sometimes fatal heart condition that affects as many as one in 200 adults worldwide.
In a study published in Circulation, JAX Associate Professor J. Travis Hinson, M.D., and his colleagues revealed a new CRISPR-based treatment that restores levels of the TTN (titin) protein, which is important in the contraction of striated muscle tissues such as those found in the heart. CRISPR is a gene editing technology that enables scientists to easily modify the DNA in living cells.
DCM is diagnosed when the left ventricle, the main pumping chamber in the heart, is dilated and has reduced contractile function. The dilation often spreads to the right ventricle and the atria, the heart’s upper chambers, limiting the heart’s ability to contract normally and sufficiently pump blood to the rest of the body. Many of the current treatments for DCM serve only to manage the condition or slow its progression, necessitating more effective therapies.
Titin truncation variants (TTNtvs), which produce shortened, dysfunctional versions of the titin protein, are the most common genetic lesion in individuals with DCM, occurring in 15 to 25% of patients. TTNtvs also reduce normal titin levels and impair the function of sarcomeres, the smallest functional unit of striated muscle tissues that drive the heart’s contraction. Because of the immense size and complexity of the TTN gene, therapeutics that target TTNtvs have been difficult to develop.
To overcome this obstacle, Hinson used a CRISPR-based approach involving an RNA -guided enzyme that was reprogrammed to function as a transcriptional activator, increasing expression of the TTN gene and production of the titin protein. In cardiac muscle cells and cardiac microtissue models carrying one normal copy of the TTN gene and one TTNtv, the method restored titin protein levels and established the feasibility of increasing overall titin levels to treat DCM.
One leading hypothesis in DCM is that a single wild-type TTN allele produces insufficient titin protein levels, thus driving the development of the disease. Hinson’s studies revealed that using CRISPR to activate expression of TTN reversed haploinsufficiency, a situation in which having only a single functional copy of a gene is not sufficient for normal function. Additionally, the CRISPR system normalized sarcomere content and improved the cardiac cells’ ability to contract.
Because this approach reversed TTNtv-related haploinsufficiency and normalized levels of the titin protein, Hinson’s findings suggest that CRISPR therapy could be developed to treat a large proportion of individuals with DCM who carry TTNvts that result in reduced titin protein levels.