Scientists Achieve First CRISPR Activation Therapy for Cardiac Disease in Mouse Model

In a groundbreaking advancement, researchers from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) along with collaborators from Hospital Universitario Puerta de Hierro and the University of California San Diego have demonstrated the potential of using CRISPR activation (CRISPRa) technology to treat genetic heart conditions in vivo. This pioneering study, published in the European Heart Journal and showcased at the European Society of Cardiology Congress in Madrid, marks a significant step toward targeted genetic therapies for cardiac diseases.

The team focused on a mouse model engineered to carry a truncating mutation in the filamin C gene (FLNC), which is a common cause of inherited cardiomyopathies like dilated and left ventricular non-dilated cardiomyopathy. These conditions are associated with serious arrhythmias and sudden cardiac death, yet current treatment options remain limited to managing symptoms rather than correcting the genetic defect.

By designing a CRISPRa-based gene-activating system encapsulated within a cardiotropic adeno-associated virus (AAVMYO), the scientists aimed to increase the expression of the FLNC gene. Unlike traditional CRISPR-Cas9 gene editing, which cuts DNA, this system activates the gene without introducing breaks. When administered to adult mutant mice, the therapy successfully normalized FLNC RNA and protein levels, restoring proper electrical function of the heart as evidenced by electrocardiogram improvements and the elimination of arrhythmias induced by flecainide.

Dr. Rodrigo Cañas Álvaro, the study’s first author, explained that this approach demonstrates the potential of CRISPRa to reverse disease manifestations even after their onset, offering a promising therapeutic avenue for hereditary cardiomyopathies. Furthermore, Dr. Pablo Garcia-Pavía highlighted its broader implications, suggesting that CRISPRa-AAV therapies could be applied to other cardiac disorders characterized by insufficient production of vital proteins that are undruggable by conventional methods.

This innovative research lays the groundwork for developing precise, gene-specific treatments for inherited cardiac diseases, potentially reducing dependence on life-long symptom management and device implantation. It signifies a major step forward in personalized cardiac medicine, providing hope for future clinical applications.