Grant: Project Grant

Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). It is characterized by a thickening of the heart wall, leading to poor heart function and risks of heart attack. The current standard of care only treats HCM symptoms, and surgical options are highly invasive and only recommended for a subset of the patient population. Recent ground-breaking work has led to the concept of personalized medicine, with a genome editing tool called CRISPR:Cas9 at the forefront. While met with initial success, this approach is limited clinically due to off-target side effects, and thus a method for safe and targeted Cas9 delivery is needed for cardiac regenerative medicine. Focused ultrasound (US) has the potential to revolutionize this approach when combined with US contrast agent. This agent, which consists of small bubbles that vibrate in an US beam, have long been used in clinics for echocardiography. Under specific conditions, they can poke tiny and reversible holes in cells and vessels to allow passage of otherwise impassable agents. The overall program goals are to develop and test focused US cardiac regeneration for HCM using CRISPR:Cas9. First, we will generate a model from human-induced pluripotent stem cells (hiPSCs) and explore US conditions that enable Cas9 delivery and subsequent targeted gene editing. Next, we will develop an image-guided US treatment protocol of our cardiac regenerative medicine platform using murine models. As contrast-enhanced echocardiography is routinely used to diagnose CVD, the development of this dual US imaging and therapeutic platform would dovetail nicely with the regular clinical workflow. As such, we hope to establish the feasibility of US-assisted cardiac gene editing, which has the potential to impact a very large patient population.