Our heart is the first functional organ and the last to stop. The largest known protein in the human body, titin, is the “giant” supporting our heart to beat for a lifetime. Genetic mutations can disrupt titin’s structure and turn the giant “poisonous.” This poisonous giant can cause thinning and weakening of the heart muscle, resulting in a debilitating disease known as dilated cardiomyopathy (DCM). Patients with DCM are at high risk of heart failure and heart transplantation.
Impact
Gene therapy is an emerging biotechnology with great potential to treat genetic disorders such as DCM. Using adeno-associated viruses (AAVs), which are nano-sized delivery vehicles that enter targeted cells, we can package genes in these AAVs to fix mutations in cardiac cells. Unfortunately, combating the poisonous giant through AAV gene therapy is challenging because titin is too large to fit inside an AAV. To overcome this challenge, we are seeking creative solutions to defeat the poisonous giant.
reNEW research
Our group designed cardiac-specific AAV therapies using a tiny gene that has been shown to play a crucial role in maintaining heart function and health. In stem cell–derived heart models carrying titin mutations, we tested this small but mighty gene therapy — our “David” against the poisonous giant.
Image description
Human stem cell–derived cardiac muscle cells with a titin mutation were treated with an AAV gene therapy. We observed that the AAV treatment successfully delivered the tiny gene, which is shown in yellow. The giant of the heart, titin, appears in magenta. A contractile protein located in the cardiac muscle cells, alpha-actinin, is shown in cyan.
Credits
Yinghan (Winnie) She, PhD Student, James McNamara, Team Leader, Porrello and Elliott Lab, reNEW Melbourne.
