Maya Ellis
Pronouns: she/her
Research Mentor(s): Adam Helms
Co-Presenter:
Research Mentor School/College/Department: Internal Medicine / Cardiovascular Medicine / Medicine
Presentation Date: April 20
Presentation Type: Poster
Session: Session 2 – 11am – 11:50am
Room: League Ballroom
Authors: Joshua Meisner , Sabrina Friedline, Yao-Chang Tsan, Adam Helms
Presenter: 6
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common inherited muscle condition (cardiomyopathy, affecting around 1/500 people. There are limited treatments targeting the molecular mechanisms of HCM and no genotype specific therapies. HCM is most often secondary to genetic variants in cardiomyocyte sarcomeric genes. The most common affected gene is myosin binding protein C3 (MYBPC3) which regulates contractile dynamics between actin and myosin. Truncating or missense variants in MYBPC3 cause autosomal dominant disease from functional protein haploinsufficiency resulting in hypercontractile cardiac mechanics. Gene therapy potentially presents a powerful tool for treating MYBPC3 related HCM to replace loss of function genetic variants. We hypothesized that gene replacement and displacement therapy can correct contractile mechanics in cardiomyocytes differentiated from induced pluripotent stem cells (iPSCs) with MYBPC3 truncating and missense variants. We developed a tetracycline inducible lentiviral vector for use with cardiomyocytes derived from MYBPC3 promotor knock out (MYBPC3-/-, complete loss of MYBPC3) and MYBPC3 missense iPSC lines (MYBPC3mut/mut). MYBPC3-/- cardiomyocytes were transduced with the tetracycline-inducible lentiviral vector and viral toxicity titration and dose titration studies were performed with confirmation of induction of MYBPC3 expression using RT-qPCR. Using these data, we will then test if MYBPC3 replacement in MYBPC3-/- and displacement in MYBPC3mut/mut cardiomyocytes is sufficient to restore normal contractile mechanics using 2 dimensional cardiac muscle bundles that are derived from iPSCs. This work will establish important proof of concept for subsequent translation to clinical therapies.
Biomedical Sciences, Interdisciplinary, Natural/Life Sciences
