Universal Cardiac Mesoangioblasts for treating DMD Dilated Cardiomyopathy

Introduction

Dilated cardiomyopathy (DCM) is the second most common cause of heart failure, currently treated with drugs that delay progress towards heart transplantation.

Current Treatment Challenges

There are currently many attempts to treat DCM with stem cells, their extracellular vesicles, or AAV vectors; however, none have reached efficacy so far.

Applicant's Background

The applicant has a long track record in cell and gene therapy for muscular dystrophy. He pioneered systemic intra-arterial transplantation of mesoangioblasts (blood vessel-derived progenitors) and, thanks to a previous ERC grant, succeeded in creating immortal, universal donor mesoangioblasts.

Immune Response

Edited cells do not activate an immune response in vitro or in vivo.

Connection to Muscular Dystrophy

Muscular dystrophy also affects the heart, causing DCM. However, a simple extension of this strategy is problematic since the existence of resident cardiac stem cells is controversial, and cardiac mesoangioblasts do not spontaneously differentiate into cardiomyocytes.

Promising Alternatives

iPS cell-derived cardiac progenitors are promising but, until now, have been used primarily for localized lesions such as myocardial infarcts.

Proposed Solution

To address this problem, we will produce immortal, immune-privileged cardiac mesoangioblasts and will convert them to cardioblasts through in vitro expression of cardiac transcription factors.

Experimental Approach

Since conversion takes about two weeks, we will test different settings to allow cells to home and differentiate in vivo in the areas of damage, characterized by inflammation.

Future Translation

The applicant is in a unique position to test the feasibility of this project for future translation into a novel clinical protocol.