REN-001 delivered locally via low-dose retrograde coronary sinus infusion demonstrated robust, diffuse cardiomyocyte transduction in a large animal heart
CAMBRIDGE, Mass.–(BUSINESS WIRE)–Renovacor, Inc. (NYSE: RCOR), a biotechnology company focused on delivering innovative precision therapies to improve the lives of patients and families battling genetically-driven cardiovascular and mechanistically-related diseases, today announced the publication of the results of a preclinical study demonstrating cardiac transduction with low-doses of REN-001 delivered via retrograde coronary sinus infusion (RCSI) in healthy Yucatan pigs. The paper, titled, “Cardiac Transduction in Mini-Pigs After Low-Dose Retrograde Coronary Sinus Infusion of AAV9-BAG3: A Pilot Study,” was published in the peer-reviewed Journal of the American College of Cardiology: Basic to Translational Science (JACC: BTS).
REN-001 is an AAV-based gene therapy designed to directly address the underlying cause of BAG3‑associated dilated cardiomyopathy (BAG3-DCM) by using a validated AAV9 capsid to deliver a functional copy of the BAG3 gene to cardiac tissue. In the pilot Yucatan pig study featured in JACC: BTS, low doses (<1e13 vector genome (vg) per kilogram (kg)) of REN-001 delivered locally to the heart using RCSI resulted in each evaluated cardiomyocyte containing, on average, at least one copy of the delivered BAG3 gene (i.e., vector copy number threshold ≥1). The study also demonstrated diffuse transduction patterns across multiple regions of the heart and documented the presence of vector mRNA / transcript. Additionally, all animals tolerated the procedure without evidence of heart injury (e.g., arrythmia, presence of myocardial scar, or coronary sinus injury at necropsy).
The pilot Yucatan pig study published in JACC: BTS included three dose groups. Group A evaluated a 1.46e12 vg/kg dose, Group B evaluated a 3.45e12 vg/kg dose and Group C evaluated a 7.58e12 vg/kg dose (based on median pig weights for each group). Levels of vector genomes and corresponding RNA transcripts were quantified. A summary of the data is shown below.
|
Group |
Vector Genomes/Porcine Cardiomyocyte (mean ± SEM) |
Vector Transcripts* (Relative Quantities; mean ± SEM) |
|
Group A (n=4) |
0.7 ± 0.2 |
4.1 ± 1.0 |
|
Group B (n=2) |
2.0 ± 0.8 |
9.0 ± 4.5 |
|
Group C (n=1) |
1.3 |
8.5 |
|
*Vector mRNA was assessed using qPCR targeting vector cDNA and expressed as relative quantities (rq) to the 18S housekeeping gene |
“We believe this publication provides important validation of the RCSI delivery method, which is a key differentiator of our REN-001 program,” said Marc Semigran, M.D., Chief Medical Officer of Renovacor and a co-author of the paper. “By delivering vector directly to the heart via the coronary venous circulation using a percutaneously placed catheter, we observed what we believe to be clinically therapeutic levels of cardiomyocyte transduction by our viral vector at lower doses than those used for systemic delivery of AAV gene therapies for other genetic diseases. We believe that RCSI delivery of our gene therapy candidate has the potential to provide safety and manufacturing advantages compared to systemic approaches, which may require higher vector doses to attain similar levels of cardiac transduction as those seen in this animal study. We look forward to advancing REN-001 by using the learnings from the newly published pilot study and are working expeditiously towards a planned IND application submission in the second half of the year.”
Arthur M. Feldman, M.D., Ph.D., Renovacor’s founder, Laura H. Carnell Professor of Medicine at the Lewis Katz School of Medicine at Temple University, and the paper’s senior author added, “The transduction levels achieved with low-dose RCSI in this pre-clinical study are promising and we believe strongly support the advancement of REN-001 into the clinic. Over 80% of BAG3-DCM patients have truncating variants of the BAG3 gene, which reduce levels of functional BAG3 protein in the heart. We believe the data showing successful cardiac delivery and transcription of BAG3 in Yucatan pigs provide strong evidence of REN-001’s ability to potentially correct this genetic abnormality. Given BAG3-DCM’s devastating nature and the lack of effective therapies, this represents an important step toward addressing an urgent unmet medical need.”
This paper was published, in its entirety, in the June 2022 issue of JACC: BTS. The paper will also be published, in its entirety, in the September 2022 issue of JACC: BTS that is dedicated to DNA and RNA cardiovascular therapeutics.
About Renovacor
Renovacor is a biotechnology company focused on delivering innovative precision therapies to improve the lives of patients and families battling genetically-driven cardiovascular and mechanistically-related diseases. The company’s lead program in BAG3-associated dilated cardiomyopathy (DCM) uses gene transfer technology to address the monogenic cause of this severe form of heart failure. Renovacor’s vision is to bring life-changing therapies to patients living with serious genetic cardiovascular and related diseases, by developing medicines that target the underlying cause of disease and provide a transformative benefit and significant improvement to quality of life.
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