Our Science

BAG3-associated dilated cardiomyopathy (DCM) is a rare, genetically driven form of heart failure, which has a high unmet medical need due to no commercially available targeted treatments.

 

BAG3 Biology

BAG3 protein is expressed predominantly in the heart, where it has multiple functions within the cell due to the presence of multiple protein binding sites. BAG3 protein has roles in maintenance of the sarcomeres, normalization of protein quality control, inhibition of programmed cell death, and responsiveness to adrenergic signals. Because BAG3 plays a role in multiple critical myocardial cell functions, we believe gene replacement therapy offers unique potential to directly restore proper cellular function.

diagram

Cardiac contractility
Enhances contractility by linking β-adrenergic receptor and the L-type Ca2+ channel
Structural support
Provides support for the sarcomere by linking actin myofibrils with the Z-disc
Protein quality control
Facilitates autophagy as a co-chaperone with heat shock proteins, recycling misfolded proteins
Anti-apoptosis
Inhibits apoptosis (programmed cell death) through binding of BCL2

Our Disease Focus

DCM patients with a BAG3 mutation are currently treated with standard of care for heart failure and have five‑year survival rates less than 50%. Currently, there are no FDA-approved therapeutic interventions designed to address specific genetic mutations that result in DCM or heart failure.

Cardiovascular Disease is the #1 Cause of Death Worldwide1

Cardiomyopathy
  • Primary disease of the heart muscle and a major contributor to burden of cardiovascular disease
  • Global mortality 300,000 in 2019, up 43% from 19902
Dilated Cardiomyopathy (DCM)
  • Decrease in contractility cause heart’s pumping chambers to enlarge
  • Most common form of cardiomyopathy
Familial DCM
  • 20-50% of DCM patients; up to 40% have identifiable genetic cause2
  • Scientific societies recently endorsed clinical genetic testing for DCM patients and families3,4
BAG 3-DCM
  • Mutations in BCL2-Associated Athanogene 3 (BAG3) gene are among the more common pathogenic genetic variants observed in DCM5
  • BAG3 expression is markedly diminished in patients with severe ischemic or nonischemic DCM6
  1. Centers for Disease Control and Prevention, Weekly Counts of Deaths by State and Select Causes, 2019-2020
  2. American Heart Association Statistical Update: Heart Disease and Stroke Statistics – 2021 Update
  3. Ackerman MJ et al. Heart Rhythm 2011;8:1308 –1339
  4. Musumuru K et al. Circulation: Genomic and Precision Medicine. 2020;13:e000067C
  5. Kirk JA et al. J Clin Invest. 2021;131(16):e149415
  6. Feldman AM et al. J. Cell. Physiol. 2014;229::697–1702.

Gene Therapy for BAG3-Associated DCM

Renovacor has designed its gene replacement therapy to treat BAG3-associated DCM through in vivo delivery of a human BAG3 gene to cardiomyocytes.

 

View Pipeline

 

 

After transducing the cardiomyocyte, the vector translocates into the nucleus, where the BAG3 gene is deposited, allowing the cell’s native expression machinery to initiate transcription of the gene. Unlike wild-type AAVs, REN-001 lacks an S1 domain, which significantly limits the potential for the vector genome to integrate into the host chromosome. Instead, the gene persists in the nucleus as episomal DNA.

The AAV9 vector has been safely and effectively utilized in many human studies and is the basis for an FDA-approved gene therapy.1 This vector preferentially transduces cardiomyocytes, allowing REN-001 to specifically target dysfunction in the heart.

Renovacor’s BAG3 gene therapy has been extensively tested in preclinical models. Key results include:

REN-001 Showed Durable Rescue in DCM Haploinsufficiency Model

 

REN-001 Restored Healthy Phenotype in Post-MI Mouse Model

 

1Zolgensma (onasemnogene abeparvovec xioi), Novartis AG

Publications

 

Feldman, A. M., R. L. Begay, T. Knezevic, V. D. Myers, D. B. Slavov, W. Zhu, K. Gowan, S. L. Graw, K. L. Jones, D. G. Tilley, R. C. Coleman, P. Walinsky, J. Y. Cheung, L. Mestroni, K. Khalili and M. R. Taylor (2014). “Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.” J Cell Physiol 229(11): 1697-1702. – PubMed

Feldman, A. M., J. Gordon, J. Wang, J. Song, X. Q. Zhang, V. D. Myers, D. G. Tilley, E. Gao, N. E. Hoffman, D. Tomar, M. Madesh, J. Rabinowitz, W. J. Koch, F. Su, K. Khalili and J. Y. Cheung (2016). “BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.” J Mol Cell Cardiol 92: 10-20. – PubMed

Knezevic, T. Myers, V.D., Su, F., Wng,J., Song, J., Zhang, X.Q., Gao, E., Gao, G., Muniswamy, M., Gupta, M.K., Gordon, J., Weiner, K.N., Rabinowitz, J., Ramsey, F.V., Tilley, D.G., Khalili, K., Cheung, J.Y., and A.M. Feldman (2016). “Adeno-associated Virus Serotype 9 – Driven Expression of BAG3 Significantly Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction.” JACC Basic Transl Sci 1(7): 646-653. – PubMed

Knezevic, T., V. D. Myers, J. Gordon, D. G. Tilley, T. E. Sharp, 3rd, J. Wang, K. Khalili, J. Y. Cheung and A. M. Feldman (2015). “BAG3: a new player in the heart failure paradigm.” Heart Fail Rev 20(4): 423-434. – PubMed

Myers, V. D., G. S. Gerhard, D. M. McNamara, D. Tomar, M. Madesh, S. Kaniper, F. V. Ramsey, S. G. Fisher, R. G. Ingersoll, L. Kasch-Semenza, J. Wang, K. Hanley-Yanez, B. Lemster, J. A. Schwisow, A. V. Ambardekar, S. H. Degann, M. R. Bristow, R. Sheppard, J. D. Alexis, D. G. Tilley, C. D. Kontos, J. M. McClung, A. L. Taylor, C. W. Yancy, K. Khalili, J. G. Seidman, C. E. Seidman, C. F. McTiernan, J. Y. Cheung and A. M. Feldman (2018). “Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals.” JAMA Cardiol. – PubMed

Myers, V. D., J. M. McClung, J. Wang, F. G. Tahrir, M. K. Gupta, J. Gordon, C. H. Kontos, K. Khalili, J. Y. Cheung and A. M. Feldman (2018). “The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease.” JACC Basic Transl Sci 3(1): 122-131. – PubMed

Myers, V. D., D. Tomar, M. Madesh, J. Wang, J. Song, X. Q. Zhang, M. K. Gupta, F. G. Tahrir, J. Gordon, J. M. McClung, C. D. Kontos, K. Khalili, J. Y. Cheung and A. M. Feldman (2018). “Haplo-insufficiency of Bcl2-associated Athanogene 3 in Mice Results in Progressive Left Ventricular Dysfunction, beta-Adrenergic Insensitivity and Increased Apoptosis.” J Cell Physiol. – PubMed

Rosati A, Khalili K, Deshmane SL, et al. “BAG3 protein regulates caspase-3 activation in HIV- 1-infected human primary microglial cells”. J Cell Physiol. 2009 Feb;218(2):264-7. – PubMed

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