You are here

Parkin activators for cardioprotective therapies

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43HL162163-01
Agency Tracking Number: R43HL162163
Amount: $296,932.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-260
Solicitation Year: 2020
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-04-01
Award End Date (Contract End Date): 2023-03-31
Small Business Information
Malvern, PA 19355-1308
United States
DUNS: 190641816
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (610) 644-6974
Business Contact
Phone: (610) 644-6974
Research Institution

Myocardial infarction followed by left ventricular remodeling is the leading cause of heart failure (HF).
Current therapies are inadequate to modulate adverse remodeling and prevent subsequent cardiac failures. As
such there is a critical unmet need to identify new therapies. There is strong evidence suggesting that mitophagy
exerts cardioprotective effects following infarction (MI) and that impaired mitochondrial biogenesis contributes to
HF. Mitochondrial dysfunction reduces energy production, releasing harmful reactive oxygen species and
proinflammatory molecules, which contribute to the ischemic reperfusion injury leading to HF. Regulated and
selective clearance of damaged mitochondria via mitophagy orchestrated by PINK1 kinase and Parkin ubiquitin
ligase, is a key mitochondrial quality control mechanism. Moreover, Parkin has been shown to regulate
mitogenesis by ubiquitinating and degrading PARIS, a key repressor of PGC1, the positive regulator of
mitogenesis. For these reasons, intervention to promote the Parkin-mediated mitochondrial quality control
pathway is a promising therapeutic strategy to prevent or ameliorate post-MI heart failure. Parkin exists in an
auto-inhibited state in cells and is activated by PINK1. Progenra utilized a novel TR-FRET assay and discovered
small molecules that bind and activate Parkin selectively. Consistent with Parkin activation, these Parkin activator
compounds (PACs) degrade Parkin substrates (e.g. PARIS) and potently upregulate mitophagy in various cell
models. In addition, PACs promoted mitochondrial turnover in Mitotimer mice after permanent coronary artery
ligation (PCAL). Most important, administration of PAC (1mg/kg) in mice after PCAL resulted in profound
mitigation of adverse cardiac remodeling and fibrosis leading to improved cardiac function and survival of wild
type mice after PCAL. Thus, we have established preliminary in vivo proof of cardioprotection by PAC. In this
phase I proposal, we will use adult rat primary cardiomyocytes as well as clinically relevant diet-induced obesity
mouse model subjected to PCAL to further evaluate and characterize the cardioprotective role of PACs.
Improvements in cardiac performance, survival, fibrosis, mitochondrial composition and function, and the
landscape of Parkin-mediated ubiquitylome will be determined. In Phase II, we will evaluate long-term safety and
efficacy of PACs in rodent and swine models, particularly their ability to improve cardiac functions post-MI,
attenuate adverse remodeling, and suppress inflammation and fibrosis driven by innate immunity. The ultimate
goal is the development of Parkin activator that can be used to treat post-MI reperfusion injury and prevent heart

* Information listed above is at the time of submission. *

US Flag An Official Website of the United States Government