Therapeutic Compounds Inhibiting DUSP5 and DUSP6 for Cardiomyocyte Proliferation and Cardiac Regeneration

Application

Therapeutics using siRNAs and small molecules to treat congenital heart defect and myocardial injuries.

Key Benefits

  • Reactivates cardiomyocyte (CM) cell replication, allowing regeneration of heart muscle after cardiac injuries.
  • Therapeutic compounds may be administered for transient regeneration/repair of heart muscle after cardiac injuries.

Market Summary

Approximately 50% of people who develop congestive heart failure will die within 5 years of diagnosis, a death rate similar to some cancers. Because adult humans fail to regenerate heart tissue, a cure for heart failure must include translatable strategies to rebuild heart muscle lost due to an acute ischemic event, or to build heart muscle in patients with depressed left ventricular (LV) systolic function due to a variety of causes. Current pharmacologic interventions and available surgical treatment options fail to restore damaged heart tissues. Therefore, a novel molecular pathway of CM replication needs to be elucidated to develop strategies for treatment to promote rebuilding of heart muscles.

Technical Summary

Emory researchers investigated cardiac biology of the developing postnatal heart and identified a novel molecular pathway of CM cell replication. They also identified compounds to inhibit dual specificity protein phosphatase 5 (DUSP5) and DUSP6 to promote heart regeneration through cardiomyocyte (CM) proliferation by activating cell cycle re-entry. They identified T3 (thyroid hormone) as a unique CM mitogen that induces growth factors as well as amplifies its mitogenic response, and also found that DUSP5 and DUSP6 inhibit ERK1/2, the last step of the T3 signaling pathway for cell cycle re-entry. Collectively, direct inhibition or indirect suppression of DUSP5/6 could be a useful strategy to allow a mitogen to induce CM replication for therapeutic cardiac regeneration. Both compounds, siRNAs for acute DUSP5 knockdown and metroprolol, a Β1-addrenergic receptor (AR) antagonist, promote cell replication and build heart muscle in combination with a CM mitogen such as T3. Administration of these therapeutic compounds after myocardial injuries will enable building or rebuilding of heart muscle in patients suffering from chronic heart dysfunction due to variety of cardiomyopathies and in all ages.

Developmental Stage

Combination of Metroprolol XL with T3 in 1-month post-myocardial infarction (post-MI) mice with depressed left ventricle ejection fraction (LV EF), produced a 2-fold increase in EF, almost normalizing systolic heart function to the pre-MI level.

Publications: Tan, L. et al. (2019). Scientific Reports, 9(1), 17731.

Patent Information

App Type Country Serial No. Patent No. File Date Issued Date Patent Status
Nationalized PCT - United States United States 17/268,590   2/15/2021   Pending
Nationalized PCT - Foreign EP 19849768.7   3/15/2021   Pending
Tech ID: NCS.26
Published: 4/22/2020