Multi Target Drugs for treatment of Heart Failure by stabilization of Ca2+ levels 

Novel Multi-Target drugs, which can modulate two key players of the Ca2+ housekeeping in heart muscle cells were jointly developed at the University Medical Center Göttingen and the MPI-NAT. The substances show increased efficiency over comparable single target RyCal drugs, which are currently under investigation in clinical trials.

Challenge

Cardiovascular diseases are the number one cause of deaths and heart failure is a continuously growing public health problem, affecting almost 40 million people worldwide. In developed countries the prevalence is as high as 1-2% of the general population. However the treatment of cardiovascular diseases and the prevention of Heart Failure is not straight forward, since it is often not based on a single defect or problem, but is a result of a complex interplay in the cellular metabolism pathways. A large part of the Heart Failures result from a dysfucntional Ca2+ metabolism in the heart muscle cells. The two transporters RyR2 (Ca2+ release) and SERCA (Ca2+ uptake) are key-players in Ca2+ cycling and known to be involved in a variety of heart and other diseases. Several therapies are currently under investigation in clinical trials, which target either RyR2 or SERCA, but none of them has proven to be sufficiently effective in stabilizing Ca2+ cycling.

Our Solution

Scientists from the University of Göttingen developed new multi target drugs, acting simultaneously on RyR2 and SERCA2a. First experiments indicate, that a superior efficiency is achieved with lead substances in comparison to drug-candidates, Treatment with substances which are currently under investigation in clinical studies like e.g. Dantrolene. Furthermore the treatment with our dual-target drug-candidate improved both aspects of the Ca2+ transients in Ca2+ cycling. It reduced the delay of the rise time (RyR2 is less leaky) AND acceleration of the decay time (SERCA2a works more efficient). Thus the activity of each protein alone (SERCA and RyR2) needs to be changed only to a smaller amount, avoiding a harsh intrusion into the metabolism of a single machine. Thus unwanted side effects for each drug may be significantly reduced – potentially reducing toxicity.

Figure: Effect of Dual Target Substance on mice after induction of a myocardial infarct.
A myocardial infarct was induced in mice and subsequently they were treated with a dual target drug or with a control substance. Data was collected after three and five weeks after the myocardial infarct. The dual target drug-candidate increased the Cardiac output by nearly 25-36%, while the muscle mass of the left ventricle was increased by 7-10%, depending on the concentration of the drug-candidate.

First in vivo experiments show the great potential resulting from an improvement of the Ca2+ housekeeping, since the regeneration of heart muscle mass and the cardiac output after a myocardial infarction are significantly improvedin comparison to a control group.

Advantages

• Disturbed Ca2+ metabolism participates in numerous heart diseases, which all may benefit from a stabilized intracellular Ca2+ metabolism
• The performance of the heart after an infarct is significantly improved
• Improved regeneration of heart muscle mass after myocardial infarct (compared to control group)
• A single molecule allows simultaneous treatment of two key players in intracellular Ca2+ cycling
• Superior efficiency is proven in Isolated cardiomyocytes and stem cell culture
• IP on newly developed Dual Target compounds for out-licensing

Applications

• A disturbed Ca2+ metabolism in the heart is one of the most striking abnormalities in a wide spectrum of pathologies:
  • Cardiac Hypertrophy
  • Heart Failure
  • Arrhythmia
  • Acquired or Genetic forms of Cardiomyopathy
  • Acute myocardial ischemia/reperfusion injury (e.g. myocardial infarction)

Development Status

Proof of efficiency in functional wt-mice heart cells and in human iPSC-derived cardiomyocytes. Proof of function in living mice. 

Patent Status

• Pending EP-Patent application: positive search report
• International PCT-patent application

References

• Wegener et al. 2023, Life Sci Alliance (doi: 10.26508/lsa.202302278)
• Mitronova et al. 2023, J. Med. Chem. (doi: 10.1021/acs.jmedchem.3c01235)

Contact

Dr. Martin Andresen
Patent Manager Life Sciences
E-Mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel.: +49 551 30724 150
Reference: BioT-2470-UMG

Tags: ARM210, S36, Dantrolene, Ca 2+, Ca2+, SERCA, Ryanodine Receptor, RyR, RyR2, SCD, heart failure, Life science