SUMO1: Therapeutic Target for Heart Failure


Heart failure (HF) represents complex patho-physiological conditions that are often final consequences of various cardiovascular disorders including atherosclerosis, cardiomyopathy, and hypertension.  The incidence of HF continues to grow worldwide.  HF is characterized by contractile dysfunction that is in large part due to abnormalities in sarcoplasmic reticulum (SR) Ca2+ cycling.  SERCA2a is a critical ATPase responsible for Ca2+ re-uptake by cardiac muscle cells during excitation-contraction coupling.  The down-regulation of SERCA2a is one of the primary abnormalities found in failing hearts.  Consistent with this observation, restoration of SERCA2a by gene transfer has proven to be effective in normalizing cardiac function in animal models and humans.


Researchers at the Icahn School of Medicine at Mount Sinai, led by Dr Roger Hajjar have shown that SERCA2a in the heart can be stabilized and its activity increased with a unique and very specific post-translational modification (PTM).  PTM is an important way to modulate the function of diverse cellular proteins by affecting their enzymatic activity, localization, stability, or turnover rates in response to environmental stimuli.  Dr Hajjar and his team showed that SERCA2a can be modified with the small ubiquitin-related modifier SUMO1, via the PTM called SUMOylation where SUMO1 can be conjugated to lysine residues of SERCA2a.  They have found that the SUMO1 level and SUMOylation of SERCA2a was greatly reduced in failing hearts.  SUMO1 overexpression restored impaired cardiac function in failing hearts partly through enhancing enzymatic activity and stability of SERCA2a, whereas SUMO1 down-regulation resulted in cardiac dysfunction. 


The data provide novel insight on the regulation of SERCA2a function by PTM (SUMOylation) and provide the basis for the design of novel therapeutic strategies for HF. These therapeutic strategies are based on gene therapy approaches to enhance SUMO function and newly discovered small molecules that enhance SERCA2a SUMOylation (see dockets 120505 and 120506).


Patent Status: Patent Pending


Keyword: Target

Patent Information:
For Information, Contact:
Maria Gamez
Business Development Director
Mount Sinai School of Medicine
Changwon Kho
Ah Young Lee
Roger Hajjar
Cardiovascular Disease
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