Addressing the irreversible loss of cardiomyocytes: a regenerative strategy for the injured heart
Myocardial infarction leads to the irreversible loss of cardiomyocytes. In adult humans, these cells are terminally differentiated and lack the ability to proliferate. Following injury, the heart forms non-contractile fibrotic tissue, permanently impairing its mechanical function. This biological limitation is a primary driver of chronic heart failure, a condition that affects over 64 million patients worldwide and for which current pharmacological and interventional therapies remain palliative rather than curative.
Despite decades of innovation, no therapeutic approach to date has succeeded in regenerating functional myocardium in situ.
Death of Cardiomyocytes and scar tissue formation (Acute Myocardial Infarction)
Cardiomyocyte loss leads to adverse cardiac remodelling and heart failure
Cardiomyocyte proliferation is physiologically active during embryonic and early postnatal development. However, this regenerative capacity is rapidly and permanently silenced within the first days of life. In adults, cardiomyocyte turnover is minimal (<1% per year), and insufficient to compensate for acute or chronic loss.
This phenomenon stands in contrast with the remarkable regenerative abilities observed in other vertebrates—such as zebrafish and axolotls—where cardiomyocyte proliferation persists throughout life. These comparative models suggest that regenerative pathways are not absent in the mammalian heart, but rather transcriptionally repressed or epigenetically silenced.Heqet Therapeutics has identified a set of endogenous, non-coding RNAs—specifically microRNAs (miRNAs)—capable of reactivating cardiomyocyte proliferation.
These miRNAs stimulate a regenerative program primarily via activation of the Hippo/YAP signaling axis. Molecules such as miR-199a-3p and miR-33b* promote nuclear translocation of YAP by directly suppressing upstream inhibitors (e.g., TAOK1) and modulating actin cytoskeletal dynamics.
miRNAs
miR-199a-3p
miR-1825
miR-33b*
LNPs
Undisclosed
Target Indications
STEMI
HFrEF
In preclinical models, transient delivery of these miRNAs induced cardiomyocyte cell cycle re-entry, DNA synthesis, mitosis, and cytokinesis—providing robust evidence of functional proliferation in post-mitotic cardiac tissue.
The use of miRNAs offers several key advantages. First, they are naturally encoded in the human genome and act by restoring intrinsic biological programs rather than introducing exogenous genes or cells. Second, their transient expression profile reduces the risk of uncontrolled proliferation or tumorigenesis. In fact, the miRNAs selected by Heqet have demonstrated favorable safety characteristics, including anti-oncogenic activity in multiple cellular contexts.
This approach contrasts with cell-based therapies or tissue engineering, offering a simpler, more controllable, and more physiologically relevant alternative.
To enable clinical translation, Heqet has developed a proprietary lipid nanoparticle (LNP) platform optimized for myocardial delivery. These LNPs encapsulate the therapeutic miRNAs and can be administered via catheter-based techniques already established in interventional cardiology, including intracoronary infusion and endocardial injection.
This targeted delivery strategy allows for local activation of regenerative pathways within the myocardium, minimizing systemic exposure and off-target effects.
By reactivating the proliferative capacity of endogenous cardiomyocytes, Heqet’s approach addresses a fundamental limitation in cardiac biology. Our goal is to transform post-injury care from symptomatic management to true myocardial repair.
This work represents a step forward in regenerative cardiology: a new class of RNA-based therapeutics designed to restore form and function in the human heart
The need to develop novel therapies for heart failure consequent to myocardial infarction is impelling
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Key publications
Mauro Giacca
May 2019
Mauro Giacca
May 2019
