Heart disease is the leading cause of death globally. Therefore, developing novel ways to treat the rare and/or common forms of the disease is critical. Now, Tenaya Therapeutics, a company focused on heart disease, has published new findings that describe the discovery of histone deacetylase 6 (HDAC6) as a promising therapeutic target. In addition, the preclinical data suggests that a small molecule drug candidate—a selective HDAC6 inhibitor—may be a potential treatment for heart failure.
This work is published in Science Translational Medicine in the article, “Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy.”
“While cardiovascular diseases remain the leading cause of death worldwide, innovation in therapeutic discovery has suffered from the challenge of identifying targets with validation in human tissue that can address underlying mechanisms of heart disease,” said Timothy Hoey, PhD, CSO of Tenaya Therapeutics. “Research presented in this paper highlight the exquisite target selectivity and cardioprotective qualities of our HDAC6 inhibitors. We look forward to advancing TN-301, the first product candidate in our pipeline to be discovered and validated using this approach, into clinical studies.” The approach, adds Hoey, combines disease models based on human cells and machine learning algorithms.
Dilated cardiomyopathy (DCM)—characterized by reduced cardiac output and thinning and enlargement of left ventricular chambers—eventually leads to heart failure. Researchers at Tenaya used induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3) as an in vitro model for DCM.
Using a library of 5500 bioactive compounds and siRNA validation, the team identified that HDAC6 inhibition was shown to protect against the damage of the sarcomere (one of the basic building blocks of heart muscle) in the BAG3-deficient human iPSC-CM models.
They then developed a series of novel HDAC6 inhibitors through medicinal chemistry efforts that included TYA-018 and TN-301, which are structurally and functionally similar. TYA-018 is used in Tenaya’s preclinical in vitro and in vivo studies of HDAC6 inhibition, while TN-301 is being advanced into clinical studies.
The team then translated this finding to a BAG3 cardiomyocyte–knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function.
More specifically, when evaluated in the BAG3 knock-out mouse model of DCM, HDAC6 inhibition with TYA-018 showed selective enzyme inhibition, with greater than 2500-fold preference for HDAC6 over other members of the HDAC family, reduced sarcomeric damage, improved heart dilation, and conferred protection of left ventricular function from rapidly progressive decline.
These findings demonstrate that combining iPSC-CMs with phenotypic screening and deep learning may be able to accelerate drug discovery. Based on this preclinical evaluation, Tenaya hopes to develop TN-301 for the potential treatment of heart failure with preserved ejection fraction (HFpEF). The company plans to submit an IND application to study TN-301 in human clinical studies to the FDA later this year.