Targeting the Dark Matter of the Genome to Treat Diseases

Episode Summary

Executive Summary: Haya Therapeutics CEO Samir Anzain argues that the “dark genome” — the 98% of DNA that does not code for proteins — contains tissue-specific regulatory RNAs that can be targeted to reprogram disease-driving cell states. The company is advancing an antisense therapy for cardiac fibrosis/HCM and says its platform is broad enough to support a Lilly collaboration in obesity and metabolic disease.

Main Topics: The dark genome as a drug target (Priority: 5/5): Anzain explains that non-coding DNA is increasingly understood as the genome’s regulatory software, controlling cell state, environmental responses, and disease pathways through elements like enhancers and non-coding RNAs. Long non-coding RNAs and mechanism of action (Priority: 5/5): Haya focuses on long non-coding RNAs (lncRNAs) as highly specific regulators that confer sequence/context specificity, scaffold condensates, and modulate epigenetic protein function. Fibrosis and cardiovascular disease as initial focus (Priority: 5/5): The company’s origins are in cardiovascular research, especially fibrosis in heart disease, where Haya identified heart-specific RNAs that drive myofibroblast activation and remodeling. Lead program in hypertrophic cardiomyopathy (Priority: 5/5): Haya’s lead experimental therapy, HTX001, targets a lncRNA called WISPA to reprogram activated cardiac myofibroblasts toward a healthier state and potentially block or reverse fibrosis in HCM and heart failure. Platform expansion into obesity with Eli Lilly (Priority: 4/5): A collaboration with Eli Lilly aims to use Haya’s dark genome platform to find RNA targets in obesity and related metabolic diseases, validating the platform beyond fibrosis. Broader pipeline and financing (Priority: 3/5): Haya also has programs in pulmonary fibrosis and the tumor microenvironment, and it is preparing for additional financing to support near-term clinical proof of concept.

Key Arguments: Most disease-relevant variation for common chronic diseases lies in non-coding DNA, making the dark genome a high-value target space. Long non-coding RNAs provide tissue- and context-specific control, potentially overcoming the lack of specificity that limits protein-targeted anti-fibrotic drugs. Fibrosis is a major unmet need because existing protein-based approaches often have narrow therapeutic windows and fail in late-stage trials. Targeting WISPA with an antisense oligonucleotide can reprogram activated myofibroblasts, reduce fibrosis, and may even reverse established remodeling. The Lilly collaboration suggests Haya’s platform can identify novel disease-modifying targets beyond cardiovascular fibrosis, including metabolic disease. Haya’s strategy is to prioritize indications where cell-state reprogramming and tissue specificity could produce meaningful clinical impact.

Data Points: Human genome non-protein coding fraction: About 98% - Described as the dark genome/non-coding portion of DNA. Genetic variation in common disease located in non-coding DNA: Over 90% - Variation associated with common and chronic diseases lies in junk DNA/dark genome. Risk of illnesses caused by fibrosis: 1 in 3 people - Anzain cites fibrosis as a broad public-health burden. HCM prevalence: 1 in 500 people - Estimated proportion who will suffer from hypertrophic cardiomyopathy. HCM patients diagnosed in the U.S.: Around 700,000 - Current diagnosed U.S. patient population. Non-obstructive HCM patients: Around 300,000 - Subset of HCM patients with fibrosis/diastolic dysfunction focus. Non-obstructive HCM representation: About 30% of HCM patients - Patients who do not have obstruction and have limited treatment options. Heart failure population impact: Around 1 in 10 people - Anzain references broader heart failure burden. Seed financing: $25 million - Haya’s seed round raised just over three years ago. Near-term clinical timeline: 12–18 months - Expected window to enter the clinic if enabling studies go well.

Pivotal Quotes: "the non-coding genome or the junk DNA, it's actually the information processing portion of the genome" — Samir Anzain: Explaining why the dark genome is biologically important rather than inert sequence. "we can start to identify very important regulators of fibrosis or fibroblast activation, but specific to the tissue and the disease context" — Samir Anzain: Describing Haya’s thesis for precision anti-fibrotic therapy. "we may have the ability to also reverse remodel the heart by reversing established chronic interstitial fibrosis" — Samir Anzain: Discussing the potential therapeutic effect of the lead antisense program.

Implications: The interview positions non-coding RNA biology as a credible next wave in precision medicines, especially for fibrotic and metabolic diseases. If Haya’s platform succeeds clinically, it could open a new class of tissue-specific, disease-modifying therapies.