How Haya Therapeutics is targeting the dark genome to treat fibrotic disease

When Samir Ounzain watched Jurassic Park at the age of 10, he knew he wanted to become a molecular biologist. Now he has a company that is trying to change the way we think about the so-called dark genome or noncoding DNA.

Previously thought of as “junk” DNA, this part of the genome, which makes up around 98% of our DNA, is now known to have many functions including regulating how our cells work and how genes are expressed.

Ounzain and Daniel Blessing, now chief scientific officer of Haya Therapeutics, cofounded the company in 2021. The initiation of the company, which has offices in the US and Switzerland, was prompted by work in Ounzain’s lab at the University of Lausanne School of Medicine. That work led to the discovery of Wisper (Wisp2 super-enhancer-associated RNA), a long noncoding (lnc) RNA that is responsible for regulating the buildup of scar tissue, or “fibrosis,” in the heart after injury.

The company has developed this discovery into a lead candidate for treating cardiac fibrosis caused by an inherited heart condition called nonobstructive hypertrophic cardiomyopathy, where a buildup of tissue in the heart wall makes it difficult for the heart to fill with blood properly.

The treatment, currently designated HTX-001, is an antisense oligonucleotide, or ASO, that targets Wisper and reduces the buildup of scar tissue in the heart. In May, HTX-001 entered clinical trials for the first time, initially in healthy volunteers.

Ounzain spoke to C&EN about the science behind the company and why it has the potential to revolutionize the way we treat disease.

What are you trying to achieve at Haya?

At Haya we’re listening to what the biology in the genome is telling us about common and chronic disease and leaning into it.

What actually causes a patient to have bad outcomes? If you take that first-principles approach, it’s very clear that these are diseases of broken cell states. And cell states control the architecture and the function of tissues and then organisms.

If you can translate cellular reprogramming through a medicine, you can truly unlock causal biology that drives function and survival outcomes in chronic diseases. If you can speak to the regulatory genome and communicate with it, you can direct cell states.

How does this relate to the dark genome?

Most of your genome is actually transcribed, even though less than 2% codes for proteins. Most of what your genome produces is regulatory RNA, for example, lncRNAs that act as the bridge between your genome and the environment. What we’ve developed at Haya is a platform that allows us to identify those lncRNA targets that bridge the world of the environment and the genome for controlling cell states.

What happened in the last 20 years that allowed the dark genome to become a genuine target for therapies, if “dark genome” is even the right term?

We like to call it the regulatory genome because we’re starting to understand what it does. And, more importantly, we’re starting to make it tractable to therapeutic intervention.

In recent years, converging technologies and data-science approaches have allowed us to start actually seeing the 98% of our genome that doesn’t code for proteins.

We’ve also started to position the cell as the fundamental causal unit of disease-driving processes and [of] the information processing that controls cellular trajectories.

How are you developing your targets?

On the front end of the Haya platform, we have a very large lab in San Diego where we are generating very high-quality multiomic data from patient biopsies and relevant translational animals. We use those data to essentially build our own curations or what we call the HAYAtlas: our own maps of the regulatory genome in a given cell state, in a given disease. We have to use a lot of AI [artificial intelligence] and machine learning to unlock that biology, to integrate it, and to identify causal targets for translation.

What is your lead drug candidate, and how do you see it being used in the clinic?

Our lead asset, HTX-001, now being tested in the clinic at Phase I, was developed to reprogram and have an antifibrotic effect on the activated disease-driving fibroblasts in the heart.

Fibroblasts in the heart, when they become activated, secrete collagen, which makes the heart stiff. But they also have a cross-talk effect where they communicate with the immune and the contractile cells in the heart. If you can reprogram those cells in the myocardium, you can have profound effects on cardiac structure and function.

The indication for this investigational medicine is patients who are symptomatic for nonobstructive hypertrophic cardiomyopathy. That represents between 30 and 50% of the hypertrophic cardiomyopathy disease population, which is about 1 in 500 people. We predict it will be dosed anywhere between 4 to 12 weeks in the long term.

And HTX-001 does this by targeting a lncRNA—what are the risks of off-target effects?

LncRNAs are like the chairpeople of the decision-making processes that control cellular states. We want to identify who’s the chairperson that coordinates these decisions and nudge that chairperson in a specific direction.

I think that’s a unique difference between lncRNAs as targets and any other biomolecules. You can get incredibly potent pharmacodynamic effects on major decisions like silencing an X chromosome, or activating a cell state by a single lncRNA, which you can’t do in the same way by targeting proteins or pathways. Most lncRNAs are cell-type and tissue-state specific. They’ll only ever be expressed in a unique context, so you significantly de-risk exaggerated pharmacology.

That is why we focused originally on fibrosis. Why do we have so much failure in antifibrotic drug development? The answer is that everybody’s been drugging pleiotropic-protein pathways that control fibrosis. They control fibrosis, but they also control many other ongoing processes all over the body.

When you’ve developed an inhibitor of those pathways, often you don’t get the efficacy signal, the reason being that your therapeutic window is so small because of safety. Now imagine if you could reprogram fibroblasts only in a specific tissue, disease, and context systemically. That’s what you can do by targeting these lncRNAs. We can control fibroblast activity only in the heart. Our target, Wisper, is not expressed in fibroblasts or activated fibroblasts anywhere else in the body.

Are there other areas of medicine where you see this might have promise if it works?

Yes, our second core program is in chronic kidney disease. The platform has already delivered development candidates for similar-type targets in pulmonary fibrosis and in fibrosis associated with solid tumors. . . . We’re exploring how to translate those, whether ourselves or with partners.

We have a very exciting collaboration with Eli Lilly and Company using this technology in obesity. I think industry is looking for translationally causal approaches for common and chronic diseases. They’re looking for differentiation and for new biology. You need to move it away from pathways and move it to cells. And our platform really unlocks cellular reprogramming in an RNA-guided fashion.. I think industry is looking for translationally causal approaches for common and chronic diseases. They’re looking for differentiation and for new biology. You need to move it away from pathways and move it to cells. And our platform really unlocks cellular reprogramming in an RNA-guided fashion.

Where do you see this field going in the next 5 to 10 years?

I think that the biology, be that academic or on the industry side, keeps bringing everybody to the same conclusion, which is that 98% of your genome is really the source code for cellular and tissue homeostasis. The opportunities around cellular reprogramming extend way beyond common and chronic diseases. Having the ability in a tractable way to precisely reprogram cellular states really opens up a lot of opportunities.

I think what we need is success. We need some clinical translational proof of concept that this biology can be targeted in a safe and effective way. If Haya and our peers show success over the next 2 to 3 years, I think everybody in the industry will become interested in this approach.