Beyond Protein Targets: Why The Regulatory Genome Could Redefine RNA Medicine (Pt. 1)

A conversation with Samir Ounzain, Ph.D., CEO & Scientific Cofounder, HAYA Therapeutics

For decades, modern drug discovery has been built on a simple premise: identify the protein driving disease and develop a therapy to modulate it. That strategy has produced countless breakthroughs, but it has also revealed important limitations, particularly for complex chronic diseases where dysfunction arises not from a single protein but from changes in cellular identity and gene regulation. Increasingly, researchers are turning their attention to the regulatory genome — the vast network of non-coding DNA and RNA that determines when, where, and how genes are expressed. As advances in genomics, single-cell biology, artificial intelligence, and RNA therapeutics converge, many believe this previously overlooked layer of biology could redefine how we understand and treat disease.

In Part 1 of his conversation with Life Science Connect Acquisition Editor Michael Soloway, HAYA Therapeutics CEO and scientific cofounder Samir Ounzain, Ph.D., explains why the regulatory genome has become one of the most exciting frontiers in RNA medicine, the central role of long non-coding RNAs (lncRNAs), and how cell state reprogramming could shift therapeutic intervention from treating disease pathways to addressing the underlying biological programs that drive them.

ARNA: For decades, drug discovery has largely focused on proteins as therapeutic targets. What has driven the industry's growing interest in the regulatory genome, and why do you believe this shift is happening now?

SO: The industry is increasingly following the evidence. Chronic diseases are rarely explained by a single defective protein. Predisposition to many diseases sits outside protein-coding genes and within the regulatory genome that influences how particular cells respond to stress, injury, inflammation, metabolism, and aging. The emerging picture is that disease arises when cells become locked into maladaptive states.

The regulatory genome is the operating layer that determines which genes are expressed, when, where, and in response to which context. LncRNAs, in particular, can act as highly contextual regulators of the networks that stabilize cellular identity.

Advances in human genetics, multiomics, single-cell technologies, and AI allow us to resolve regulatory biology at unprecedented depth, while the maturation of RNA medicines gives us a practical way to intervene.

ARNA: When you refer to the "regulatory genome," what exactly does that encompass, and how does it differ from the way most scientists and drug developers have traditionally thought about disease biology?

SO: The regulatory genome encompasses the non-protein-coding elements and molecular systems that determine when, where, and how genes are used, including enhancers, promoters, chromatin architecture, transposable elements, and regulatory RNAs. These form an information processing layer shaping cell identity and behavior.

RNA is a central substrate of this system. LncRNAs, in particular, can interact with DNA, RNA, and proteins to organize transcriptional and epigenetic machinery. Some lncRNAs sit high in the regulatory hierarchy and help stabilize entire cell states. They can determine whether a cell repairs, regenerates, or becomes locked into a pathological state.

Traditionally, we’ve reduced disease to a defective protein or linear pathway. That framework is productive in monogenic disease, but not suited to conditions such as heart failure, kidney disease, and cancer. The central pathology is often not one broken component but a cell that has adopted the wrong identity and remains trapped there – a fundamentally different way of thinking about disease.

ARNA: Much of modern medicine has focused on treating downstream disease pathways. How does targeting the regulatory genome create opportunities to intervene further upstream in disease processes?

SO: Downstream pathways are important, but they are shared across tissues, making them difficult to modulate without affecting normal physiology. Targeting the regulatory genome allows us to move closer to the point at which disease is actually being programmed and the pathological cell state wired.

By targeting high-hierarchy regulatory elements such as lncRNAs, we can potentially remove the molecular constraints that maintain that pathological state. The aim is to reset the upstream program and allow cells to return to a healthier state. This gives the opportunity to move from managing the consequences of disease to intervening in the cellular logic that generates and sustains it.

ARNA: LncRNAs have emerged as a particularly exciting area of research. What role do lncRNAs play in regulating cellular behavior, and why do you believe they represent an attractive therapeutic opportunity?

SO: My academic career was devoted to understanding lncRNAs in heart development and disease. What struck me early was that many of the most interesting lncRNAs were absent from existing annotations, expressed in specific cell types, and influencing fundamental physiological traits such as cardiac structure, function, and repair. These molecules were not transcriptional noise but part of the regulatory architecture controlling cellular identity.

LncRNAs act as scaffolds, guides, and organizers of chromatin regulators, transcription factors, and biomolecular condensates, helping determine when and where entire gene programs are activated. These molecules act as “chairpersons” of cellular decision-making: they may be present at relatively low abundance, but through sub-stoichiometric mechanisms they can organize much larger molecular assemblies and exert control over cell state.

This creates a highly attractive therapeutic opportunity. Compared to broadly expressed proteins, lncRNAs are more restricted, giving us the possibility of targeting the regulatory program driving pathology while preserving normal biology elsewhere.

RNA therapeutics also allow us to recognize lncRNAs through sequence-specific base pairing and modulate them in a controlled, reversible manner. The combination of high biological leverage, exceptional contextual specificity, and a clinically validated therapeutic modality is what led us to establish HAYA.

ARNA: Many RNA therapeutic approaches focus on replacing, silencing, or editing genes. How does targeting the regulatory genome differ from these strategies, and what unique advantages might it offer?

SO: Many current RNA medicines can be highly effective when disease is driven by a discrete genetic defect. However, by targeting lncRNAs, we are not changing the level of a single downstream protein. We are intervening at high-hierarchy control points. The objective is to release pathologically locked cells and allow their endogenous regulatory machinery to move back toward a healthier state.

Compared to gene editing approaches, we are not making a permanent change. Using antisense oligonucleotides (ASOs), we can modulate regulatory RNAs in a sequence-specific tunable and reversible manner. That provides precise control over the magnitude and duration of the therapeutic effect.

ARNA: HAYA has often described its approach as one of cell state reprogramming. What does that concept mean in practice, and how could it change the way we think about treating complex diseases?

SO: Cell state reprogramming starts from the recognition that cellular identity is not fixed, and is more plastic than once believed.

At HAYA, we are not trying to erase a cell’s identity, force it into an artificial lineage, or push it back to an embryonic state. In complex disease, the relevant cell has retained its basic identity but has become locked into a maladaptive state. For example, a fibroblast can remain persistently activated and drive fibrosis, inflammation, and tissue remodeling long after the original injury has passed.

We aim to identify the regulatory genome mechanisms that stabilize that pathological state and selectively release the lock.

In Part 2, we’ll explore how these ideas translate into drug discovery, fibrosis, AI-driven target identification, delivery, and what regulatory genome medicine means for the future of RNA therapeutics.

About The Expert

Samir Ounzain, Ph.D., is a molecular biologist and entrepreneur with over 20 years of experience exploring the regulatory “dark matter” of the human genome. As CEO and cofounder of HAYA Therapeutics, he is pioneering a new class of precision RNA medicines that target long non-coding RNAs (lncRNAs) to reprogram the root causes of disease — at the level of cell state. Under his leadership, HAYA has grown from foundational discovery to platform-enabled execution, securing top-tier venture backing and forging transformative partnerships, including one of the largest collaborations to date in the regulatory genome space with Eli Lilly and Company. This alliance is focused on uncovering novel lncRNA targets for the development of new therapies in obesity and related metabolic diseases. Ounzain’s vision is to build a future where medicine is programmable, preventative, and patient-centric — powered by real-time interaction with the regulatory genome. He was named among the top innovators on The Power List 2025 in the Advanced Medicine category by Medicine Maker. Before cofounding HAYA, Ounzain was a project leader and research fellow at Lausanne University Hospital (CHUV), where he led the discovery of hundreds of novel cardiac-enriched lncRNAs, including CARMEN, Meteor, and WISPER — the latter forming the scientific and therapeutic foundation for HAYA’s lead program.