Guest Column | September 22, 2023

The Regulatory Genome: "Digital Software" For Drug Development

By Samir Ounzain, Ph.D., CEO and cofounder, HAYA Therapeutics

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Over the last decade, the life sciences community has made significant strides in understanding how the regulatory genome influences health and disease. Historically, scientists and drug hunters have focused on the 2% of the genome that encodes for proteins, mainly because it was tractable, easily detectable, and well understood. However, decreases in the cost of parallel high-throughput next-generation sequencing (NGS) have allowed us to uncover all aspects of genomic activity, including the 98% of the traditionally unexplored genome, now known as the regulatory genome.

Today, widely accessible sequencing technologies and multi-omic approaches have allowed us to study the regulatory genome and the RNA unexpectedly produced by this region at depths and magnitudes not previously imaginable. These advances have become drivers in uncovering the genetic variation within the regulatory genome and the underlying biological mechanisms that cause common and chronic diseases.

RNA As Digital Software

Cost-effective, widely available omic-based platforms have revealed many of the fundamental mechanisms of human health and disease. As such, we can begin to shift our mindsets, evolving our concept of biological processes as digital software rather than purely hardware or mechanical. More specifically, we can move away from the mechanical, analog way of thinking about the functional machinery of proteins and begin to take an informational, code-based approach, where RNA is the perfect informational molecule. In this sense, we are changing the paradigm, moving away from a mechanical dogma to a digital dogma.

The regulatory genome and the long non-coding RNAs (lncRNA) produced by it are emerging as the interface between the environment, common genetic variations, and changes in cell state that ultimately drive disease. Furthermore, we know that these genomic components control molecular, biochemical, and cellular pathways at multiple levels, ultimately dictating physiology and pathophysiology.

Beyond Next-Generation Sequencing (NGS): Tapping Technologies To Study The Regulatory Genome

While NGS was a great starting point, allowing us to study RNA as informational and understand the regulatory genome as digital software, there are two other technological breakthroughs or developments that enabled us to make that transition.

The first is Big Data analytics. With the massive amounts of NGS data, the advances in bioinformatics, artificial intelligence, and machine learning have been critical to evaluating the complex layers and levels of the entire regulatory genome.

The next major breakthrough is the advances in chemistry approaches enabling us to create RNA therapeutics. We have reached a point where we can make RNA-targeting and RNA-based therapeutics safer and more stable. The breakthroughs in RNA chemistry have greatly influenced absorption, distribution, metabolism, and biodistribution of antisense oligonucleotides and small interfering RNAs (siRNAs) and the emergence of genome editing based technologies like CRISPR. Scientists now have a comprehensive armory of tools to start targeting the regulatory genome and drugging RNA ready for deployment in the clinic.

With this convergence of omic-based NGS, Big Data analytics, and novel chemistry-based tools, we can discover, curate, and identify targets associated with disease and pathophysiology. This has allowed us to develop efficient RNA-targeting and RNA-based therapeutics that can be rapidly leveraged to modify the regulatory genome.

Reprogramming Disease-Driving Cell States

The regulatory genome and its associated lncRNAs confer specialized activity on all the cells in the body, specifically by driving disease-causing cell states. In fibrosis, for example, the mechanisms and information that cause the transition of fibroblasts into myofibroblasts is unique to every tissue and environmental context. Therefore, a fibroblast turning into a myofibroblast in the heart is regulated differently than in other organs, like the lung or liver, with different characteristics that fit within each tissue-specific microenvironment and environmental and genetic context.

Intrinsically, fibroblasts have a unique identity and mechanism of these transitions that drive disease in specific tissues. This specificity, information, and response to stress for disease-driving cell states in individual tissues is encoded by the regulatory genome and lncRNAs, not from the proteins, which are similar across all the tissues.

Therefore, when compared to messenger RNA (mRNA) or proteins, targeting lncRNAs with therapeutics holds greater potential for more precise and safe disease-modifying therapeutic effects.

Translational Advantage Of Targeting The Regulatory Genome With Therapeutics

From a target product profile and translational perspective, we need a therapeutic to be safe and effective, de-risking toxicological liabilities as the drug moves toward the clinic. The issue with conventional drug discovery is that most drug candidates engage targets in multiple cell types because most targets are mRNA or proteins and, thus, expressed in many tissues. Fortunately, the regulatory genome is exquisitely specific by nature. In particular, we know that lncRNAs regulate epigenetic disease states and are tissue- and cell-specific. From a pharmacological perspective, this specificity makes these molecules a highly attractive target for therapeutic intervention.

Furthermore, we know that many drugs fail in clinical development because their therapeutic window is relatively small, mainly because of this lack of specificity and subsequent off-target effects. To address this challenge, many drug developers will recommend lower therapeutic doses, which can lead to lack of efficacy. By targeting lncRNAs, which are highly tissue-specific and trigger disease-associated cell states, there is minimal risk associated with small therapeutic windows.

Beyond specificity, we also know that lncRNAs have low expression. However, despite these low copy numbers, lncRNAs have significant and potent pharmacodynamic effects due to their unique sub-stoichiometric mechanisms of action. These molecules work through liquid-liquid phase separation biology, where they induce phase separation within compartments inside the cell that drives condensate formation, known as membraneless condensates, which concentrates biochemical activity. Thus, a small amount of RNA can seed the formation of a biochemical hub with very potent regulatory effects.

This attractive property of lncRNAs allows for a relatively low drug dose with a significant therapeutic outcome. In contrast, drugging proteins, protein coding genes, and miRNAs typically requires higher therapeutic doses to saturate the target, leading to a greater potential for off-target effects and chemistry-associated accumulation toxicities.

The Future Of The Regulatory Genome

In essence, disease is caused by cells changing behavior or identity in response to environmental signals or genetic variations. Because the regulatory genome plays an intrinsic, yet specific, role in these cell state transitions, we can create therapeutics that specifically target lncRNAs that are expressed precisely in the disease process. To that end, platforms that focus on identifying targets within the regulatory genome could transform how we discover RNA-based medicines, not just for fibrosis in the heart but for a wide range of conditions from liver to lung disease and cancer.

The field continues to evolve with technologies that can curate, identify, track, and drug the regulatory genome at scale. By taking this approach, we can bring more reliable RNA-based biomarkers to the clinic and deliver targeted therapeutics precisely to cell and tissue-specific targets with greater efficacy and safety.

About The Author:

Samir Ounzain, Ph.D., CEO & cofounder of HAYA Therapeutics, is a molecular biologist exploring the regulatory genome and its role in health and disease. Previously, Ounzain was a project leader and research fellow at the Lausanne University Hospital (CHUV), where his research directly led to the discovery of novel heart-enriched lncRNAs.