If you still think that “junk DNA” is junk or that long noncoding RNAs (lncRNAs) are just a bunch of superfluous genome nonsense, well, you’re in for a rude awakening.
Clue #1: Big Pharma has made significant investments in this field, notably Eli Lilly in HAYA Therapeutics for up to $1 billion and Bayer in Dana-Farber spinout NextRNA for up to $547 million.
Clue #2: The FDA has granted Orphan Drug Designation (ODD) to antisense oligonucleotide (ASO) drug programs that target lncRNAs that are already in the clinic, including CAMP4 Therapeutics’ candidate for urea cycle disorders (UCDs) and Ionis Pharmaceuticals’ candidate for Angelman syndrome, the latter of which is in Phase III.
Clue #3: More clinical programs are marching to the clinic, the latest of which is the (aforementioned) HAYA Therapeutics.
HAYA Therapeutics today announced a $65 million Series A funding led by Sofinnova Partners and Earlybird Venture Capital (with a syndicate including Eli Lilly) to advance the clinical development of their heart failure lead candidate and expand their platform targeting the regulatory genome. Leading HAYA’s preclinical pipeline is HTX-001, an antisense oligonucleotide designed to target the lncRNA, WISPER, which has been shown to be a master regulator of cardiac fibroblast cell state. HTX-001 is currently in Investigational New Drug (IND)-enabling studies for the treatment of non-obstructive hypertrophic cardiomyopathy (nHCM).
“We’re very close to entering the clinic with our lead program,” Samir Ounzain, PhD, co-founder and CEO of HAYA Therapeutics, told Inside Precision Medicine. “This Series A is really to finance our clinical proof-of-concept study. We plan to enter the clinic at the start of the next year.”
HAYA will showcase its latest advances in an invited presentation focused on HAYA’s lead program at ASCGT 2025.
Cell state thesis of complex diseases
HAYA’s therapeutic approach is rooted in unraveling the riddle of the multifactorial nature of complex disease pathology. Ounzain believes that the solution lies in understanding the first principles of the indications in question and not by pushing the latest and greatest therapeutic technology, cautioning that relying solely on the latest therapeutic modality advancements is not the solution to complex diseases and can lead to blinders.
“We need tractable medicines for complex diseases fast, but there’s been so much focus on modality in technology, we’ve in some ways been missing the forest for the trees,” said Ounzain. “These diseases are not Mendelian traits with a single protein target. These are the cells that are driving the disease. It’s cellular behavior, which is multifactorial. It’s on a different dimension to, I would say, individual proteins and individual pathways.”
Ounzain added, “Ultimately, you have to target the right biology, and when looking at these common and chronic disease indications, there are huge opportunities if you take a first principles approach. We understand that common genetic variation and environmental factors are changing the identity of cells, which ultimately drives the pathophysiology behind many of these processes. So, let’s focus on those first principles.”
For many years, Ounzain and HAYA co-founder Daniel Blessing, PhD, have been investigating regulators of cell identity and states that are driving complex diseases. This led them to look at the world of lncRNAs—and that’s backed by some pretty good reasons. First, complex diseases require more than patching up a pathway by targeting a single gene. Second, most genome-wide association studies (GWAS) point to disease-associated variants falling into noncoding regions.
All that together has led Ounzain and HAYA on a path built around one core question. “We’re asking the question, ‘When you holistically understand the activity of the regulatory genome in response to environmental stimuli that are transforming cell states, what is the dark genome telling us and where are the causal loci within the dark genome that allow you to reprogram the cell state?’” said Ounzain. “We can think about this multidimensional intervention through the integrated activity of the regulatory genome. So, we’re taking the holistic approach to cell state reprogramming and not focusing on individual lncRNAs associated with one gene in haploinsufficiency or an antisense lncRNA regulating a protein-coding gene.”
Ounzain started investigating heart diseases and found the lncRNA WISPER, which is expressed in heart cells and in higher amounts in people with HCM. Research from Ounzain and HAYA has shown that high WISPER expression drives excessive interstitial fibrosis, which is thought to contribute to the underlying pathophysiology of HCM, especially nHCM. In turn, interstitial and replacement fibrosis are known to lead to worse outcomes, including diastolic dysfunction, arrhythmias, heart failure, and death.
To silence WISPER, HAYA created HTX-001, a synthetic ASO designed to lower WISPER RNA levels, decrease heart tissue scarring, reverse current heart scarring, and provide a focused treatment for patients with HCM. Given the state of the market and the U.S. economy, HAYA’s preclinical work on HTX-001 is a key reason for the relatively sizeable Series A financing round.
LncRNAs as master regulators
But HTX-001 isn’t the only reason HAYA has attracted investors—a lot of that has to do with the platform built by HAYA to systematically identify target lncRNAs as therapeutic targets. Multimodal genomics on patient biopsies anchors HAYA’s platform, enabling them to create their in-house version of the Encyclopedia of DNA Elements (ENCODE). Ounzain stated that HAYA’s platform has curated and annotated 300,000 lncRNAs absent from any public reference database.
“The public domain annotations of lncRNAs are terrible, so, to discover lncRNAs that are of high causality and value in specific cell states, you have to profile and explore at the right level of depth and in the right dimensions,” said Ounzain. “We take a multi-dimensional approach to the genome’s activity, both in three dimensions at a single cell and at the RNA level. This approach enables us to maintain our own proprietary curation.”
To build the platform, HAYA deploys over 10 genomic approaches, such as single-nucleus ATAC-seq, micro-C 3D genome mapping, and five different types of RNA sequencing, including single-molecule, long-read, and short-read, on patient biopsies, all integrated to build an atlas of epigenomic states and gene expression regulation. The next major step is figuring out how to identify lncRNA targets that can causally reprogram the epigenome for cell state control.
Part of predicting causality has to do with being able to predict lncRNA function, of which there is quite a bit of diversity. Much of the research on lncRNAs focuses on what they do inside the cell nucleus, where they interact closely with chromatin-modifying complexes and help start or maintain the activity of specific genes from enhancer regions. Some studies have found that specific ‘architectural’ lncRNAs connect with various nuclear clusters that have different lifespans and functions, such as those in centrosomes, nucleoli, and nuclear speckles that are full of RNA-processing factors. These lncRNAs play key roles in managing when and where genes are expressed during development, helping shape the epigenetic and transcriptional environments crucial for different cell types.
“We’ve built a first-in-biology platform at the leading edge in genomics and data science. We do a lot of machine learning, but our focus is the product. We’re showcasing the rapid translation of insights requiring AI, ML, and sophisticated multi-modal omics into actual drug products. We are excited about this financing because it allows us to take everything we have accomplished in the last four years regarding biology, platform development, and our understanding of how to target and drug these molecules into the clinic, marking a significant milestone for us.
Once candidate lncRNAs have been identified and modeled, HAYA primarily looks to apply next-generation ASOs designed for tissue-selective delivery. So far, according to Ounzain, their approach has looked promising in large animal preclinical models, having achieved dose-dependent target engagement in the heart and lungs without exaggerated pharmacology in off-target tissues like the liver or kidneys. This safety profile is critical for translating findings to patients.
“Once you profile deeply, you find those highly specific and sensitive to environmental signals, and we’re finding significant enrichment of GWAS variants in these targets,” said Ounzain. “The integration of all that information provides us with the raw material needed to triage and identify causal targets, and we’ve validated this approach across multiple novel targets, at least in preclinical studies. Now it’s time to prove that this translates.”
Transforming into a clinical company
Ounzain, elaborating on the promising pharmacological profile, said that the second-generation ASOs HAYA have excellent tissue selectivity and penetration. Specifically, research shows that these ASOs penetrate the heart, lungs, and other tissues dose-dependently. The kidney and liver have the highest penetrance and potency of the ASOs, so dose dependence is essentially negligible in those tissues—no matter how much is dosed, the effect will be saturated. However, in the case of WISPER, which is not expressed in the kidney and liver, they are not seeing off-target pharmacological effects, implying that the drugs can be dosed at safe and effective levels in patients.
HAYA has mainly concentrated on fibroblast plasticity because it is believed that creating anti-fibrotic drugs would greatly improve the use of tissue-specific regulators of fibroblast plasticity. However, this does not imply that HAYA’s pipeline is limited to fibrosis. To this point, HAYA has demonstrated the preclinical success of its platform with multiple targets, from the heart to the lung to the tumor microenvironment.
“This is the ultimate value of the technology, which is that the cell state doesn’t have to be a fibroblast—it can be any type of cell state transition and cellular reprogramming—and we believe this technology allows you to precisely reprogram cell states,” said Ounzain. “We’re at that exciting point, which is generating clinical proof-of-concept. We believe that demonstrating the opportunity for cell state reprogramming through the dark genome will unlock biological insights.
At this stage, HAYA has begun transforming into a clinical company and, accordingly, has begun building the team. Toward the end of summer 2024, HAYA built out a C-level executive team, bringing in Richard Law, PhD, as chief business officer and Eric Adam, PhD, as COO. Law, a former Exscientia executive who helped build the company and facilitate its merger with Recursion Pharmaceuticals, joins to accelerate HAYA’s strategic business operations and partnering, and Adam most recently served as global head of operations within neuroscience and rare diseases in pharma research and early development (pRED) at Roche.
“We’ve put in place now a C-level team that allows us to scale both operationally and in terms of transitioning and becoming a clinical-stage company,” said Ounzain. “Our obsession is to unlock the regulatory genome for these common and chronic diseases we care about. We believe we can demonstrate clinical proof of mechanism or establish a path to causality in the clinic. This will open up many opportunities around this biology for other cell states, and [Rich and Eric] are here to help us get these to patients faster.”
This next step will be critical for HAYA and Ounzain, who have worked on lncRNAs for over a decade. Up until now, Ounzain has successfully navigated each step of the journey, and now he has the financial resources to reach the summit of the next one.
