Why fibrosis matters in cardiovascular diseases: the role of the dark genome
January 11, 2023
Our new Director of Biology and Functional Genomics Rudi Micheletti talks about cardiovascular disease and fibrosis, rejoining Samir Ounzain after a decade to discover novel targets and create precision genomic medicines for hard-to-treat chronic diseases.
By Rudi Micheletti, Director of Biology & Functional Genomics
I began working with Samir Ounzain at the Lausanne University Hospital in 2011 with the aim of identifying novel tissue-specific targets within the non-coding portion of the genome that is involved in heart development and function. As we began to scrutinize and profile the transcriptome of the heart, we uncovered the functional relevance of cardiac-associated long non-coding RNAs (lncRNAs). Since then, several of the lncRNAs like Meteor, CARMN, and Sweetheart, we originally described have been validated by independent laboratories and demonstrated to be relevant to the heart.
Fast forward to 2017, our team discovered the lncRNA Wisper, a cardiac myofibroblast–enriched lncRNA that regulates cardiac fibrosis after injury. Using loss-of-function experiments in vitro and in vivo, we provided evidence that Wisper functions as a specific regulator of cardiac myofibroblast activation, migration, and survival. Importantly, we showed that Wisper is highly transcribed only in cardiac myofibroblasts and is not expressed in the fibrotic tissue from other organs such as kidney or lung. This remarkable characteristic makes Wisper an attractive therapeutic target which opens the unprecedented opportunity to reverse interstitial fibrosis in the heart and prevent adverse remodeling in the injured heart.
With a new-found lncRNA target and an innovative platform technology to unearth the inner workings of the dark genome, Samir Ounzain and Daniel Blessing launched HAYA Therapeutics shortly after we discovered Wisper. Over the last several years, HAYA has made tremendous progress and is advancing its lead therapeutic candidate, HTX-001 -- an antisense oligonucleotide targeting Wisper, for the treatment of non-obstructive hypertrophic cardiomyopathy, a common genetic heart disease significantly affected by fibrosis.
Fibrosis, cardiovascular disease and the dark genome
Fibroblasts play a vital role in maintaining the structural framework of the heart. Resident fibroblasts produce matrix components that help the heart maintain its shape and function. Upon injury, such as myocardial infarction or heart attack, fibroblasts transition to their activated form, also known as myofibroblasts. These cells are critical regulators of cardiac fibrosis, a wound-healing process characterized by the extensive deposition of extracellular matrix, crucial for scar formation.
Inflammation and other pathological stimuli typical of the infarcted heart cause a persistent detrimental activation of myofibroblasts, triggering the fibrotic tissue to spread deep into the cardiac muscle. This condition, known as interstitial fibrosis, increases the stiffness of the heart which leads to long-term cardiac dysfunction and to the development of life-threatening pathological conditions such as ventricular arrhythmia and heart failure. Historically, it has been very challenging to target interstitial fibrosis, specifically in heart disease because fibrosis is a conventional wound-healing response to injury in a variety of human tissues including lung, kidney and liver.
Most of the existing anti-fibrotic therapies are targeting protein-coding genes or proteins involved in fibrosis but unfortunately, those proteins are expressed and conserved in many organs of a person’s body, meaning that those therapies might lead to unwanted consequences and to damage of healthy tissues away from the heart. Because of the clinical importance of tackling interstitial fibrosis and excess matrix deposition, we urgently need alternative therapeutic strategies to specifically target myofibroblasts exclusively in the heart to significantly improve the life expectancy of patients affected by cardiac pathologies.
Advancing our understanding of the dark genome for hard-to-treat diseases
Beyond tackling cardiac pathologies, HAYA developed a platform that has advanced to the point where we can potentially regulate how genes are transcribed in other tissues by targeting different types of lncRNAs because lncRNAs are specific for tissues, cells, or after pathological stimuli. HAYA’s technology has demonstrated applicability in other indications, such as squamous cell carcinoma, and has the potential to identify clinically relevant targets in other chronic diseases.
Beyond therapeutics, lncRNA and the dark genome have the potential for improved diagnostics. For example, identifying fibrotic progression in cardiac diseases is incredibly challenging. While there are contrast scanning techniques that may be viable, the best way to measure fibrosis is through heart biopsy, which is typically reserved for when a patient requires surgery, like replacing a valve. These types of procedures have an inherent risk. If we can leverage lncRNA as potential biomarkers that can be assessed in the blood, this would significantly impact how we treat cardiovascular disease and a broad range of illnesses that are affected by levels of lncRNA.
Rejoining the fight against chronic diseases
While I was part of the original Lausanne University team to discover Wisper, I spent the last five years completing my postdoc in the Michael G. Rosenfeld lab at UC San Diego. During my training, I developed state-of-the-art multi-omics technologies to characterize the epigenome which ultimately extended my understanding of the molecular basis of gene transcription regulation in health and disease conditions.
But now, I am excited to rejoin Samir at HAYA as the company’s Director of Biology and Functional Genomics, and look forward to what the team can accomplish. By understanding the dark genome's biology and context-dependent disease drivers, we can identify novel targets and create precision genomic medicines with a meaningful therapeutic effect that are safer and more accessible.