The therapeutic field of long non-coding (lnc) RNAs has flown under the radar for quite some time now since they emerged as targets belonging to the dark genome to treat various diseases. But recent deals have zoned in on drugs that target lncRNAs and major moves are currently being made on the research and development (R&D) front.
Swiss biotech HAYA Therapeutics’ $1 billion collaboration with pharma giant Lilly is one for the books. According to the deal, Lilly will use HAYA’s RNA platform to create drugs that could treat metabolic diseases like obesity. As obesity has more than tripled globally in the past five decades, according to a report by the World Obesity Federation, more and more ways to treat the condition are cropping up.
HAYA’s genome discovery platform aims to pave the way for the genetic medicines that enhance the efficacy of current incretin-based therapies like GLP-1 drugs that are much in demand now, explained Samir Ounzain, chief executive officer (CEO) of HAYA Therapeutics.
“HAYA will use its full-stack regulatory genome platform to identify disease-driving cell states and novel lncRNA therapeutic targets, which will be further characterized and validated by the HAYA team. Lilly will provide support and expertise in deciding which targets to move forward as well as assess such novel targets in advanced preclinical therapeutic models and be in charge of any further potential development and commercialization,” said Ounzain.
LncRNA: a promising drug target
But what exactly is lncRNA? Dominique Verhelle, CEO of American biotech NextRNA Therapeutics – specializing in lncRNA-based therapies – explained that lncRNA is a type of RNA that does not code for proteins. These RNA strands are pretty long – over 200 base pairs in size – and not linear, meaning that they form a specific structure. These RNA molecules interact with proteins and recruit them to do specific tasks in a cell. While their regular expression mirrors cell growth and activation, when they are overexpressed, it leads to abnormalities in the way cells function, and ultimately, diseases. So, targeting these lncRNAs can help combat these diseases.
“There is work out there showing that they can work in oncology, neuroscience, cardiometabolism, and inflammation. At NextRNA, we’ve been mainly focusing on oncology, which is a therapeutic area that is very close to my heart and my experience,” said Verhelle.
NextRNA has joined forces with German multinational Bayer in a $547 million partnership to develop small molecules that target lncRNAs to treat cancer. While small molecules are not a new class of drugs, these drugs will be used to intervene in a new mechanism of action, Verhelle pointed out.
“What we’ve done is develop the capability to not only validate the lncRNA and the function in disease but also identify the mechanism of action, which protein is important to interact with the lncRNA, and what is the domain that is required for this interaction. And with this knowledge, we are developing a small molecule that inhibits this interaction,” said Verhelle. “We can either develop a small molecule on the RNA side of the interaction or on the protein side of the interaction. So, that gives us two shots on goal when we are moving forward in drug discovery to target the function of the lncRNA.”
NextRNA and HAYA charm big pharmas with lncRNA potential
Apart from developing small molecules, the partnership will also focus on identifying lncRNAs drug targets and advancing a preclinical program testing how viable these targets are.
“This is a really exciting partnership,” said Verhelle. “It really shows that a company like Bayer trusts a company like NextRNA and our expertise but also believes in the opportunity of the lncRNA space. We think that it’s a really promising area of research and in drug discovery.”
The biotech will employ its lncRNA platform to advance drug discovery in cancer – a therapeutic field with multiple drug targets yet quite hard to treat.
“It’s really innovative with the potential to develop transformative therapeutics but it’s also really vast. It gives us a lot of opportunities to drug many different types of cancer.”
Echoing these thoughts on the lncRNA space, HAYA’s Ounzain thinks that there has been a growing realization of the “potential for lncRNA to be an entirely new area of therapeutic development with a massive potential to impact common and chronic diseases that plague humanity.”
Besides the Lilly collaboration, HAYA is moving its lead program HTX-001 up the R&D ladder. HTX-001 is a medicine that targets the lncRNA WISPER, a driver of fibrosis in the heart. The drug is gearing up for clinical trials and will be used to treat people with nonobstructive hypertrophic cardiomyopathy, a condition that causes the heart muscle to thicken without blocking blood flow.
Targeting lncRNAs: drugs move towards the clinic
Moreover, it’s not just HAYA and NextRNA advancing in the field. New Zealand-based Amaroq Therapeutics also has a pipeline dedicated to lncRNA-based cancer therapies, all of which are in preclinical studies. And so does Flamingo Therapeutics. The Belgian biotech won a €1.7 million ($1.88 million) grant last year to conduct preclinical work in its lncRNA program targeting MALAT-1 in breast cancer and other solid tumors. The candidate FTX-001 is set to hit the clinic soon.
Still regarded as an “unexplored therapeutic target landscape,” Ounzain believes that these long stretches of DNA that do not code for proteins – which make up the dark genome – hold a lot of promise.
“It’s not an exaggeration to say there are lncRNA efforts underway among several disease areas,” said Ounzain. “We are excited to continue to expand the use of our platform in other disease indications and pathological processes beyond fibrosis. We believe that our approach holds the potential to have an extremely positive impact on patients’ outcomes and global healthcare.”
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