The company is developing therapeutics for rare genetic diseases affecting the central nervous system, starting with Rett syndrome
By Lindsay Brownell
(BOSTON) — Today, Unravel Biosciences and the Wyss Institute for Biologically Inspired Engineering at Harvard University announced that Unravel has licensed a drug discovery platform technology from Harvard and Tufts University. The company will use the technology, invented at the Wyss Institute, to decode and model complex diseases to accelerate the development of new and more effective therapies.
Harvard’s Office of Technology Development is providing an exclusive, worldwide license to Unravel for the diagnosis, treatment, and prevention of certain neurodevelopmental disorders using new and existing drugs developed with the platform.
The company is validating the technology by developing an effective therapy for Rett syndrome, a rare genetic disease that mostly affects girls and causes progressive loss of motor and language skills, seizures, and intellectual disabilities. By combining predictive algorithms, a high-throughput tadpole-based screening system, and an iterative discovery process, Unravel is taking a patient-centric approach to identify drugs that can restore health, first in Rett syndrome and later in other cognitive and behavioral disorders.
“Unravel’s approach flips the traditional drug development process on its head. For the past 50 years, most pharmaceutical companies have started by identifying a molecular target of interest and then developed drugs to disrupt that target. But 90% of the drugs created via this process don’t work in patients. In contrast, we start with an individual patient and ask, ‘What is different about this patient that’s causing this disease?’ We computationally predict which existing drugs could restore health in that patient, validate those drugs in our engineered animal models and focused clinical trials, and from there identify the underlying molecular targets that could be drugged to treat the disease across patient populations,” said Richard Novak, Ph.D., a former Lead Staff Engineer at the Wyss Institute who is now CEO and co-founder of Unravel.
From DARPA project to Validation Project
The roots of the platform technology licensed by Unravel stretch back to 2015, when Novak and other members of the Wyss Institute led by Founding Director Don Ingber, M.D., Ph.D. started working on a DARPA-funded research project to identify drugs that could induce human tolerance to sepsis and other forms of infection. To figure out whether their candidate drugs might have any unexpected side effects on the brain, the team developed a cognitive assay and behavioral screening system using Xenopus laevis frog tadpoles in collaboration with Wyss Associate Faculty member Mike Levin, Ph.D.
“Xenopus embryos are an amazingly tractable and powerful system for exploring the ‘full stack’ of biology: from genes, to physiology, to anatomy, to behavior. The whole brain and nervous system forms in front of your eyes in a week! I was really excited about collaborating to use automated assays in this exquisite little animal to impact human medicine,” said Levin, who is also the Vannevar Bush Chair of the Department of Biology and Director of the Allen Discovery Center at Tufts University.
The scientists quickly realized that their system, called CogniXense, could be used to evaluate the effects of a wide range of drugs on the cognitive and behavioral systems of a whole organism. This would allow them to identify drugs that can restore complex mental abilities that are often impaired in neurological diseases, a metric that is important to patients but difficult to measure in standard preclinical models.
A team was formed to develop CogniXense for that purpose. Shortly thereafter, the system highly impressed a visitor to the Wyss Institute, who had a daughter with a rare genetic disease that was classified as a form of Rett syndrome. This condition, which causes debilitating physical and mental problems in the ~10,000 patients who are born with it every year, has no cure or treatment.
Ingber suggested to Novak that CogniXense could be used to identify drugs to treat Rett syndrome, and the team got to work building a Xenopus model of the disease. In their first test, they found that their model replicated behavioral differences observed between healthy patients and those with Rett syndrome. They also identified several drugs that reversed the tadpoles’ symptoms. Based on this potential, the team was awarded Validation Project funding from the Wyss Institute in 2018 and 2019 to further de-risk and develop CogniXense into a high-throughput and automated drug discovery platform.
CogniXense consists of three main parts. The first is NeMoCAD, a computational algorithm that analyzes the transcriptome network features of existing drugs to predict which ones are most likely to reverse the features of a given disease. Second, Xenopus tadpoles are genetically modified using CRISPR to replicate the genetic signature of the disease and the resulting spectrum of behavioral and cognitive features in as little as three weeks. Finally, the modified tadpoles are placed into a screening instrument called the TadPool, which allows real-time non-invasive analysis of more than 1,000 swimming tadpoles simultaneously.
The TadPool evaluates each tadpole’s decision-making skills, ability to learn, swimming patterns, and circadian rhythms to produce a multidimensional picture of their behavior. Comparing these behaviors with and without a given drug indicates whether the drug effectively reverses the features of the disease. Drug screening results then feed back into NeMoCAD in an iterative process to identify drug targets that underlie successful treatment, which can be used to develop even more effective new drugs.
Treat the patient, treat the disease
Based on CogniXense’s success in the lab, Unravel was launched to commercialize the technology. The company has customized it to create their proprietary BioNAV™ platform, which incorporates transcriptome and proteome data from patients.
“By using real patient data, we ensure that our predictive algorithms actually identify drugs that can treat a disease in a person who suffers from it. When we repeat this process for multiple patients across the spectrum of neurologic diseases and look at that combined information, we can pinpoint drugs that will work for certain groups of patients regardless of their formal clinical diagnosis or genetic mutations. So, we’re applying a personalized medicine approach across conditions that were previously considered independent of each other to identify effective treatments for the more than 15,000 patients who suffer from rare diseases,” said Frederic Vigneault, Ph.D., a former Senior Staff Scientist at the Wyss Institute who is now the CSO and co-founder of Unravel. “And, if no existing drugs can effectively treat a particular population, we use our platform to design new ones.”
In July 2022, Unravel announced a partnership with TMA Precision Health (TMA) to leverage TMA’s database of patients with rare diseases in regions across the globe that have historically been underrepresented in medical research. The companies are aiming to use this patient access to bring Unravel’s first drug candidate, a proprietary oral liquid formulation for the treatment of Rett Syndrome, to clinical trials by the end of 2022.
Unravel plans to pursue multiple rare disorders in parallel, building on the rapid clinical translation of their Rett syndrome program. The company is partnering with academic and industry groups to use patient transcriptome data to redefine how rare diseases are treated and enable effective therapies to reach patients in need more quickly.
“You hear a lot about how artificial intelligence is going to impact drug discovery, but examples of success are few and far between. I am extremely proud of this team for their ability to collaborate across disciplines and to develop this powerful first-of-its-kind drug discovery platform that combines computation with experimentation in an iterative way that is absolutely critical for clinical success, as well as their determination to spin it out into a company as quickly as possible to maximize its impact. Unravel is a perfect example of how pursuit of academic innovation with an entrepreneurial mindset can lead to development of disruptive technologies that can change the world for the better,” said Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.