Unravel: from tools for studying pathogen tolerance to hope for rare disease patients

A new AI-enabled drug discovery paradigm developed and refined through government-funded research led to an effective treatment for Rett syndrome

Part of the Wyss Institute’s series on the positive, life-altering impact of federal research funding

By Jessica Leff

There are approximately 350 million people in the world with a rare disease, including 25-30 million Americans. About 80% of the disorders are genetic, and 95% of them have no FDA-approved treatments. Finding an effective drug is no small task; after an expensive and long development process, 90% of drugs fail in clinical trials. Often, this happens because the target, or molecule that a drug interacts with, is ineffective in patients, or there are unintended side effects. Through government-funded projects, Wyss researchers developed tools to revolutionize the drug discovery paradigm by starting with patients themselves and offering hope to those with rare diseases and their families.

The power of THoR

In May 2016, the Wyss Institute was selected to lead a $9.9M multi-institutional effort funded by the Defense Advanced Research Projects Agency (DARPA). The initiative, called Technologies for Host Resilience (THoR), aimed to investigate why some host organisms are tolerant to infection by pathogens and to uncover which biological mechanisms are responsible for their resilience.

The team, led by Wyss Founding Director and Core Faculty member Don Ingber, M.D., Ph.D., and current Director of Immuno-Materials Michel Super, Ph.D., aimed at identifying drug compounds that could create resilience in individuals who were susceptible to various infections. In light of the low success rate of clinical trials designed to test therapies using existing drug discovery methods, they developed an alternative approach. At its heart was nemoCAD, a computational pipeline that enabled them to predict drug candidates based on changes that occur in the entire gene network across multiple organ systems in an infected individual, rather than by merely focusing on a specific target molecule.

In parallel, they developed a high-throughput drug screening system, using whole organisms, namely Xenopus laevis tadpoles, which can be subjected to behavioral assays and easily analyzed with regard to their gene expression and changes in their pathological features.

Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences.

How to stop time

A few years later, DARPA signed a $25.5M contract with the Wyss to pursue an even more ambitious goal: to stop biological time. The objective of the Time Tolerant Biostasis Therapeutics project, led by Ingber and then-Senior Staff Engineer Richard Novak, Ph.D., was to create solutions for combat and disaster victims for which surgical and therapeutic interventions are not immediately available. Their aim was to find strategies that could extend the “golden hour” in patients, the first hour following a traumatic injury in which interventions are most likely to have positive outcomes. They hypothesized that certain classes of chemicals could achieve this by rapidly and reversibly slowing down central metabolic processes in the body without external cooling.

To do this, they leveraged and further evolved the computational nemoCAD platform developed in the THoR program to find and design biostasis-inducing chemical compounds based on molecular data from hibernating animals, and demonstrated that candidate compounds emerging from this analysis can slow biochemical and metabolic activities in animal and human disease models.

Biostasis served as a test bed for the technologies beyond the pathogenic infection focus of THoR. It showed that we could discover effective drugs and from those, new targets, using our combined AI nemoCAD and tadpole model iterative framework.

“Biostasis served as a test bed for the technologies beyond the pathogenic infection focus of THoR. It showed that we could discover effective drugs and from those, new targets, using our combined AI nemoCAD and tadpole model iterative framework,” explains Novak, who is now the Co-Founder and CEO of Unravel Biosciences.

Overhauling drug discovery for rare diseases and beyond

By extensively working and refining their platform, the researchers realized that, beyond infectious disease and biostasis applications, it could be used to predict and test the cognitive and behavioral effects of a wide range of drugs, especially for complex central nervous system disorders. They validated these expanded capabilities with the help of internal Validation Project funding provided by the Wyss Institute, and further automated and multiplexed their platform.

The team’s first disease target was Rett Syndrome, a rare genetic disease with devastating outcomes affecting primarily girls, for which no disease-modifying therapy is available. Novak and Frederic Vigneault, Ph.D., who is now the Co-Founder and CSO of Unravel Biosciences, along with Ingber and Wyss Associate Faculty member Michael Levin, Ph.D., genetically engineered tadpoles that developed Rett-like disease and, using NemoCAD’s analytical and predictive capabilities with Rett patient data, identified an existing drug, known as vorinostat, that can reverse symptoms of the disease across multiple tissues.

In 2021, Unravel Biosciences launched from the Wyss Institute to commercialize this platform technology. The company further customized nemoCAD to create their proprietary BioNAV™ platform, which uses transcriptome and proteome data from patients as the starting point for identifying and developing effective drugs. Rather than starting with a target molecule and designing drugs to disrupt it, Unravel’s growing workforce uses BioNAV™ to predict new therapeutic mechanisms for each patient with the theoretical ability to restore health by normalizing gene networks across multiple tissues affected by a given disorder.  By simultaneously finding existing drugs to extensively validate the discovered therapeutic mechanisms in Xenopus tadpole models and focused, rapid clinical trials, they can obtain new insights into the underlying mechanisms causing a disease and find new therapeutic possibilities.

In May 2024, Unravel received Orphan Drug Designation from the FDA for vorinostat (RVL-001) as a treatment for Rett Syndrome. In late April 2025, they submitted an application for proof-of-concept clinical trials to investigate vorinostat as a treatment for Rett syndrome and Pitt Hopkins syndrome, which causes symptoms similar to Rett Syndrome. The proof-of-concept trial designed to test the safety and efficacy of vorinostat in 15 female patients in Colombia is to commence later this year.

“The discovered drug candidate generated significant excitement among patient groups, as our preclinical mouse data suggest that RVL-001 may have the potential to treat Rett syndrome in even older and more severely affected patients. We routinely field insightful questions about the upcoming clinical trial from patient groups and clinicians at conferences,” Novak explains. “In Colombia, caregivers of Rett patients have become active partners, actively following our trial preparations and regulatory submissions.”

For the first time, patients with Rett syndrome can envision their future differently, and their families see a way to potentially alleviate their loved ones’ suffering.  This medical milestone wouldn’t have been possible without the initial support from DARPA.

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