AI breakthrough reveals promising treatment for Rett syndrome

AI breakthrough reveals promising treatment for Rett syndrome

Rett syndrome is a devastating rare genetic childhood disorder that primarily affects girls. Only 1 in 10,000 girls are born with it and far fewer boys. It is caused by mutations in the MECP2 gene on the X chromosome, resulting in a spectrum of cognitive and physical impairments, including repetitive hand movements, speech difficulties and seizures.

In addition to severe impairment of neurological functions, which was the focus of researchers, Rett syndrome also disrupts the functions of many non-neurological organs, including the digestive, musculoskeletal and immune systems. This complexity has made developing an effective cure that can treat the disease across multiple tissues capable of becoming extremely challenging.

Now, a highly multidisciplinary research team at Harvard University's WYSS Institute has achieved a significant breakthrough by using an AI-driven drug discovery process combined with innovative disease modeling. Their study identified a drug known as vorinostat as a promising treatment for Rett syndrome, which demonstrated disease-modifying abilities across multiple neuronal and non-neuronal tissues in preclinical models of Rett syndrome that were superior to trofletide, the only approved treatment for rescue syndrome. The results will be published inCommunication medicine.

Since vorinostat has already been approved by the Food and Drug Administration (FDA) to treat a blood disorder, the WYSS-enabled startup BioscosoSciences was able to unravel that this drug is quickly being used as a therapy for rescue syndrome. Unravel Biosciences' lead pipeline asset, RVL-001, is a proprietary formulation of vorinostat that recently received an orphan drug designation from the FDA. Resolving will initiate a proof-of-concept clinical trial to evaluate the drug's efficacy and safety in 15 female patients with Rett syndrome in Colombia later this year, and an "N-of-1" study design to evaluate different vorinostat treatments within individual patients, which will address the complexity of the disease and rare disease communities more broadly Notoriety is more appropriate.

The identification and advancement of vorinostat as a potential first curative treatment for Rett syndrome would not have been possible without our unique AI-enabled computational approach to drug discovery and its combination with an innovative disease model that mimics the characteristics of Rett syndrome in general. This new target-agnostic approach to drug discovery has proven to be extremely rapid and effective and, together with our unique technology mania capabilities, creates a model for us to address other diseases of relentless need that present similarly enormous challenges. “

Donald Ingber, MD, Ph.D., senior author and Wyss founding director

Ingber is also the oneJuda Folkman Professor of Vascular Biologyat Harvard Medical School and Boston Children's Hospital and theHansjörg Wyss Professor of Biologically Inspired Engineeringat the Harvard John A. Paulson School of Engineering and Applied Sciences.

A new paradigm for drug discovery

Key to the discovery of vorinostat as a potential Rett syndrome therapy was the WYSS Institute's computational Nemocad pipeline, which allowed the team to predict drug candidates based not on a specific disease target molecule - like most traditional drug discovery approaches - but on changes occurring throughout the gene -Network across multiple organ systems in rescue -Syncrom occurs in rescue systems. Richard Novak, Ph.D., then a staff scientist on the Ingber team at the WYSS Institute and now CEO of Unravel, and other members of the team developed Nemocad as part of the WYSS-led DARPA Thor project to find out why some patients were more tolerant to pathogens than others. This DARPA-funded project led the way to other successful demonstrations of drug discovery by the WYSS Institute across diverse medical challenges, from neuropsychiatry to artificial hibernation.

As a starting point for developing treatment for the full clinical spectrum of symptoms experienced by patients with RATT diseaseXenopus laevisin which they used CRISPR genome engineering technology to create different mutations that inactivate the MECP2 gene to reflect the different patient population. The constructed tadpoles recapitulated a number of critical features of Rett syndrome, including developmental and behavioral delay, seizures, and intestinal, muscle, and brain abnormalities. Importantly, researchers would be able to analyze this new rescue model for changes in gene expression across multiple organs that are associated with Rett syndrome-specific neurological and non-neurological changes in behavioral and tissue function.

The researchers then used Nemocad to compare all gene expression changes that occurred in mecp2-defective tadpoles compared to healthy tadpoles to predict drug compounds from a public database curated by the NIH that could reverse the pathological changes in the same gene expression networks. Lincs, as the database is called, contains gene expression signatures induced by more than 19,800 drug compounds in a variety of human cell lines, including drugs already approved by the FDA to treat other diseases. This type of analysis far exceeds traditional gene expression analysis, which determines the expression changes of individual genes or smaller groups of genes in isolation from all other changes.

"Critically ill patients require accelerated discovery of new treatment options for their underlying diseases. Calculating how the entire gene expression networks change in a concerted manner allowed us to predict which drugs are most likely to disrupt the RET-specific gene expression network in multiple organs and unguided projects with Co-Funduster, along with Co-Co-Co-Co-Cofuster, back to the normal state and the Co-Co-Cofuster-Cofuster-Cofuster-Cofuster-Cofuster-Cofuster-Cofuster-Cofuster-Cofuster-Cofuder-Co-Co-Co-Co-Co-Co-Co-Co-Fundu, were changed. “We then went from a list of predicted candidatesin silicodirect validation of the top candidatesIn vivoIn our tadpole model within a few weeks, demonstrating an efficient method for identifying previously unknown therapeutic mechanisms," Novak added.

Vorinostat scored highest on the list and produced the strongest therapeutic effects in the genetically engineered tadpoles, which showed impressive reversal of their disease characteristics on a whole organismic level. Symptoms such as seizures, unusual swimming movements similar to repetitive behavior seen in patients with Rett syndrome, and gastrointestinal and muscular symptoms were all greatly suppressed by the drug. And vorinostat was much more effective at suppressing these symptoms than trofinetide.

"Important for its translation toward patients, vorinostat also consistently reversed several symptoms of Rett syndrome in a preclinical mouse model, even when it was already in full progression after symptoms were remedied. WYSS staff scientist who worked closely with Novak and Vigneault on Ingber's team. "With some additional formulation work, vorinostat also achieved this significant therapeutic results as an oral treatment.”

New drug, new findings

Through their gene network predictions and an in-depth analysis of the molecular and cellular processes affected in mecp2-defective tadpoles and after treatment with vorinostat, the researchers discovered an unexpected driving force of the disease. MECP2 encodes a protein that regulates the expression of hundreds of genes. This happens by binding to regions of DNA that carry so-called methyl groups and form complexes with other proteins. One such class of proteins is known as histone deacetylases (HDAC), which modify other proteins by removing another small chemical group known as an acetyl group. The acetylation status of proteins such as histones and other proteins is misregulated in Rett syndrome due to inactivation of MECP2.

However, the team's study in whole organisms completely redefined this view. They found that in Rett syndrome models, although histones were actually under-acetylated in brain cells, they were surprisingly over-acetylated in other tissues affected by the disease, such as the gastrointestinal (GI) tract. Importantly, the team's network analysis had predicted that vorinostat also affected the acetylation of A-tubulin, a protein that plays an important role in neurodegenerative disorders and other diseases. A-tubulin assembles various cytoskeletal structures in cells that contribute critically to their functions, such as:

"In our models, A-tubulin in cilia was also hypo-acetylated in brain tissue, but hyperacetylated in the other tissues such as the GI tract, which correlated with signs of functional abnormalities, including inflammation," Lin said. “Vorinostat was able to reverse this dysregulated A-tubulin acetylation pattern in both directions, showing us that it must have targets beyond the HDAC family for which it is known and that Rett syndrome is caused across multiple organs by mechanisms that should be further investigated.”

Unravel Biosciences, founded by Novak and Vigneault, along with associate faculty member Ingber and the WYSS Institute, Michael Levin, Ph.D., is building on vorinostat and the team's discovery of a new therapeutic mechanism to create what may be the first curative therapy for a rescue therapy for to promote a first patient with the patient. “We are excited to reach clinical phases after this rapid journey of discovery and development and hope to impact the lives of patients with Rett syndrome in unprecedented ways,” said Novak.

The study was also conducted by Shruti Kaushal, Megan Sperry, Erica Gardner, Sahil Loomba, Kostyantyn Shcherbina, Vishal Keshari, Alexandre Dinis, Anish Vasan, Vasanth Chandrasekhar, Takako Takeda, Rahul Nihalani, Sevgi Ugrase, and Jerrold, and Jerrold, and Jerrold, and Jerrold, and Jerrold, and Jerrold, and Jerrold, and the Jerradni, Sevi, Sevgi, and "

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