“BRD9 inhibition is a novel target for the treatment of HD identified by our proprietary high throughput organoid phenotypic screening platform,” said Fred Etoc, Chief Scientific Officer of Rumi. “We have previously demonstrated, in vitro, that BRD9 inhibition rescues several of the biochemical dysfunctions known to occur in HD and thus could be disease modifying. The new in vivo data reported in this presentation provide both behavioral and molecular validation of this target. We are currently working on developing a brain penetrant BRD9 inhibitor that can ultimately enter IND enabling studies. Finally, these experiments demonstrate the usefulness of RUMI’s platform to discover potential new targets in a therapeutic disease area such as HD where new hypotheses are needed.”

To demonstrate in vivo proof of concept, the researchers employed a long-lasting siRNA to block BRD9 in R6/2 mice, an animal model for HD, then evaluated the mice versus control animals on several behavioral and biochemical parameters. Compared to control R6/2 mice, treated mice showed a statistically significant reduction in mutant huntingtin (mHTT) protein aggregations in both the cerebral cortex and dorsal striatum. Aggregation of mHTT in neurons is a molecular hallmark of HD and a marker for disease progression. Additionally, two validated HD behavioral assays were evaluated: distance traveled and rearing behavior. Treated mice demonstrated a significantly increased total distance traveled at eight weeks post treatment compared to untreated mice. Rearing behavior also showed a statistically significant increase in total rearing at 10 and 12 weeks of age compared to control mice. Both measures are behavioral biomarkers for improved mobility, which is rapidly impaired in this mouse model. These data demonstrate the potential of a novel disease modifying therapeutic target to reverse pathologies in a HD animal model. 

Title: Deep learning analysis of micropattern-based organoid screens reveals BRD9 as a new potential target for Huntington’s disease
Authors: Shaun Peterson, Tomomi Haremaki, Yudelca Ogando, Carlota Pereda, Arjun Adhikari, Ali Brivanlou, Fred Etoc
Time/Date: 1-4 p.m. CEST, April 26

About Rumi Scientific
Rumi Scientific’s mission is to identify and develop novel therapeutics for rare and neurodegenerative diseases by employing its revolutionary synthetic human tissue platform to produce more predictive data leading to a safe and faster clinical trial process. The Company’s lead program is an orally available bromodomain-containing protein 9 (BRD9) inhibitor in lead optimization for the treatment of Huntington’s disease. Founded in 2016, Rumi licensed foundational technology from The Rockefeller University developed by co-founders Ali H. Brivanlou, Ph.D., and Eric D. Siggia, Ph.D. For more information on Rumi Scientific, please see www.rumiscientific.com or contact info@rumiscientific.com.

Rumi Scientific:
Allen Fienberg, Ph.D.
Chairman and Chief Executive Officer
allen@rumiscientific.com

Fred Etoc, Ph.D.
Chief Scientific Officer
fred@rumiscientific.com

Investors:
Burns McClellan
Lee Roth / Cameron Radinovic
lroth@burnsmc.com / cradinovic@burnsmc.com

Source: https://www.globenewswire.com/news-release/2023/04/26/2654886/0/en/Rumi-Scientific-Announces-Data-Demonstrating-Disease-Modifying-Effect-of-BRD9-Inhibition-in-a-Huntington-s-Disease-Animal-Model.html

“Our human organoid-based high throughput drug discovery platform has already identified multiple molecules and targets warranting further development,” said Ali H. Brivanlou, Ph.D., co-founder of Rumi Scientific, and the Robert and Harriet Heilbrunn Professor and head of the Laboratory of Synthetic Embryology at The Rockefeller University. “Having reached this point, it became clear that a CEO with expertise in advancing preclinical programs to clinical-stage candidates was needed to drive our continued progress. Allen’s extensive neuroscience research and drug development experience positions him ideally to lead the advancement of our lead program in Huntington’s disease (HD) and of our earlier-stage programs in autism spectrum disorder and Alport syndrome. On behalf of the Rumi Scientific team, I am pleased to welcome Allen to the Company and look forward to its ongoing evolution under his leadership.”

Dr. Fienberg joined Rumi after serving for more than 20 years as Vice President of Business Development at Intra-Cellular Therapies, Inc. (ITI), which he co-founded in 2002. While at ITI, he was responsible for all business development activities along with various preclinical science initiatives. As a co-founder Dr. Fienberg also participated in early-stage fundraising, investor relations, legal and various administrative functions. From 1999-2001, Dr. Fienberg was a staff scientist at the Genomics Institute of the Novartis Research Foundation and was appointed a Research Assistant Professor at The Rockefeller University from 2001-2002. Dr. Fienberg earned his A.B. degree in Genetics from the University of California, Berkeley, and his Ph.D. in Human Genetics from Yale University. He completed post-doctoral studies at The Rockefeller University under the direction of the late Dr. Paul Greengard from 1991-1999.

“What attracted me to Rumi was their highly innovative, phenotype-based drug discovery capabilities based on their unique high throughput organoid screening platform,” said Dr. Fienberg. “The platform evaluates drug-induced changes in phenotypes observed in neural organoids, rather than employing the traditional approach of identifying targets against which molecules are then tested. The platform has already identified molecules with the potential to impact several underlying pathological processes in HD. The platform is adaptable to almost any disease and thus has tremendous potential. I look forward to working with the talented team at Rumi to advance this and other potential therapeutic candidates.”

About Rumi Scientific
Rumi Scientific’s mission is to identify and develop novel therapeutics for rare and neurodegenerative diseases by employing its revolutionary synthetic human tissue platform to produce more predictive data leading to a safe and faster clinical trial process. The Company’s lead program is an orally available bromodomain-containing protein 9 (BRD9) inhibitor in lead optimization for the treatment of Huntington’s disease. Founded in 2016, Rumi licensed foundational technology from The Rockefeller University developed by co-founders Ali H. Brivanlou, Ph.D., and Eric D. Siggia, Ph.D. For more information on Rumi Scientific, please see www.rumiscientific.com or contact info@rumiscientific.com.

Rumi Scientific:
Allen Fienberg, Ph.D.
Chairman and Chief Executive Officer
allen@rumiscientific.com

Fred Etoc, Ph.D.
Chief Scientific Officer
fred@rumiscientific.com

Investors:
Burns McClellan
Lee Roth / Cameron Radinovic
lroth@burnsmc.com / cradinovic@burnsmc.com

Source: https://www.globenewswire.com/news-release/2023/03/30/2637568/0/en/Rumi-Scientific-Appoints-Allen-A-Fienberg-Ph-D-as-Chief-Executive-Officer-and-Chairman-of-the-Board-of-Directors.html

Link: https://www.cell.com/cell-reports-methods/fulltext/S2667-2375(22)00179-5

New York, NY (January 2021) – The Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai and Rumi Scientific announced today that they will team up to initiate a drug discovery pipeline for rare genetic disorders that carry a high risk of autism. The project will initially involve the development and use of a platform that mimics the development of brain tissues, at high speed, allowing researchers to gain insights into how cells respond to three known genes implicated in autism.

“Over the past several years, more than 100 genes have been identified that confer very high risk to autism when mutated, and the Seaver Center at Mount Sinai is one of the lead sites for these autism gene discoveries,” said Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “We are eager to work together with Rumi Scientific, using their outstanding proprietary technology, to build a drug discovery pipeline for these monogenic causes of autism, with the ultimate goal of identifying lead therapeutic candidates that can be evaluated clinically.”

Rumi Scientific’s cutting-edge phenotypic platform mimics the development of human brain tissues, at high speed, using a proprietary technique to create highly reproducible organoids—tiny, self-organized tissue cultures that are derived from induced pluripotent stem cells (iPSCs), which can be crafted to replicate an organ or to express selected aspects like genetic mutations. The Rumi system incorporates sensitive machine-learning algorithms, helping to very precisely identify effects on a cell, thus predicting the therapeutic effect a drug could have on a human’s diseased brain tissues. This advanced technology allows for an unprecedented ability to identify and quantify differences between diseased and healthy cells. Uniquely, Rumi’s organoids focus on early development phenotypic signatures (how the gene mutation leads to disease), and since a large portion of autism genes are active even early in development, these tissue cultures present interesting possibilities for drug screening.

Initially, Mount Sinai’s Seaver Center will provide iPSCs for three autism genes—ADNP, DDX3X, and FOXP1—and Rumi Scientific will probe the existence of phenotypic signatures associated with these genetic mutations using its proprietary organoid technology. The aim of creating a model platform for each of the three genes of interest is to allow translation of these proof-of-concept experiments into a robust high-throughput screening platform across which thousands of therapeutic compounds can be efficiently tested.

“We are very excited to be working with the world-class team at the Seaver Autism Center on their visionary approach to finding cures for autism. To date, no one has evaluated how specific autism mutations affect neural organization in a human context and at the level of a tissue; this collaboration creates the opportunity to discover robust phenotypic signatures which in turn could lead to valuable therapeutic possibilities” said Ilona Nemeth, Chief Executive Officer of Rumi Scientific.

About Rumi Scientific

Founded in 2016 on technology initially conceived at Rockefeller University, Rumi Scientific’s mission is to revolutionize drug discovery, using synthetic human tissue to produce more predictive data leading to a safe and faster clinical trial process. Rumi Scientific’s technology is a powerful engine for the discovery of new drugs to cure genetic diseases. Rumi’s headquarters and laboratories are located in New York City. For more information on Rumi Scientific, please see www.rumiscientific.com or contact info@rumiscientific.com.

Source: Mount Sinai Newsroom

The first signs of Huntington’s, an inherited disease that slowly deteriorates bodies and minds, don’t typically surface until middle age. But new findings suggest that something in the brain might be amiss long before symptoms arise, and earlier than has ever been observed. Using a new technology, Rockefeller scientists were able to trace the causes of the disease back to early developmental stages when the brain has only just begun to form.Developed in the lab of Ali Brivanlou, the Robert and Harriet Heilbrunn Professor, the system uses neuroloids—tiny, three-dimensional tissue cultures that serve as models for whole organs. The researchers create these cell clumps from human embryonic stem cells and manipulate them in the lab to study how developmental diseases arise.Previous work in the Brivanlou lab found evidence that the disease arises in young neurons; but this latest study takes the developmental timeframe back even further, to the step in the brain’s development when cellular uniformity gives way to the emergence of particular structures, a process called neurulation. When the researchers introduced into neuroloids a mutation known to cause Huntington’s, it consistently caused dramatic effects with abnormally shaped tissue structures. “Something’s collapsed,” Brivanlou says.The researchers have started using the technology to screen for drugs that prevent these abnormalities, an approach they hope will provide a powerful alternative to similar work being done in animal models.“This technology really opens a door toward identifying that mechanisms that govern brain development, understanding how they go awry in disease, and testing drugs that set these mechanisms back on the right course,” says Brivanlou.

Source: Ali Brivanlou, Robert and Harriet Heilbrunn Professor, Laboratory of Stem Cell Biology and Molecular Embryology https://www.rockefeller.edu/news/26560-study-gives-clues-origin-huntingtons-disease-new-way-find-drugs/

Image caption: Huntington’s neurons show multiple nuclei (blue) within the same cell, and other signs of trouble, long before symptoms emerge.

With new findings, scientists may be poised to break a long impasse in research on Huntington’s disease, a fatal hereditary disorder for which there is currently no treatment.

One in 10,000 Americans suffer from the disease, and most begin to show symptoms in middle age as they develop jerky movements—and as these patients increasingly lose brain neurons, they slide into dementia. But the new research suggests that these symptoms may be a late manifestation of a disease that originates much earlier, in the first steps of embryonic development.

A team at Rockefeller led by Ali Brivanlou, the Robert and Harriet Heilbrunn Professor, developed a system to model Huntington’s in human embryonic stem cells for the first time. In a report published in Development, they describe early abnormalities in the way Huntington’s neurons look, and how these cells form larger structures that had not previously been associated with the disease.

“Our research supports the idea that the first domino is pushed soon after fertilization,” Brivanlou says, “and that has consequences down the line. The final domino falls decades after birth, when the symptoms are observable.”

The findings have implications for how to best approach treating the disorder, and could ultimately lead to effective therapies.

A new tool

Huntington’s is one of the few diseases with a straightforward genetic culprit: One hundred percent of people with a mutated form of the Huntingtin (HTT) gene develop the disease. The mutation takes the form of extra DNA, and causes the gene to produce a longer-than-normal protein. The DNA itself appears in the form of a repeating sequence, and the more repeats there are, the earlier the disease sets in.

Research on Huntington’s has thus far relied heavily on animal models of the disease, and has left many key questions unanswered. For example, scientists have not been able to resolve what function the HTT gene serves normally, or how its mutation creates problems in the brain.

Suspecting that the disease works differently in humans, whose brains are much bigger and more complex than those of lab animals, Brivanlou, along with research associates Albert Ruzo and Gist Croft, developed a cell-based human system for their research. They used the gene editing technology CRISPR to engineer a series of human embryonic stem cell lines, which were identical apart from the number of DNA repeats that occurred at the ends of their HTT genes.

“We started seeing things that were completely unexpected,” says Brivanlou. “In cell lines with mutated HTT, we saw giant cells. It looked like a jungle of disorganization.”

When cells divide, they typically each retain one nuclei. However, some of these enlarged, mutated cells flaunted up to 12 nuclei—suggesting that neurogenesis, or the generation of new neurons, was affected. The disruption was directly proportional to how many repeats were present in the mutation: The more repeats there were, the more multinucleated neurons appeared.

“Our work adds to the evidence that there is an unrecognized developmental aspect to the pathology,” Brivanlou says. “Huntington’s may not be just a neurodegenerative disease, but also a neurodevelopmental disease.”

Toxic or essential?

Treatments for Huntington’s have typically focused on blocking the activity of the mutant HTT protein, the assumption being that the altered form of the protein was more active than normal, and therefore toxic to neurons. However, Brivanlou’s work shows that the brain disruption may actually be due to a lack of HTT protein activity.

To test its function, the researchers created cell lines that completely lacked the HTT protein. These cells turned out to be very similar to those with Huntington’s pathology, corroborating the idea that a lack of the protein—not an excess of it—is driving the disease.

“We should rethink our approach to treating Huntington’s,” he says. “Both the role of the HTT protein and the timing of treatment need to be reconsidered; by the time a patient is displaying symptoms, it may be too late to medicate. We need to go back to the earliest events that trigger the chain reaction that ultimately results in disease so we can focus new therapies on the cause, not the consequences.”

The researchers hope their new cell lines will be a useful resource for studying the cellular and molecular intricacies of Huntington’s further, and suggest they may provide a model for examining other diseases of the brain that are specific to humans.