Jasper Therapeutics and Aruvant Announce Research Collaboration to Study JSP191, an Antibody-Based Conditioning Agent, with ARU-1801, a Novel Gene…

REDWOOD CITY, Calif. and NEW YORK and BASEL, Switzerland, June 21, 2021 /PRNewswire/ --Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, andAruvant Sciences, a private company focused on developing gene therapies for rare diseases, today announced that they have entered a non-exclusive research collaboration to evaluate the use of JSP191, Jasper's anti-CD117 monoclonal antibody, as a targeted, non-toxic conditioning agent with ARU-1801, Aruvant's investigational lentiviral gene therapy for sickle cell disease (SCD). The objective of the collaboration is to evaluate the use of JSP191 as an effective and more tolerable conditioning agent that can expand the number of patients who can receive ARU-1801, a potentially curative treatment for SCD.

"This research collaboration with Aruvant is the first to use a clinical-stage antibody-based conditioning agent and a novel clinical-stage gene therapy, giving this combination a clear advantage by moving beyond the harsh conditioning agents currently used for gene therapy and establishing this next-generation potentially curative treatment as a leader in sickle cell disease," said Kevin N. Heller, M.D., executive vice president, research and development of Jasper. "Our goal is to establish JSP191 as a potential new standard of care conditioning agent, broadly in autologous gene therapy and allogeneic hematopoietic stem cell transplantation."

Gene therapies and gene editing technologies generally require that a patient's own hematopoietic stem cells first be depleted from the bone marrow to facilitate the engraftment of the new, gene-modified stem cells through a process called conditioning. Other investigational gene therapies and gene editing approaches in SCD use a high-dose chemotherapy such as busulfan for the conditioning regimen, which can place patients at prolonged risk for infection and bleeding, secondary malignancy and infertility. ARU-1801 is currently the only gene therapy that has demonstrated durable efficacy using both a lower dose of chemotherapy and a different agent than busulfan with a more limited side effect profile. The Aruvant-Jasper partnership is focused on evaluating the potential of using JSP191, a highly targeted anti-CD117 (stem cell factor receptor) monoclonal antibody agent, as the foundationof a novel conditioning regimen for use in combination with ARU-1801 to further reduce the negative side effects while maintaining efficacy.

"The unique attributes of ARU-1801 enable us to bring a potentially curative one-time therapy to individuals with sickle cell disease that can be delivered in the safest way possible," said Will Chou, M.D., Aruvant chief executive officer. "By partnering with Jasper to evaluate the use of JSP191 with ARU-1801, we are one step closer to developing a next-generation definitive therapy with an even more patient-friendly conditioning regimen. We believe that this combination may be able to further expand the number of patients who can benefit from ARU-1801 in the future, including potentially those with more moderate disease."

About JSP191 JSP191 is a humanized monoclonal antibody in clinical development as a conditioning agent that blocks stem cell factor receptor signaling leading to clearance of hematopoietic stem cells from bone marrow, creating an empty space for donor or gene-corrected transplanted stem cells to engraft. While hematopoietic cell transplantation can be curative for patients, its use is limited because standard high dose myeloablative conditioning is associated with severe toxicities and standard low dose conditioning has limited efficacy. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients. It is currently enrolling in two clinical trials for myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and severe combined immunodeficiency (SCID) and expects to begin enrollment in four additional studies in 2021 for severe autoimmune disease, sickle cell disease, chronic granulomatous disease and Fanconi anemia patients undergoing hematopoietic cell transplantation.

About ARU-1801 ARU-1801 is designed to address the limitations of current curative treatment options, such as low donor availability and the risk of graft-versus-host disease (GvHD) seen with allogeneic stem cell transplants. Unlike investigational gene therapies and gene editing approaches which require fully myeloablative conditioning, the unique characteristics of ARU-1801 allow it to be given with reduced intensity conditioning ("RIC"). Compared to myeloablative approaches, the lower dose chemotherapy regimen underlying RIC has the potential to reduce not only hospital length of stay, but also the risk of short- and long-term adverse events such as infection and infertility. Preliminary clinical data from the MOMENTUMstudy, an ongoing Phase 1/2 trial of ARU-1801 in patients with severe sickle cell disease, demonstrate continuing durable reductions in disease burden.

The MOMENTUM Study Aruvant is conducting the MOMENTUM study, which is evaluating ARU-1801, a one-time potentially curative investigational gene therapy for patients with SCD. This Phase 1/2 study is currently enrolling participants, and information may be found at momentumtrials.comwhich includes a patient brochure, an eligibility questionnaireand information for healthcare providers.

About Jasper Therapeutics Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, a first-in-class anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic and autologous hematopoietic cell transplants and gene therapies. In parallel, Jasper Therapeutics is advancing its preclinical engineered hematopoietic stem cell (eHSC) platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

About Aruvant Sciences Aruvant Sciences, part of the Roivant family of companies, is a clinical-stage biopharmaceutical company focused on developing and commercializing gene therapies for the treatment of rare diseases. The company has a talented team with extensive experience in the development, manufacturing and commercialization of gene therapy products. Aruvant has an active research program with a lead product candidate, ARU-1801, in development for individuals suffering from sickle cell disease (SCD). ARU-1801, an investigational lentiviral gene therapy, is being studied in a Phase 1/2 clinical trial, the MOMENTUM study, as a one-time potentially curative treatment for SCD. Preliminary clinical data demonstrate engraftment of ARU-1801 and amelioration of SCD is possible with one dose of reduced intensity chemotherapy. The company's second product candidate, ARU-2801, is in development to cure hypophosphatasia, a devastating, ultra-orphan disorder that affects multiple organ systems and leads to high mortality when not treated. Data from pre-clinical studies with ARU-2801 shows durable improvement in disease biomarkers and increased survival. For more information on the ongoing ARU-1801 clinical study, please visit http://www.momentumtrials.comand for more on the company, please visit http://www.aruvant.com. Follow Aruvant on Facebook, Twitter @AruvantSciencesand on Instagram @Aruvant_Sciences.

About Roivant Roivant's mission is to improve the delivery of healthcare to patients by treating every inefficiency as an opportunity. Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch Vants nimble and focused biopharmaceutical and health technology companies. For more information, please visit http://www.roivant.com.

SOURCE Aruvant Sciences andJasper Therapeutics

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Gamida Cell Announces Publication in Blood, the Journal of the American Society of Hematology, of the First Pivotal Trial to Evaluate a Cell Therapy…

BOSTON--(BUSINESS WIRE)--Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for blood cancers and serious hematologic diseases, today announced that the results of a Phase 3 clinical study of omidubicel have been published in Blood, the official journal of the American Society of Hematology. Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell transplant solution for patients with hematologic malignancies.

The results demonstrate that transplantation with omidubicel leads to faster neutrophil and platelet recovery compared to a standard umbilical cord blood graft, and results in fewer early bacterial and viral infections and less time in the hospital.

We are pleased that the data from this well-conducted international Phase 3 trial have been published in Blood, the highly respected, peer-reviewed journal of the American Society of Hematology, said Ronit Simantov, M.D., chief medical officer of Gamida Cell. The robust results of this clinical trial have demonstrated that omidubicel could provide an important new option for patients with hematologic malignancies in need of a bone marrow transplant.

Data from this study were previously presented at the Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy and Center for International Blood & Marrow Transplant Research, and most recently during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation. The pivotal study was an international, multi-center, randomized Phase 3 trial designed to compare the safety and efficacy of omidubicel to standard umbilical cord blood transplant in patients with high-risk hematologic malignancies undergoing a bone marrow transplant.

Previous studies have shown that engraftment with omidubicel is durable, with some patients in the Phase 1/2 study now a decade past their transplant. The Phase 3 data reinforce omidubicels potential to be a new standard of care for patients who are in need of stem cell transplantation but do not have access to an appropriate matched donor, said Mitchell Horwitz, M.D., lead author of the paper and a professor of medicine at the Duke Cancer Institute.

The full Blood manuscript is available here: https://ashpublications.org/blood/article/doi/10.1182/blood.2021011719/476235/Omidubicel-Versus-Standard-Myeloablative-Umbilical.

Details of Phase 3 Efficacy and Safety Results Shared in Blood

The intent-to-treat analysis included 125 patients aged 1365 years with a median age of 41. Forty-four percent of the patients treated on study were non-Caucasian, a population known to be underrepresented in adult bone marrow donor registries. Patient demographics and baseline characteristics were well-balanced across the two study groups. Patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome or lymphoma were enrolled at more than 30 clinical centers in the United States, Europe, Asia, and Latin America.

Gamida Cell previously reported in May 2020 that the study achieved its primary endpoint, showing that omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment, a measure of how quickly the stem cells a patient receives in a transplant are established and begin to make healthy new cells and a key milestone in a patients recovery from a bone marrow transplant. The median time to neutrophil engraftment was 12 days for patients randomized to omidubicel compared to 22 days for the comparator group (p<0.001).

All three secondary endpoints, details of which were first reported in December 2020, demonstrated a statistically significant improvement among patients who were randomized to omidubicel compared to patients randomized to standard cord blood graft. Platelet engraftment was significantly accelerated with omidubicel, with 55 percent of patients randomized to omidubicel achieving platelet engraftment at day 42, compared to 35 percent for the comparator (p = 0.028). Hospitalization in the first 100 days after transplant was also reduced in patients randomized to omidubicel, with a median number of days alive and out of hospital for patients randomized to omidubicel of 61 days, compared to 48 days for the comparator (p=0.005). The rate of infection was significantly reduced for patients randomized to omidubicel, with the cumulative incidence of first grade 2 or grade 3 bacterial or invasive fungal infection for patients randomized to omidubicel of 37 percent, compared to 57 percent for the comparator (p=0.027). Additional data reported in the manuscript included a comparison of infection density, or the number of infections during the first year following transplantation, which showed that the risk for grade 2 and grade 3 infections was significantly lower among recipients of omidubicel compared to control (risk ratio 0.5, p<0.001).

Data from the study relating to exploratory endpoints also support the clinical benefit demonstrated by the studys primary and secondary endpoints. There was no statistically significant difference between the two patient groups in incidence of grade 3/4 acute GvHD (14 percent for omidubicel, 21 percent for the comparator) or all grades chronic GvHD at one year (35 percent for omidubicel, 29 percent for the comparator). Non-relapse mortality was shown to be 11 percent for patients randomized to omidubicel and 24 percent for patients randomized to the comparator (p=0.09).

These clinical data results form the basis of a Biologics License Application (BLA) that Gamida Cell plans to submit to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2021.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplants for patients with hematologic malignancies (blood cancers), for which it has been granted Breakthrough Status by the FDA. Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit http://www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the FDA or any other health authority.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the potential for omidubicel to become a new standard of care and the anticipated submission of a BLA for omidubicel, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to Gamida Cells ability to prepare regulatory filings and the review process therefor; complications in Gamida Cells plans to manufacture its products for commercial distribution; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on March 9, 2021, as amended on March 22, 2021, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

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Gamida Cell Announces Publication in Blood, the Journal of the American Society of Hematology, of the First Pivotal Trial to Evaluate a Cell Therapy...

More than 800 medicines are in development for diseases that disproportionately affect racial and ethnic communities – PRNewswire

WASHINGTON, June 22, 2021 /PRNewswire/ -- We are in a new era of medicine where groundbreaking biopharmaceutical research and development is transforming medicine, but these innovations are meaningless if they don't reach patients, including those in underserved communities. Health disparities are not new, but the COVID-19 pandemic put a spotlight on long-standing health inequities that affect diverse racial and ethnic communities in America. Data shows these populations have been disproportionately impacted by COVID-19. In fact, American Indian/Alaskan Native, Hispanic, and Black populations are approximately twice as likely to die from COVID-19, as compared to non-Hispanic whites.

Researchers have found that people with certain health conditions, including chronic conditions such as Alzheimer's disease, certain cancers, chronic kidney disease, chronic lung diseases, type 2 diabetes, heart conditions, HIV infection, liver disease, obesity, sickle cell disease and stroke, are at higher risk of severe illness or death from COVID-19. Many of these conditions are tied to health disparities that disproportionality affect racial and ethnic communities for genetic and environmental reasons, or due to inequities in social and economic conditions.

Today, PhRMA released a new report exploring the 829 medicines in development that aim to address the diseases and conditions that affect racial and ethnic communities at a higher rate and are also associated with worse COVID-19 outcomes.

Among the medicines in development to improve management of these diseases are:

It is critical that all patients, including historically underserved racial and ethnic communities, have access to medicines. One way to reduce barriers to health care access and enable everyone to benefit from new medicines is to ensure that clinical trials are diverse and inclusive and include participants representative of the population the medicine intends (or aims) to treat. The biopharmaceutical industry has been working with patients, communities, regulatory authorities, health care practitioners, academics and policymakers to enhance diversity in clinical trials, so the clinical trial population testing medicines better reflect the patients that will use the new therapies and medicines should they are approved by the U.S. Food and Drug Administration.

To this end, PhRMA and its member companies have voluntarily adopted first-ever industry-wide principles on clinical trials diversity, adding a new chapter to the already existing Principles on Conduct Clinical Trials & Communication of Clinical Trial Results.The new clinical trial diversity principles are designed to build trust, reduce barriers to clinical trial access, enhance an understanding of drug effects in diverse patient populations, and promote the sharing of information on policies and practices to increase clinical trial diversity.

Equity is critical to the health and well-being of diverse racial and ethnic communities, and it remains essential to a robust ecosystem of innovation. America's biopharmaceutical companies are pushing for necessary systemic and long-term change to better meet the needs of underserved communities in America.

To learn more about the PhRMA Equity Initiative and PhRMA's commitment to inclusion, visit https://phrma.org/Equity and tune in to The Atlantic's Health Equity Summit where PhRMA's Chief Operating Officer, Lori Reilly, and Genentech's Chief Diversity Officer, Quita Highsmith, will have a conversation about building trust in clinical trials.

Learn more about the medicines in development to address health equity here.

This post originally appeared on the Catalyst blog.

CONTACT:Andrew Powaleny,[emailprotected], 202-835-3460

SOURCE Pharmaceutical Research and Manufacturers of America (PhRMA)

https://phrma.org/

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Andrs Garca Receives Distinguished Professor Award | Research – Research Horizons

Vision. Collaboration. Innovation. The qualities for which Georgia Tech has become so well-known were embodied in people like Bob Nerem, founding director of the Parker H. Petit Institute for Bioengineering and Bioscience (IBB) from 1995 to 2009, Parker H. Petit Distinguished Chair for Engineering in Medicine, and Institute professor emeritus until his death in March 2020.

In 1997 Nerem recruited Andrs Garca and his wife, Michelle LaPlaca, to join the pioneering IBB program at Tech after they completed their work as postdoctoral fellows at the University of Pennsylvania his in cell and molecular biology, hers in neurotrauma.

In 1998 when Garca and LaPlaca joined Tech, IBB launched its National Science Foundation Engineering Research Center in Tissue Engineering with Emory University, making it a strategic community for Garca to join to start his research program in an emerging field. Now as executive director of IBB and a Regents Professor in the Woodruff School of Mechanical Engineering, Garca is continuing Nerems legacy of vision, collaboration, and innovation in everything he does. In recognition of his work, he is the 2021 recipient of the Class of 1934 Distinguished Professor Award, the highest honor given to a Georgia Tech professor. The award is presented to a professor who has made significant, long-term contributions to teaching, research, and public service.

Known as a global pioneer in developing biomaterials systems for translational applications in regenerative medicine, Garca holds more than a dozen U.S. patents. Discoveries include the development of hydrogels for protein and cell delivery in regenerative medicine, engineering biofunctional materials to improve islet survival, and the design of infection-fighting materials. His research focuses on creating an engineered class of materials that can be used for applications to transplant a graft without immune-suppressive drugs. Human studies are planned to start next year. Researchers in his lab are developing new ways to treat Type 1 diabetes, eventually working with adult stem cells to reprogram them into insulin-producing cells. Future applications include addressing kidney failure and other diseases.

Creating Opportunities for Collisions

Garca is enthusiastic about his research, as well as all of the collaborative research in IBB. IBB is a fantastic community of faculty, trainees, and staff who come together in making discoveries and developing the technologies in bioengineering and bioscience that will change the world, he said. His goal is that IBB will continue to expand research and integrative opportunities to have a major economic impact, creating an environment to translate research into commercial products and therapies. With IBB we want to provide opportunities for collisions, unexpected interactions that lead to the discoveries. It was Bob Nerems vision to drive that sort of collaboration, he said.

Garca shared an example of one such collision: As part of a grant from the Juvenile Diabetes Research Foundation (JDRF), I was required to present unpublished research progress at a meeting with other researchers from throughout the country. After I made my presentation that morning, a JDRF director announced that for the next three-year cycle of funding we would need to collaborate with someone in the room on research. We went to lunch, and as I was building my sandwich, an immunologist introduced himself to me, complimented me on my presentation, and asked me if I thought I could develop a biomaterial to deliver the particular protein he was working with. You never ask an engineer if they think they can do something. Theyll find a way. I said I could, and we started working together.

An elected member of both the National Academy of Inventors and the National Academy of Engineering, Garca has established three startup companies in the past seven years. He has received numerous awards for his teaching and research and has published more than 230 peer-reviewed papers in prestigious journals.

Mentoring Students

Garca has supervised 15 postdoctoral researchers and advised/co-advised 37 Ph.D. students. He is known for his long-term commitment to his trainees, as well as mentoring students outside of his laboratory and classroom. While he has not taught for the past three years because of his responsibilities as IBB executive director, he still mentors students in his lab.

I take my responsibility as a mentor and supervisor seriously. It is important to have one-to-one interactions, Garca said. I take a practical approach and feel it is critical to explain why learning a topic is important, sharing practical applications, and offering experiential hands-on learning. I have had very supportive and engaged mentors and would like to pass that on to others.

Background

A native of Puerto Rico, Garca originally came to the states to study at Cornell University. He was very interested in the emerging field of biomedical engineering, but his father, an industrial engineer, advised him to major in another engineering discipline as a backup in case the biomedical field didnt develop as anticipated. Garca took his fathers advice, earning his bachelors degree in mechanical engineering and also taking biology and bioengineering classes.

During his senior year Garca participated in a project to design a structure to support fractured legs for horses. He worked to optimize the way a boot attached to the bone so that it wouldnt fracture again. He became interested in research, and his professors recommended that he go to graduate school. He earned his masters and Ph.D. in bioengineering from the University of Pennsylvania. Garca was the first person in his immediate family to earn a doctoral degree.

Garca and his family have embraced all things Georgia Tech. He and LaPlaca have two sons, Rafael, a Tech mechanical engineering (ME 2018) graduate working at GTRI, and Andrs, a fourth-year mechanical engineering student at Tech. They hold season basketball and football tickets. One of their dogs is named Buzz.

Garca said he was deeply honored, humbled, and shocked when Georgia Tech President ngel Cabrera called and told him he had been selected for this years Distinguished Professor Award. The award is special to me because it reflects the great contributions my friends, family, and peers have made in my life to get me to this point. I am grateful for my trainees, my collaborators, and colleagues, and for the support that Georgia Tech has provided in giving me the tools to succeed. Georgia Tech is the best, Garca said.

Quotes From Colleagues and Former Students

Professor Garca has been an integral part of growth of the international reputation of our bioengineering program and the Institute for Bioengineering and Bioscience. Having seen the sustained impact that he has had on students from K-12 (Project Engages) through graduate students, he is a remarkable educator who I feel is well deserving of this award.

Sam Graham Eugene C. Gwaltney Jr. School Chair in Mechanical Engineering Georgia Tech

He remains on my short list of speakers because I resonate so strongly with his approach very deep technical skills, outstanding problem definition, and tremendous colleague in service and collegiality. He is also a terrific mentor, and his former lab members are stars. He cares about doing great science and teaching people what he learned. Andrs Garca is a gem at Georgia Tech, and as an alum I hope you can keep him there he is doing some of the best biology on campus and is a superb attractor of the best students from MIT.

Linda G. Griffith S.E.T.I. Professor of Mechanical and Biological Engineering Director, MIT Center for Gynepathology Research Chair, MIT Biological Engineering Undergraduate Programs Committee

The lab around Professor Garca performs research at a unique broadness and depth. His remarkable combination of professional and personal skills is the key for his success and makes him a highly estimated collaboration partner for other scientists across disciplines and continents. He is the most invited American scientist at plenary lectures in European conferences on biomaterials. This is not only due to the high quality of his work, but also to his ability as a communicator and active discussion partner, his openness to address new topics in collaboration, and his passion for science and education that truly inspires and motivates young researchers.

Arnzazu del Campo Director INM-Leibniz Institute for New Materials Professor, Materials Synthesis, Saarland University

The five years that I spent in Andrs lab were transformative for me, and the influence of that experience is difficult to put into words. Andrs taught me many things how to be a scientist; how to develop creative and impactful ideas; how to execute on those ideas; how to write; how to present, etc. But more important than all the technical aspects of what I learned from Andrs, I learned from him who I wanted to be. Most of my professional life, and much of my personal life, is modeled after what I have learned from watching Andrs as a professor, colleague, friend, father, and husband.

Charles Gersbach Professor, Department of Biomedical Engineering Director, Center for Biomolecular and Tissue Engineering Director, Center for Advanced Genomic Technologies Duke University

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Local foundation awards $1.25 million to MIND Institute to study rare genetic condition – UC Davis Health

The RDM Positive Impact Foundation is funding an ambitious $1.25 million research project at the UC Davis MIND Institute to study SYNGAP1. The rare genetic condition causes seizures (epilepsy), intellectual disability and developmental delays. It is also highly associated with autism; about half of all SYNGAP1 patients have an autism diagnosis.

A staff member conducts research in the Segal Lab.

Ron Mittelstaedt and his wife, Darin, who live in El Dorado Hills, run the foundation. Hes the executive chairman of Waste Connections, a solid waste and recycling company with 20,000 employees in North America, and his family operates Toogood Estate Winery in Somerset. The Mittelstaedts have donated millions of dollars to organizations that help children over the past 15 years.

This time, its personal.

About three and-a-half years ago, Ron Mittelstaedts best friend died, leaving behind three sons and their families. Ive become sort of a surrogate dad, and now a surrogate grandfather, explained Mittelstaedt. One of those grandsons was diagnosed with a SYNGAP1 mutation a year and-a-half ago. With the familys support, Mittelstaedt is providing meaningful funding to the MIND Institute to advance research about the syndrome.

The reality is, like many rare conditions, there arent a lot of great options. So, were trying to find potentially life-changing treatment that hopefully may impact the lives of people with SYNGAP1, he said.

Mittelstaedt was previously on the MIND Institutes inaugural National Council of Visitors (then called the MIND Institute Advisory Council), and funded a successful research project that developed a blood test for Tourette syndrome.

A staff member in the Silverman lab conducts behavioral neuroscience research.

We are grateful to the Mittelstaedts for their generosity, said MIND Institute Director Leonard Abbeduto. As a collaborative hub for preclinical and clinical research on neurodevelopmental disability, the MIND Institute is uniquely suited to build on past successes and tackle the complexities of SYNGAP1 to provide help for families.

The funding also supports UC Davis' $2 billion fundraising campaign, Expect Greater: From UC Davis, For the World, the largest philanthropic endeavor in university history. Together, donors and UC Davis are advancing work to prepare future leaders, sustain healthier communities, and bring innovative solutions to today's most urgent challenges.

SYNGAP1-related non-syndromic intellectual disability is a rare neurodevelopmental condition caused by a variation in one gene. The gene, SYNGAP1, contains instructions for making a protein (SynGAP). This protein is located at the junctions between nerve cells, called synapses, and helps regulate changes important for memory and learning. The protein also helps regulate communication between neurons.

When the variation is present, the SYNGAP1 protein in cells is reduced which causes an increase in the excitability in the synapses. This makes it difficult for neurons to communicate and increases the likelihood of seizure events. This can lead to a variety of symptoms:

Jill Silverman

SYNGAP1 syndrome affects 1-4 out of 10,000 people. The first patient was identified in 2009.

The MIND Institutes interventional genetics team includes faculty who specialize in multiple research areas.

Ron Mittelstaedt

Each of us is a world expert in our particular discipline, so bringing us all together means the chances of success are much more likely, said Jill Silverman, associate professor in the Department of Psychiatry and Behavioral Sciences and an internationally recognized expert in the use of rodent models for therapeutic development. Silvermans Lab is known for its expertise in behavioral neuroscience research.

In addition to Silverman, the SYNGAP1 team includes three other MIND Institute faculty members:

The sum of the group is going to be much greater than anything we could have done alone, said Fink, whose lab focuses on therapeutic development for neurodevelopmental conditions and neurodegenerative diseases. The fact that the foundation has funded us as a team, across multiple centers and programs is really unique. This funding brings us all together for an important project.

Kyle Fink in his lab, which focuses on therapeutic development for neurodevelopmental conditions and neurodegenerative diseases.

The researchers will work on parallel tracks, each contributing a piece of the puzzle.

Silverman will conduct specialized behavioral tests on mouse models of SYNGAP1, using tools with corresponding metrics in humans, such as EEGs (a type of brain scan) to determine clinically relevant outcomes.

Nord and Fink will create a new mouse model that contains the mutated human SYNGAP1 gene, while Segal and Fink will create new molecular therapies to counter that mutated gene. Theyll also figure out how to deliver those therapies to the brain.

Were not just trying to treat the symptoms of the disease with a drug, explained Segal, whose lab specializes in molecular analysis. We are trying to change the underlying genetic condition, and our particular approach is to do that in a way that does not change the DNA sequence. We use tools to change the gene expression instead, which we think will make safer therapies. Its really a state-of-the-art approach. Its molecular therapy.

David Segal working in his lab, which specializes in molecular analysis.

The collaborative approach, often called team science, coupled with the RDM Positive Impact Foundations support, allows for an ambitious, fast-tracked research program. The $1.25 million frees the researchers from the need to apply for multiple federal grants and enables them to focus immediately on SYNGAP1.

The team excels in whats often called bench to bedside research, translating results from the lab directly into therapies for patients.

We see these patients, we meet with them, were on Zoom calls with them and I want to find something that works for them. I want to change their lives. Thats what Im driven by, Silverman said.

Silverman, Fink and Segal have had previous success with their work on another rare genetic condition, Angelman syndrome, which causes developmental delay, speech and balance challenges and intellectual disability.

David Segal

Their labs helped to create and characterize the first rat model of Angelman syndrome last year. The Segal lab also created a protein therapeutic that could increase the level of the affected gene in mouse models of Angelman syndrome, a major discovery.

All three labs are still working on a wide range of therapeutics for Angelman, including molecular therapies delivered with viruses or stem cells and novel small molecule compounds.

Ron Mittelstaedt is hoping for another success story, this time with SYNGAP1, but hes also realistic about the research process.

We are all very aware that going down this path doesnt guarantee anything except the ability to get up to bat, and we could get a hit or strike out. But doing nothing guarantees you dont get a hit, so its important for us to take action, and were hopeful well hit a home run.

UC Davis researchers get $3 million FAST grant to find treatment for Angelman syndrome

The UC Davis MIND Institute in Sacramento, Calif. was founded in 1998 as a unique interdisciplinary research center where families, community leaders, researchers, clinicians and volunteers work together toward a common goal: researching causes, treatments and potential prevention of neurodevelopmental disabilities. The institute has major research efforts in autism, fragile X syndrome, chromosome 22q11.2 deletion syndrome, attention-deficit/hyperactivity disorder (ADHD) and Down syndrome. More information about the institute and its Distinguished Lecturer Series, including previous presentations in this series, is available on the Web at mindinstitute.ucdavis.edu.

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Local foundation awards $1.25 million to MIND Institute to study rare genetic condition - UC Davis Health

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion – Science Magazine

MeCP2 binds hydroxymethylated CA repeats

Despites of decades of research on the Rett syndrome protein MeCP2, its function remains unclear. Ibrahim et al. show that MeCP2 is a hydroxymethylated cytosine-adenosine (CA) repeat-binding protein that modulates chromatin architecture at a distance from the transcription start site (see the Perspective by Zhou and Zoghbi). MeCP2 accumulates and spreads around modified CA repeats and competes for nucleosome occupancy. Loss of MeCP2 results in a widespread increase in nucleosome density inside lamina-associated domains and transcriptional dysregulation of genes enriched in CA repeats. These results shed light on the underlying molecular mechanism of Rett syndrome, a severe disease associated with mutations in MeCP2.

Science, abd5581, this issue p. eabd5581; see also abj5027, p. 1390

Rett syndrome is a severe neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MeCP2). Initially, MeCP2 was identified as an essential brain protein that binds to methylated CpG (mCG) via its methyl-binding domain (MBD) and acts as transcriptional repressor. However, during early brain development, the postnatal accumulation of MeCP2 parallels the genome-wide high-level accumulation of hydroxymethylcytosine (hmC) and methylated CpA (mCA), suggesting that MeCP2 may also recognize and bind to DNA sequences that contain these modified nucleotides.

The ability of MeCP2 to recognize both mCA and hmC as well as mCG has led to conflicting conclusions regarding its function in transcriptional regulation, because these cytosine modifications are associated with either repression (mCA and mCG) or activation (hmC) of transcription. The unambiguous identification of the MeCP2 target sequence(s) would help to clarify this issue.

CA repeats (CAn) represent ~1% of the mouse genome and belong to the microsatellite family. They are widely distributed throughout the genome and have been shown to affect transcription of nearby genes. Our recent data reveal that CAn are methylated (mCAn) or hydroxymethylated (hmCAn) in various cell types. In a search for proteins that could specifically recognize and bind these CA repeats, we identified MeCP2 as a specific reader of CA repeats. We hypothesized that the methylation status of CAn is essential for the recognition and binding of MeCP2, possibly through recognition of the modified nucleotides in CA repeats with distinct affinities, relevant for its neuronal function in transcriptional regulation.

Here we show that within the MBD family, MeCP2 is the only protein that specifically recognizes and binds to CA repeats, with much stronger affinity than mCG and mCA. MeCP2 selectively recognizes CA repeat DNA in a strand-specific manner and requires at least five consecutive CA dinucleotides to optimally bind DNA. While MeCP2 can bind in vitro to modified and nonmodified CA repeats, it exhibits impressive selectivity toward hydroxymethylated CA repeats, which are modified by DNA (cytosine-5)-methyltransferase 3A. The modified cytosine, only when located within a CA repeat, serves as a nucleation point for both MeCP2 accumulation and spreading around the repeat, which, in turn, correlates with nucleosome exclusion. In addition, loss of MeCP2 results in widespread increase in nucleosome density within lamina-associated domains (LADs) and transcriptional dysregulation of CA repeatenriched genes located outside LADs.

We have also dissected the molecular basis of the MeCP2 hydroxymethylated CA repeat recognition by solving the crystal structure of MeCP2 in complex with hmCAn. The CA repeat creates a well-defined DNA shape, with a considerably modified geometry, including a widened major groove and negative roll parameters, located precisely at the modification site. We show that the molecular recognition of the hydroxymethylated CA repeat specifically occurs through Arg133, a key MeCP2 residue whose mutation causes Rett syndrome.

Our work identifies MeCP2 as a hydroxymethylated CA repeat DNA binding protein that targets the 5hmC-CA-rich sequence, which are specifically located on one strand. Our data provide insights into the origin of Rett syndrome at the molecular level and suggest that this neurodevelopmental disorder could be viewed as a chromatin disease, originating from the inability of mutant MeCP2 to bind and protect the CA repeats from nucleosome invasion. Our results open a previously unexplored area of research focused on understanding the role of specific protein binding to microsatellites and other repeats in neurological diseases of unknown etiology.

MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters the chromatin organization of CA repeats and LADs and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. WT, wild-type; KO, knockout.

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

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MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion - Science Magazine