Monthly Archives: May 2024

A new analysis has revealed detailed information about genetic variation in brain cells that could open new avenues for the targeted treatment of diseases such as schizophrenia and Alzheimers disease.

The findings, reported May 23 in Science, were the result of a multi-institutional collaboration known as PsychENCODE, founded in 2015 by the National Institutes of Health, which seeks new understandings of genomic influences on neuropsychiatric disease. The study was published alongside related studies in Science, Science Advances, and Science Translational Medicine.

Previous research has established a strong link between a persons genetics and their likelihood of developing neuropsychiatric disease, saysMark Gerstein, the Albert L. Williams Professor of Biomedical Informatics at Yale School of Medicine and senior author of the new study.

The correlations between genetics and your susceptibility to disease are much higher for brain diseases than for cancer or heart disease, said Gerstein. If your parents have schizophrenia, youre much more likely to get it than you are to get heart disease if your parents have the disease. There is a very large heritability for these brain-related conditions.

Whats less clear, however, is how this genetic variation leads to disease.

We want to understand the mechanism, said Gerstein. What is that gene variantdoingin the brain?

For the new study, researchers set out to better understand the genetic variation across individual cell types in the brain. To do so, they performed several types of single-cell experiments on more than 2.8 million cells taken from the brains of 388 people, including healthy individuals and others with schizophrenia, bipolar disorder, autism spectrum disorder, post-traumatic stress disorder, and Alzheimers disease.

From that pool of cells, the researchers identified 28 different cell types. Then they examined gene expression and regulation within those cell types.

In one analysis, the researchers were able to link gene expression to variants in upstream regulatory regions, bits of genetic code situated before the gene in question that can increase or decrease the genes expression.

Thats useful because if you have a variant of interest, you can now link it to a gene, said Gerstein. And thats really powerful because it helps you interpret the variants. It helps you understand what effect theyre having in the brain. And because we looked across cell types, our data also allow you to connect that variant to an individual cell type of action.

The researchers also assessed how particular genes, such as those associated with neurotransmitters, varied across individuals and cell types, finding variability was usually higher across cell types than across individuals. This pattern was even stronger for genes that code for proteins targeted for drug treatment.

And thats generally good for a drug, Gerstein said. It means that those drugs are homing in on particular cell types and not affecting your whole brain or body. It also means those drugs are more likely to be unaffected by genetic variants and work in many people.

Using the data generated by the analysis, the researchers were able to map out within-cell type genetic regulatory networks and between-cell communication networks, and then plug those networks into a machine learning model. Then, using an individuals genetic information, the model could predict whether they had a brain disease.

Because these networks were hard coded in the model, when the model made a prediction we could see which parts of the network contributed to it, said Gerstein. So we could identify which genes and cell types were important for that prediction. And that can suggest candidate drug targets.

In one example, the model predicted an individual with a particular genetic variant might have bipolar disorder, and the researchers could see that prediction was based on two genes in three cell types. In another, the researchers identified six genes in six cell types that contributed to a schizophrenia prediction.

The model also worked in the opposite direction. The researchers could introduce a genetic perturbation and see how that might affect the network and an individuals health. This, Gerstein says, is useful for drug design or previewing how well drugs or drug combinations might fare as treatments.

Together, the findings could help facilitate precision-medicine approaches for neuropsychiatric disease, said the researchers.

To further this work, the consortium hasmade its results and model availableto other researchers.

Our vision is that researchers interested in a particular gene or variant can use our resources to better understand what its doing in the brain or to perhaps identify new candidate drug targets to investigate more, said Gerstein.

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Tracking the cellular and genetic roots of neuropsychiatric disease - Yale News

Cartesian Therapeutics investigational cell therapy Descartes-08 has been granted regenerative medicine advanced therapy (RMAT) designation by the U.S. Food and Drug Administration (FDA) for the treatment of myasthenia gravis (MG).

RMAT status is intended for experimental regenerative medicines to treat, modify, reverse, or cure a serious or life-threatening disease and which have shown preliminary clinical evidence of being able to address an unmet need for treating that disease.

Developers of RMAT-designated treatments receive all the incentives of fast track and breakthrough therapy designations, including early and intensive interactions with the FDA that can help hasten treatment development.

Descartes-08 has also been granted orphan drug designation by the FDA for MG, another status intended to speed the therapys development by offering regulatory support and financial incentives.

Receipt of RMAT designation underscores our belief that Descartes-08 could serve as a meaningful addition to the MG treatment landscape, Carsten Brunn, PhD, president and CEO of Cartesian, said in a company press release.

We look forward to working closely with the FDA to efficiently advance the development of Descartes-08 for this underserved population, Brunn added.

Meanwhile, Descartes-08 is being tested in MG patients in a Phase 2b clinical trial, called MG-001 (NCT04146051). Cartesian remains on track to announce top-line results from the study by mid-year.

MG, an autoimmune disease, is caused by self-reactive antibodies that attack healthy proteins residing at the site of communication between nerve and muscle cells. These antibodies are produced by certain types of immune B-cells.

Descartes-08 is designed to deplete the levels of these B-cells, thereby lowering the production of disease-driving antibodies and easing MG symptoms.

Immune T-cells have the means to kill off these B-cells, but they dont naturally know they should target them. With Descartes-08, T-cells are removed from a patients body and engineered in the lab to be equipped with a chimeric antigen receptor, or CAR, that specifically binds to a protein found on immune B-cells, called BCMA. When the modified T-cells are infused back into the patient, they are now equipped to specifically bind and destroy the harmful B-cells.

While the concept of CAR T-cell therapy for treating autoimmune diseases isnt new, Descartes-08 takes a unique approach to help avoid toxicity-related safety issues that are common with this type of therapy.

With most CAR T-cell therapies, the CAR is introduced by providing T-cells with DNA that encodes its production. While having the advantage of being a one-time treatment, this also requires that patients undergo chemotherapy to kill off existing immune cells before the treatment, leading to toxicity-related side effects.

Instead of delivering DNA, Descartes-08 delivers RNA, an intermediate molecule thats produced when converting the information in DNA to a working protein. While this RNA-based version requires repeat dosing, it also avoids the need for chemotherapy and is thought to have a better safety profile. That also means it can be administered as an outpatient procedure without hospital admission.

The MG-001 trial included Phase 1b, Phase 2a, and Phase 2b parts, all involving adults with generalized MG (gMG). After an initial Phase 1b dose-finding portion, 11 gMG patients were enrolled in the Phase 2a study. There, they were assigned to receive six into-the-vein infusions of Descartes-08 in various dosing schedules.

Across both the Phase 1b and Phase 2a parts, the treatment was well tolerated and not associated with side effects common with DNA-based CAR T-cell therapies, including neurotoxicity and cytokine release syndrome, both of which are serious types of immune responses.

Evidence of clinically meaningful improvements in measures of MG disease severity were observed among Phase 2a participants that persisted for months after the six-week treatment period ended in most patients. Levels of disease-driving antibodies in the bloodstream were also reduced.

In the ongoing Phase 2b study, up to 30 adults with gMG will be randomly assigned to receive six weekly doses of Descartes-08 or a placebo. The groups will then be switched, with those initially given Descartes-08 receiving a placebo and vice versa.

The main goal of this part of the trial is to compare the effects of Descartes-08 versus a placebo on a standard measure of patient-reported disease severity.

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FDA grants CAR T-cell therapy Descartes-08 its RMAT designation - Myasthenia Gravis News

Two Bristol academics, Professors Eugenia Piddini and Gene Feder OBE, have been elected to the Academy of Medical Sciences respected and influential Fellowship. They join 58 exceptional biomedical and health scientists selected for their exceptional contributions to the advancement of medical science.

The new Fellows, announced on Tuesday 21 May, have been recognised for their remarkable contributions to advancing biomedical and health sciences, groundbreaking research discoveries and translating developments into benefits for patients and wider society.

Awardees join an esteemed Fellowship of over 1,400 researchers who are at the heart of the Academy's work, which includes nurturing the next generation of researchers and shaping research and health policy in the UK and worldwide. The expertise of Fellows elected this year spans a wide range of clinical and non-clinical disciplines, from midwifery to cancer stem cell biology.

Eugenia Piddini, Professor of Cell Biology in the School of Cellular and Molecular Medicine, is conducting innovative work to identify cell competition-based strategies to gain control over tissue colonisation, its impact in tissue colonisation in regenerative medicine and to prevent tumour expansion in cancer.

A cell and developmental biologist,Eugenia is known for her seminal work in the field of cell competition the mechanism of tissue quality control that removes damaged cells from tissues. Eugenias discoveries have helped widen the scope of cell competition in terms of physiological relevance and potential therapeutic impact. Recently, Eugenias group demonstrated that cell competition acts in adult tissues. There it can potentially slow down the onset of disease/ageing by eliminating damaged cells.

Eugenias team has also shown that tumour cells kill surrounding normal cells via cell competition to free space for their own growth. Their work has identified many mechanisms and signals that cells use to compete. By explaining the mechanisms that cells use to compete the Piddini group aims to identify cell competition-based strategies to gain control over tissue colonisation.

In recognition of her work Eugenia, who is also School Research Director, was awarded the British Society for Cell Biology Hooke Medal in 2019 and in 2023, was elected as a Member of the European Molecular Biology Organisation.

Gene Feder, is a GP and Professor of Primary Care at Bristols Centre for Academic Primary Care, Bristol Medical School and Director of VISION, a UK Prevention Research Partnership (UKPRP) consortium.

Professor Feder leads ground-breaking national and international research on domestic violence and abuse (DVA) from epidemiology to health care response. He is the architect of IRIS, a national DVA programme for general practice, and co-founded IRISi, a social enterprise implementing IRIS nationally. He has extended his research globally through EU and Medical Research Council grants, and co-leadership of HERA, a National Institute for Health and Care Research (NIHR) Global Health Group in collaboration with researchers in Brazil, Nepal Sri Lanka, and the occupied Palestinian territories (oPT).

Committed to developing and evaluating effective and compassionate health care, Professor Feder has championed the use of randomised controlled trials to test improvements in general practice care of patients with heart and respiratory conditions, and robust methods to develop and implement clinical guidelines that make a difference to patients. He extended epidemiological, trial and meta-analytic methods to research on gender-based violence, combining quantitative and qualitive data to evaluate interventions, collaborating with statisticians, epidemiologists, economists, and social scientists. He has chaired four NICE guidelines and the World Health Organisation (WHO) intimate partner and sexual violence guideline development group.

In 2012, he co-founded the Foundation for Family Medicine in Palestine, which aims to support universal health coverage throughout the occupied Palestinian Territories based on effective, efficient and high-quality primary care. In 2016, Professor Feder was awarded an OBE for services to health care and survivors of domestic violence. In 2022, Gene was appointed Director of VISION, a five-year UKPRP inter-disciplinary consortium researching the intersection of violence and health to reduce and mitigate the effects of violence through better measurement and analysis of health care, police, criminal justice, and voluntary sector data. He is an expert advisor to UK Government and WHO.

Professor Andrew Morris PMedSci, President of the Academy of Medical Sciences, said: It is an honour to welcome these brilliant minds to our Fellowship. Our new Fellows lead pioneering work in biomedical research and are driving remarkable improvements in healthcare. We look forward to working with them, and learning from them, in our quest to foster an open and progressive research environment that improves the health of people everywhere through excellence in medical science.

This year's cohort marks a significant milestone in the Academy's efforts to promote equality, diversity and inclusion (EDI) within its Fellowship election. Among the new Fellows, 41 per cent are women, the highest percentage ever elected. Additionally, Black, Asian and minority ethnic representation is 29 per cent, an 11 per cent increase from the previous year. The new Fellows hold positions at institutions across the UK, including in Edinburgh, Birmingham, Liverpool, Manchester, Sheffield, Nottingham and York.

Professor Morris added: It is also welcoming to note that this year's cohort is our most diverse yet, in terms of gender, ethnicity and geography. While this progress is encouraging, we recognise that there is still much work to be done to truly diversify our Fellowship. We remain committed to our EDI goals and will continue to take meaningful steps to ensure our Fellowship reflects the rich diversity of the society we serve."

The new Fellows will be formally admitted to the Academy at a ceremony on Wednesday 18 September 2024.

The Academy of Medical Sciences is the independent, expert body representing the diversity of medical science in the UK. Its mission is to advance biomedical and health research and its translation into benefits for society. The Academy's elected Fellows are the most influential scientists in the UK and worldwide, drawn from the NHS, academia, industry and the public service.

About the Academy of Medical SciencesThe Academy of Medical Sciences is the independent, expert voice of biomedical and health research in the UK. Our Fellowship comprises the most influential scientists in the UK and worldwide, drawn from the NHS, academia, industry, and the public service. Our mission is to improve the health of people everywhere by creating an open and progressive research sector. We do this by working with patients and the public to influence policy and biomedical practice, strengthening UK biomedical and health research, supporting the next generation of researchers through funding and career development opportunities, and working with partners globally.

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May: academy-medical-sciences | News and features - University of Bristol

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Benefits of Stem Cell Therapy: Unlocking Regenerative Medicine's Potential - Intelligent Living