New stem cell model developed for treatment of newborn lung … – Innovation Origins

Congenital diaphragmatic hernia is one of the deadliest birth defects. To better understand and treat this condition in the future, an international team of researchers involving Leipzig University Hospital designed a new cell model in the laboratory and tested a drug therapy on it, the institution announced in a press release. The promising results of their recent study have been published in the prestigious American Journal of Respiratory and Critical Care Medicine.

Congenital diaphragmatic hernia (CDH) is a common condition, affecting one in every 2500births. Up to 30per cent of affected babies die from it. The main problem is the underdeveloped lung. The condition also involves a hole in the diaphragm, which paediatric surgeons correct by closing it in the first week of life. Until now, there has been little medical knowledge about how CDH develops what exactly goes wrong during embryonic development. Dr Richard Wagner, a paediatric surgeon and scientist at Leipzig University Hospital, teamed up with researchers from Massachusetts General Hospital in Boston to establish a new patient-specific cell model at Harvard Medical School. Using their model, the researchers investigated possible ways of treating this condition.

German stem cell research has its eye on retinal diseases

Human-induced pluripotent stem cells (HiPSCs) can be used to generate brain organoids that have an ocular structure.

Babies with CDH are placed on a ventilator immediately after birth. We were able to isolate stem cells from the fluid that is sucked out of the childrens lungs and otherwise disposed of, and grow them in the laboratory, explains Dr Wagner, first author of the study. While working as a postdoctoral researcher in the US, the doctor from Leipzig examined the stem cells in the laboratory together with the American researchers, designing cell models of the airways of the tiny patients. This gave them access for the first time to living human lung tissue from patients with CDH. They then compared the stem cells from healthy and underdeveloped lungs.

When the researchers looked at the molecular properties of the stem cells, they found that they had been altered due to inflammation. However, drug therapy in the cell model was able to restore functionality. We also tested this process in animal models and showed that the treatment contributed to better lung development there, too. With the same drug therapy, we were therefore able to achieve positive effects both in human cells in the Petri dish and in the living organism in the established animal model, explains Dr Wagner.

The treatment was performed with the steroid dexamethasone. This drug is already used in clinical practice to induce lung maturity in the foetus when there is a risk of premature birth during pregnancy. What is most appealing is the fact that we already know that this drug is not harmful in pregnancy. If we were to collect more data in laboratory research, it would be possible to investigate later in clinical trials whether there are advantages to administering the drug during pregnancy in order to slow down the possible inflammation in the organism and help the lungs grow, says DrWagner, adding that the aim in future is to be able to intervene with a drug directly after the diagnosis of a diaphragmatic hernia, which happens at around the 20thweek of pregnancy.

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Scientists create mice with two fathers after making eggs from male cells – The Guardian

Genetics

Creation of mammal with two biological fathers could pave way for new fertility treatments in humans

Scientists have created mice with two biological fathers by generating eggs from male cells, a development that opens up radical new possibilities for reproduction.

The advance could ultimately pave the way for treatments for severe forms of infertility, as well as raising the tantalising prospect of same-sex couples being able to have a biological child together in the future.

This is the first case of making robust mammal oocytes from male cells, said Katsuhiko Hayashi, who led the work at Kyushu University in Japan and is internationally renowned as a pioneer in the field of lab-grown eggs and sperm.

Hayashi, who presented the development at the Third International Summit on Human Genome Editing at the Francis Crick Institute in London on Wednesday, predicts that it will be technically possible to create a viable human egg from a male skin cell within a decade. Others suggested this timeline was optimistic given that scientists are yet to create viable lab-grown human eggs from female cells.

Previously scientists have created mice that technically had two biological fathers through a chain of elaborate steps, including genetic engineering. However, this is the first time viable eggs have been cultivated from male cells and marks a significant advance. Hayashis team is now attempting to replicate this achievement with human cells, although there would be significant hurdles for the use of lab-grown eggs for clinical purposes, including establishing their safety.

Purely in terms of technology, it will be possible [in humans] even in 10 years, he said, adding that he personally would be in favour of the technology being used clinically to allow two men to have a baby if it were shown to be safe.

I dont know whether theyll be available for reproduction, he said. That is not a question just for the scientific programme, but also for [society].

The technique could also be applied to treat severe forms of infertility, including women with Turners syndrome, in whom one copy of the X chromosome is missing or partly missing, and Hayashi said this application was the primary motivation for the research.

Others suggested that it could prove challenging to translate the technique to human cells. Human cells require much longer periods of cultivation to produce a mature egg, which can increase the risk of cells acquiring unwanted genetic changes.

Prof George Daley, the dean of Harvard Medical School, described the work as fascinating, but added that other research had indicated that creating lab-grown gametes from human cells was more challenging than for mouse cells. We still dont understand enough of the unique biology of human gametogenesis to reproduce Hayashis provocative work in mice, he said.

The study, which has been submitted for publication in a leading journal, relied on a sequence of intricate steps to transform a skin cell, carrying the male XY chromosome combination, into an egg, with the female XX version.

Male skin cells were reprogrammed into a stem cell-like state to create so-called induced pluripotent stem (iPS) cells. The Y-chromosome of these cells was then deleted and replaced by an X chromosome borrowed from another cell to produce iPS cells with two identical X chromosomes.

The trick of this, the biggest trick, is the duplication of the X chromosome, said Hayashi. We really tried to establish a system to duplicate the X chromosome.

Finally, the cells were cultivated in an ovary organoid, a culture system designed to replicate the conditions inside a mouse ovary. When the eggs were fertilised with normal sperm, the scientists obtained about 600 embryos, which were implanted into surrogate mice, resulting in the birth of seven mouse pups. The efficiency of about 1% was lower than the efficiency achieved with normal female-derived eggs, where about 5% of embryos went on to produce a live birth.

The baby mice appeared healthy, had a normal lifespan, and went on to have offspring as adults. They look OK, they look to be growing normally, they become fathers, said Hayashi.

He and colleagues are now attempting to replicate the creation of lab-grown eggs using human cells.

Prof Amander Clark, who works on lab-grown gametes at the University of California Los Angeles, said that translating the work into human cells would be a huge leap, because scientists are yet to create lab-grown human eggs from female cells.

Scientists have created the precursors of human eggs, but until now the cells have stopped developing before the point of meiosis, a critical step of cell division that is required in the development of mature eggs and sperm. Were poised at this bottleneck at the moment, she said. The next steps are an engineering challenge. But getting through that could be 10 years or 20 years.

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Identifying potential treatments for ALS – National Institutes of Health (.gov)

March 7, 2023

Amyotrophic lateral sclerosis, or ALS, is a rare but devastating neurological disease. In ALS, misfolded proteins build up within motor neuronsthe nerve cells in the brain and spinal cord that control voluntary muscle movement. The inability to clear this toxic protein buildup leads to muscle weakness, paralysis, and eventually death.

Some cases of ALS are caused by known, inherited genetic mutations. But most are from sporadic, unknown causes. Rather than target each genetic cause of ALS, researchers have been seeking treatments that could be used across different types. An NIH-funded research team led by Dr. Justin Ichida from the University of Southern California has been searching for cellular processes that couldbe manipulated to treat ALS regardless of the genetic drivers of a persons disease.

The first of two new studies from the team was published in Cell on February 16, 2023. In earlier work, they found that compounds that blocked a protein called PIKFYVE kinase extended the lives of ALS motor neurons. One of these compounds was a small molecule called apilimod.

In their follow-up study, the team tested apilimod in motor neurons with many different drivers of ALS. They also used several genetic methods to shut down PIKFYVE. All methods of PIKFYVE inhibition extended the lives of the various ALS neuron types tested.

Further work teased out the cellular mechanisms responsible for this protective effect. The researchers found that inhibiting PIKFYVE helped neurons clear misfolded, toxic proteins. This happened because a waste-removal process called exocytosis became activated when PIKFYVE was shut down.

The toxic version of a protein called TDP-43 has been linked to ALS and other neurodegenerative diseases. This protein was effectively cleared from the cells through exocytosis after PIKFYVE was inhibited.

When the researchers blocked PIKFYVE in several animal models of ALSincluding mice with a misfolded version of TDP-43motor function was improved, and the animals lived longer.

The teams second study was published on February 2, 2023, in Cell Stem Cell. In that work, the researchers screened a library of almost 2,000 approved drugs and other compounds for their ability to extend the life of ALS motor neurons. They found that some of the most promising compounds altered cellular signaling driven by hormones called androgens (such as testosterone) in the body.

The long-term manipulation of such hormones may have unwanted side effects. So, the researchers searched for other targets that altered gene activity levels in similar ways in motor neurons. Their top candidate was called SFY2.

The team found that suppressing SYF2 levels using genetic techniques increased survival in most types of ALS motor neurons tested, including those that accumulate toxic TDP-43.

In mice, suppressing SYF2 changed the way TDP-43 was exported from the nuclei of cells. This stopped the buildup of toxic protein clumps within neurons. Reducing the amount of SYF2 in the mice improved motor functioning as well.

Our discoveries bring us closer to achieving our big picture goal: finding treatments that can be broadly effective for all patients who suffer from ALS, Ichida says.

Before these approaches could be tested in people, future work will be needed to identify the safest ways to suppress such cellular pathways.

by Sharon Reynolds

References:PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Hung ST, Linares GR, Chang WH, Eoh Y, Krishnan G, Mendonca S, Hong S, Shi Y, Santana M, Kueth C, Macklin-Isquierdo S, Perry S, Duhaime S, Maios C, Chang J, Perez J, Couto A, Lai J, Li Y, Alworth SV, Hendricks E, Wang Y, Zlokovic BV, Dickman DK, Parker JA, Zarnescu DC, Gao FB,Ichida JK. Cell. 2023 Feb 16;186(4):786-802.e28. doi: 10.1016/j.cell.2023.01.005. Epub 2023 Feb 7. PMID:36754049.

SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS. Linares GR, Li Y, Chang WH, Rubin-Sigler J, Mendonca S, Hong S, Eoh Y, Guo W, Huang YH, Chang J, Tu S, Dorjsuren N, Santana M, Hung ST, Yu J, Perez J, Chickering M, Cheng TY, Huang CC, Lee SJ, Deng HJ, Bach KT, Gray K, Subramanyam V, Rosenfeld J, Alworth SV, Goodarzi H,Ichida JK. Cell Stem Cell. 2023 Feb 2;30(2):171-187.e14. doi: 10.1016/j.stem.2023.01.005.PMID:36736291.

Funding:NIHs National Institute of Neurological Disorders and Stroke (NINDS); US Department of Defense; Donald E. and Delia B. Baxter Foundation; Tau Consortium; Ford Foundation; Muscular Dystrophy Association; New York Stem Cell Foundation; Alzheimer's Drug Discovery Foundation; Association for Frontotemporal Degeneration; Pape Adams Foundation; John Douglas French Alzheimer's Foundation; Harrington Discovery Institute; Milken Family Foundation; USC Broad Innovation Award; Southern California Clinical and Translational Science Institute; Keck Medicine of USC; Target ALS Foundation; John Douglas French Alzheimers Foundation; Broad Institute; ALS Association; Lawrence and Isabel Barnett Drug Development Award; Frick Foundation for ALS Research; University of Southern California Alzheimers Disease Research Center; California Institute for Regenerative Medicine.

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Identifying potential treatments for ALS - National Institutes of Health (.gov)

Researchers discover therapeutic target to aid in glaucoma treatment – Science Daily

Indiana University School of Medicine researchers have identified a new therapeutic target that could lead to more effective treatment of glaucoma.

Glaucoma is a neurodegenerative disease that causes vision loss and blindness due to a damaged optic nerve. More than 200,000 people are affected by glaucoma in the United States each year. Unfortunately, there is currently no treatment. In a newly published paper in Communications Biology, researchers found neurons use mitochondria for a steady source of energy, and restoring mitochondrial homeostasis in the diseased neurons can protect the optic nerve cells from being damaged.

"Age-related neurodegenerative disease, which includes glaucoma, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), is the biggest global health problem," said Arupratan Das, PhD, assistant professor of ophthalmology and principal investigator of the study. "The fundamental mechanisms that we discovered can be used to protect neurons in glaucoma and be tested for the other diseases. We have identified a critical step of complex mitochondrial homeostasis process, which rejuvenates the dying neuron, similar to giving a lifeline to a dying person."

The research team, led by Michelle Surma and Kavitha Anbarasu from the Department of Ophthalmology, used induced pluripotent stem cells (iPSCs) from patients with and without glaucoma as well as clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells with glaucoma mutation. Using stem cell differentiated retinal ganglion cells (hRGCs) of the optic nerve, electron microscopy and metabolic analysis, researchers identified glaucomatous retinal ganglion cells suffer mitochondrial deficiency with more metabolic burden on each mitochondrion. This leads to mitochondrial damage and degeneration. Mitochondria are the tube like structures in cells which produce adenosine triphosphate, cell's energy source.

However, the process could be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed retinal ganglion cells are highly efficient in degrading bad mitochondria, but at the same time producing more to maintain homeostasis.

"Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing," Das said. "However, when triggered to produce more mitochondria, the adenosine triphosphate production load was distributed among more mitochondrion which restored the organelle physiology. It is similar to a situation where a heavy stone is carried by fewer people versus a greater number of people -- each person will have less pain and injury, just like each mitochondrion will have less difficulty and damage."

In the future, Das would like to test if these mechanisms protect the optic nerve in animal models under injury before testing in humans to hopefully lead to new clinical interventions.

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Researchers discover therapeutic target to aid in glaucoma treatment - Science Daily

Exciting Cell & Gene Therapy Research Updates in Glaucoma and … – geneonline

Exciting Cell & Gene Therapy Research Updates in Glaucoma and Nerve Regeneration

As the Cell & Gene Therapy Research & Development Congress 2023 entered its second day, experts from around the world continued to share their latest exciting research findings and possible future directions in the related fields.

Day two of the event began with a virtual keynote address themed Gene Therapy for Glaucoma by Paul Kaufman, MD, Professor of Ophthalmology & Visual Sciences at the University of Wisconsin-Madison School of Medicine & Public Health. As an incurable, age-related degenerative optic neuropathy, glaucoma affects approximately 80 million people globally and is one of the worlds leading causes of preventable blindness. In most cases, the disease is caused by a buildup of fluid in the front part of the eye, which elevates intraocular pressure (IOP), causing damage to the optic nerve and possibly leading to permanent vision loss. With this in mind, lowering IOP is the top priority in devising ways to treat glaucoma and prevent disease progression.

Following an overview of glaucoma, professor Kaufman introduced some new approaches to managing the disease, with an emphasis on modifying the aqueous humor dynamics in the eye, such as encapsulated cell technology (ECT) and devices for micro-invasive glaucoma surgery (MIGS). Then he focused on the development of gene therapy for glaucoma and the findings obtained by his research team.

Related Article: Cell & Gene Therapy Congress Asia Day One: Advances in the Research

Theoretically, it is possible for gene therapies to achieve IOP reduction and preserve vision by different means such as protecting neurons of the optic nerve, decreasing aqueous humor production and enhancing aqueous humor outflow.

With an interest in the mechanisms of aqueous humor formation and drainage, Prof. Kaufmans team sets their strategy to go after the physiology of the system, focusing on the trabecular meshwork (TM) and the uveoscleral pathway for outflow enhancement. They aim at identifying genes that would act on cells involved in these pathways so as to increase the fluid flow in the eye without actually replacing a gene that happens to be defective. Ultimately, their goal is to deliver a gene into the tissues and obtain a long-lasting therapeutic effect, allowing patients to avoid using time-consuming daily treatments

The team hypothesizes that in live non-human primates (NHPs), administration of viral vector-transgene constructs incorporating the C3 transferase or caldesmon transgene directly into Schlemms canal will decrease conventional aqueous humor outflow resistance and thereby reduce intraocular pressure.

Professor Kaufman also shared the research findings regarding the Wnt signaling pathway in human TM cells, showing that restoring the overexpression of certain proteins in this pathway may be a possible way for IOP reduction, thereby treating glaucoma.

Towards the end of his presentation, Professor Kaufman also mentioned current constraints and challenges of gene therapy for glaucoma, including vector-associated side effects (toxicity), difficulties in turning on or off the gene, gene-targeting technology, regulatory hurdles as well as the gap between theories and experimental observations that have yet to be resolved. Nevertheless, he still feels hopeful that the current research findings may provide insights for developing potential human therapeutics and that they could eventually move into the pre-drug phase and become part of a clinical trial.

The second keynote speech of the day was delivered by professor Ing-Ming Chiu, Chair Professor at Graduate Institute of Biomedical Sciences at China Medical University, with the theme Neural Stem Cells and Neurotrophic Factors in Nerve Regeneration.

Since the discovery of the regeneration of neurons after birth in animals, scientists around the world have been engaging in neural stem cell (NSC) research. It has been found that fibroblast growth factors FGF1 and FGF2 are required for the maintenance of NSCs in early development.

Moreover, FGF1 and interleukin 12 (IL12), separately, are beneficial in nerve repair via promoting axonal growth. With the sciatic nerve injury mouse model, Prof. Chius team has found that the implantation of NSCs combined with nerve conduit and IL12 can increase neuroregeneration and improve motor recovery.

IL12 is a dimeric protein that is formed by the combination of p35 and p40 subunits. In particular, the team has found that mouse IL12p80 (homodimer of two p40 subunits) facilitates nerve regeneration and promotes functional recovery in vivo. In vitro studies of the molecular mechanism reveal that IL12p80 stimulates the Schwann cell differentiation of mouse NSCs through the phosphorylation of Stat3 in NSCs.

Furthermore, the team later used human IL12p80 in mouse models and it has been found that hIL12p80 also facilitates nerve regeneration in mice. One of their ongoing studies involves an attempt of using hIL12 and human nerve in the mouse model. In the event that positive outcomes are achieved, these findings may provide insights for developing potential therapies for neurological diseases in humans.

Developments in Regenerative Medicine: Gene Delivery Tools and Cell Therapy for Parkinsons Disease

2023-03-08

Revolutionizing Eye Disease Treatment with iPSC Therapy

2023-03-07

Global Head of Research of Kite Pharma Unveiled the Key Elements to Success in Adoptive Cell Therapy

2023-03-07

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Exciting Cell & Gene Therapy Research Updates in Glaucoma and ... - geneonline

Cell Therapy Market: Increasing use of human cells in cell therapy … – Digital Journal

PRESS RELEASE

Published March 10, 2023

According to the report, the global Cell Therapy Market is expected to grow from USD 21.6 Billion in 2022, which is expected to reach USD 78.80 Billion by 2033, growing at a CAGR of 14.15% from 2023 to 2033. Cell therapy is a type of medical treatment that involves the use of living cells to repair, replace, or regenerate damaged or diseased tissue in the body. The cells used in cell therapy may be sourced from the patients own body (autologous) or a donor (allogeneic) and can be obtained from various tissues, such as bone marrow, adipose tissue, or blood. The cells used in cell therapy can be either unmodified or genetically engineered to perform specific functions or to express therapeutic proteins. Some of the most common types of cells used in cell therapy include stem cells, immune cells, and cells that produce insulin. Cell therapy has been used to treat a wide range of conditions, including cancer, autoimmune diseases, neurological disorders, and cardiovascular diseases. The goal of cell therapy is to improve the bodys ability to repair and regenerate tissues, which can lead to better outcomes and improved quality of life for patients.

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Key Highlights:

Evolve Business Intelligence has published a new market research report on the Global Cell Therapy Market focusing on various aspects including market size and forecast, market dynamics, competitors market share analysis, market size in terms of value and volume, SWOT analysis, product benchmarking, key players recent developments, and opportunities, among others. The market has also been analyzed based on 4 indicators in the market dynamic chapter which include Drivers, Restraints, Key Trends, and Challenges. The overall sum of these sections will help to understand the best strategies to be adopted to prosper in this industry over the short and long terms. The quantitative analysis includes our authentic findings of this research study where we provided additional insight into what our readers can do to embrace new opportunities or plan against threats that might hinder the market.

The New Normal

As businesses recover from the COVID-19 pandemic, they have a new set of priorities to cope with. Throughout this crisis, they were forced to deal with shifting situations and often fell short of their ultimate goals. Now that a cure has been found and the pandemic is dying down, they will need to recuperate from this epidemic by setting forth new objectives to succeed in the future.

In terms of COVID-19 impact, the Cell Therapy Market report also includes the following data points:

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Key Players

Some of the major Cell Therapy Market players holding high market shares include Kolon TissueGene Inc, Osiris Therapeutics Inc, JCR Pharmaceuticals Co Ltd, PHARMICELL Co Ltd, and Castle Creek Biosciences Inc. These players use partnerships and new product development as key strategies to gain significant market share to compete with market leaders.

The key players profiled in the report are:

Segmental Analysis

Market Segment By Cell Type with a focus on market share, consumption trend, and growth rate of the Cell Therapy Market:

Market Segment By Therapy Type with a focus on market share, consumption trend, and growth rate of the Cell Therapy Market:

Market Segment By Therapeutic Area with a focus on market share, consumption trend, and growth rate of the Cell Therapy Market:

Market Segment By End User with a focus on market share, consumption trend, and growth rate of the Cell Therapy Market:

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Global Cell Therapy Market Geographic Coverage:

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About EvolveBIEvolve Business Intelligence is a market research, business intelligence, and advisory firm providing innovative solutions to challenging pain points of a business. Our market research reports include data useful to micro, small, medium, and large-scale enterprises. We provide solutions ranging from mere data collection to business advisory.

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Cell Therapy Market: Increasing use of human cells in cell therapy ... - Digital Journal

Gates Grubstake Fund Awards Over $1.5 Million to Campus Researchers – University of Colorado Anschutz Medical Campus

The Gates Grubstake Fund invokes the memory of Gold Rush prospectors who received seed money, grubstakes, for food and supplies so they could search for treasure. The funding supports the work of modern-day prospectors translational researchers affiliated with Gates Institute whose work developing cell- and gene-based therapies could make a difference in human lives. In 2022, four awardees received $350,000 each to support their work.

In addition, second-tranche awards are made to eligible previous Grubstake recipients who have demonstrated success in developing technology toward a clinical trial using original Grubstake funding, along with evidence that additional funding would allow them to reach an additional inflection point toward commercialization.

In total, over $1.5 million was awarded by the Gates Grubstake Fund to CU Anschutz researchers.

Ganna Bilousova, PhD: Somatic Cell Rejuvenation for Skin Transplantation and Wound Healing

With a steady increase in the aging population, the care of acute and chronic wounds in the elderly has become a priority topic for clinicians. Many options to treat wounds are currently available. However, none of them restores the functionality of aged skin cells, hence low success rate in the elderly. Ganna Bilousova, PhD, associate professor of dermatology, and Igor Kogut, PhD, assistant professor of dermatology, are developing a permanent corrective therapy for acute and chronic wounds in the elderly by rejuvenating the patients own skin cells using a patent-pending RNA cocktail of factors. The Grubstake Award will allow their teams to finalize their therapeutic product and compare its efficacy with the competition to accelerate development toward pre-investigational new drug (IND) filing with the Food & Drug Administration.

Mi-Hyun Nam, PhD: Restoration of Vision in Glaucoma Through Cell Therapy

Principal investigator Mi-Hyun Nam, PhD, research instructor in ophthalmology, and her co-PI, Natalia Vergara, PhD, assistant professor of ophthalmology, are developing a human stem cell-based therapy for treating glaucoma, the second-leading cause of blindness worldwide. Current medical therapies are limited to lowering intraocular pressure, which may prevent further vision loss, but no treatment to date can restore vision once it has been lost. The Grubstake funding will enable them to perform preclinical studies to determine the feasibility and efficacy of their therapy.

Eric Kohler, MD, PhD: Adjunctive LAT-Activating Chimeric Antigen Receptor T cells (ALA-CART) Strengths

CAR-T cells have revolutionized the treatment of leukemia and lymphoma, inducing responses against cancers that no longer respond to traditional therapies. However, current CAR-T cell strategies are unable to induce long-term remissions in the majority of patients, owing to limitations in their persistence, potency and sensitivity. By studying CAR-T cell signaling, the lab of Eric Kohler, MD, PhD, assistant professor in the Department of Pediatrics, identified that inefficient activation of the molecule LAT was responsible for many of the limitations in current CAR-T cell therapies. Using this finding, they rationally designed a new Adjunctive LAT-Activating CAR-T cell (ALA-CART) that restores LAT signaling and demonstrates enhanced potency and persistence in preclinical models. Furthermore, ALA-CART cells demonstrated increased sensitivity to tumor cells with low levels of the targeted antigen, allowing for eradication of leukemia that would otherwise not be seen by current CAR-T cell therapies. These advancements hold the potential to close many of the vulnerabilities of CAR-T cell therapies and improve their long-term effectiveness for patients. Grubstake funding will be used to generate safety data and establish manufacturing workflows at the Gates Biomanufacturing Facility to transition this work to clinical trials.

Daniel Sherbenou, MD, PhD: Response Prediction for T Cell Engaging Bispecific Antibodies in Multiple Myeloma

Daniel Sherbenou, MD, PhD, associate professor in hematology, Department of Medicine, received a Gates Grubstake Award to commercialize the new myeloma drug sensitivity testing (My-DST) assay for profiling responses to T cell engaging bispecific antibodies for patients with multiple myeloma, an incurable blood cancer afflicting more than 150,000 Americans. Bispecific antibodies are a promising new class of therapy that redirect a patients own T cells to kill the cancerous myeloma cells. To improve the clinical application of these drugs, My-DST has potential as a new laboratory test for measuring responses of an individual patients tumor cells from biopsy specimens. In this project, Sherbenous team will pursue regulatory approvals and scale up efforts to establish My-DST as a personalize medicine approach for the various bispecific antibodies in clinical use or in clinical trials.

Michael Verneris, MD: Multiomic Approach to Establish Mechanisms of Efficacy of Stem Cell-Derived Innate Lymphoid Cells in Gastrointestinal Tract Repair

Michael Verneris, MD, professor in the Department of Pediatrics, received a second-tranche award of $100,000. Innate lymphoid cells are tissue resident lymphocytes that can be restorative to injured mucosal tissues. In Crohns disease (CD), a subpopulation of ILCs (ILC3s) are depleted and the loss of these cells is thought to be part of the pathogenesis of CD. Replacement of ILC3s in CD may be therapeutic. Verneris laboratory has developed methods to generate ILC3s from hematopoietic stem cells and has found that adoptive transfer of these cells can improve the intestinal dysfunction in TNFdARE mice, which is a model of CD. With this funding they will perform CITE-SEQ and Xenium in situ analysis on ILC3 treated (and untreated) mice to better understand the impact of ILC3s adoptive transfer at single cell resolution. Additionally, they will continue to perform scale-up experiments with the goal of transferring this technology to the Gates Biomanufacturing Facility.

Eduardo Davila, PhD: Manufacturing of Genetically Engineered Tumor Infiltrating Lymphocyte (TIL) Therapy

Eduardo Davila, PhD, professor in the Division of Medical Oncology, was awarded $50,000 in second-tranche funds. This funding will accelerate development toward pre-IND filing with the FDA by completing studies related to (1) specificity and potency assays to test TIL function; investigate changes in the T cell repertoire; and confirm that TILs do not become leukemic.

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Mass General Researchers Discover the Role of Intestinal Fibrosis … – Massachusetts General Hospital

Intestinal fibrosis is a common feature of inflammatory bowel disease (IBD) and the primary cause of end-stage organ failure. Traditionally considered a bystander of inflammation, with negligible involvement in disease pathogenesis, new research published in Gastroenterology now shows that fibrosis has a direct bearing on disease progression in IBD.

The investigation was spearheaded by Nima Saeidi, PhD, Associate Professor of Surgery at the Massachusetts General Hospital (MGH) and Harvard Medical School, along with co-first authors, Shijie He, PhD, and Peng Lei, PhD.

The critical question posed by the investigators was how tissue stiffening influences the growth and differentiation of intestinal stem cells, which fuel the regeneration of intestinal epithelium?

This was addressed by developing a new in vitro platform, which allowed intestinal organoids to be cultured on an open lumen, planar system that could be manipulated experimentally.

The platform permitted the use of soft yet tunable substrates with biophysical properties mimicking native tissue, facilitating the long-term growth and differentiation of intestinal stem cells, similar to native epithelium.

Saiedi and colleagues discovered that upon elevating substrate stiffness to a similar range observed in IBD patients, both the number and capacity of stem cells to maintain homeostasis and cellular composition of the epithelium were potently reduced.

Concomitantly, the stem cells preferentially differentiated into goblet cells, leading to epithelial deterioration. Similar phenotypes were also noted in mouse models of IBD as well as in samples from human patients.

The investigators concluded that interfering with the molecular machinery involved in the cellular sensing of stiffness conferred protection against the detrimental effects of fibrosis and stiffening.

These findings demonstrate that intestinal fibrosis and stiffening are critical components of IBD pathogenesisand that targeting mechanosensing and mechanotransduction pathways may offer an attractive therapeutic strategy for IBD, says Saeidi.

The scientists also observed that despite the significant reduction in a specific population of stem cells, stiffening led to the expansion of another stem cell marker (OLFM4) outside the stem cell zone.

Our observations that stiffening increased the expression of OLFM4 may have significant implications for the development of colitis-associated colorectal cancer, says Dr. He.

A collaborative work between scientists from the Massachusetts General Hospital, MIT, Boston Children's Hospital, Harvard T.H. Chan School of Public Health, and Boston University, additional MGH co-authors included Dr. Richard Hodin and Dr. Ruslan Sadreyev.

This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. TheMass General Research Instituteconducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in theU.S. News & World Reportlist of "Americas Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.

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Mass General Researchers Discover the Role of Intestinal Fibrosis ... - Massachusetts General Hospital

Blood-Based MRD Testing Identifies AML Patients at Risk of … – Precision Oncology News

NEW YORK Using DNA sequencing to detect measurable residual disease (MRD) in acute myeloid leukemia (AML) patients about to undergo a stem cell transplant can help predict who will have their disease recur, according to a new study by researchers at the US National Heart, Lung, and Blood Institute and elsewhere.

"Having this increased risk for relapse may not impact a person's decision about having a bone marrow transplant, but it could influence their next steps in care," said Christopher Hourigan, chief of the laboratory of myeloid malignancies at NHLBI and the study's corresponding author, in a statement.

Many AML patients who go into remission after their initial treatment will receive a hematopoietic cell transplant, but about 30 percent of them end up having their disease come back, the most common cause of death after transplant.

While previous studies showed that MRD testing can help predict who is at risk of relapse, there has not been a standardized method for MRD testing in AML, and there have been concerns about the standardization of flow cytometry-based testing.

To find out whether DNA sequencing-based testing could provide a good alternative, the NHLBI group looked for specific AML-associated variants in the blood of patients prior to their stem cell transplant and studied whether these correlated with higher rates of relapse or death after transplant.

For their study, published in JAMA on Tuesday, the researchers tested blood samples from a total of 1,075 patients, provided through the Center for International Blood and Marrow Transplant Research, who subsequently had a stem cell transplant between 2013 and 2019.

Using a custom sequencing panel, they looked for variants in hotspot regions of five genes FLT3, NPM1, IDH1, IDH2, or KIT. All of the patients had AML associated with variants in one of these genes, and they all had gone into apparent complete remission before their transplant. The researchers divided them into a discovery cohort of 454 and a validation cohort of 621 patients. Variants present at an allele fraction of 0.01 percent or higher counted as a positive result for MRD.

For their analysis, the researchers decided to focus on the two most common AML mutation types FLT3 internal tandem duplications and NPM1 variants which were present in the initial disease of 822 of the patients tested. They found that patients in both the discovery and validation cohorts who had these mutations show up in their blood, about 17 percent, were at significantly higher risk of relapse and death compared to those without them.

Specifically, 68 percent of patients who were MRD-positive for these mutations relapsed, and only 39 percent survived for three years. This is compared to 21 percent of patients without MRD relapsing, and 63 percent surviving for three years.

In addition, having these variants in the blood was associated with lower rates of relapse-free survival after three years, though mortality for causes other than relapse was similar to patients without the variants.

Whether or not blood-based DNA mutation testing prior to transplant will actually result in better outcomes for AML patients at high risk of relapse remains to be seen.

Hourigan suggested that patients deemed to be at high risk of relapse may want to enroll in a clinical trial or consider "additional or different therapies."

"This information can also empower physicians to tailor transplant strategies, including considering different pre-transplant conditioning regimens and chemotherapies, to reduce an AML patient's risk for relapse and improve their long-term chance for survival," added Rear Admiral Richard Childs, clinical director and acting scientific director of NHLBI, in a statement.

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Blood-Based MRD Testing Identifies AML Patients at Risk of ... - Precision Oncology News

Sightings Of Double Murder Suspect Reported: Reward Offered – KPQ

A man suspected of killing an elderly couple in the Okanogan community of Chesaw more than a year ago is still on the loose.

And now a reward is being offered for information leading to the arrest of Dylan Harrington.

Chief Criminal Deputy Rick Balam of the Okanogan County Sheriff's Office says tips on his whereabouts have come in.

"There's been reported sightings, and over a period of time, people think they see things that may or may not be true. We have to take into account that there's a possibility that he is in fact in the (North Central Washington) area." Balam said.

Dave and Gerlyn Covey of Omak were found deceased at their property near Chesaw Feb. 16, 2022.Their bodies had been burned and a sheet of plywood placed over them in an apparent effort to conceal them. The search for the Coveys began after the couples truck had been found abandoned Feb. 13, 2022.

Detectives with the Okanogan County Sheriff's Office identified Harrington as a person of interest after they found the bodies. Detectives believe he had been squatting nearby and stealing supplies from the Coveys.

"Based on the information we have. We don't know for sure if he's even alive at this point. We assume he is that's why the Marshal's office is involved in it." Balam said.

Harrington is charged with two counts of first degree murder and two counts ofunauthorized removal or concealment of a body with national extradition.

The Pacific Northwest Violent Offender Task Force led by the U-S Marshal's Serviceis offering up to $5,000 for information that helps them track down Harrington.

If you have any information, you're asked to call the U-S Marshal's Serviceat(866) 865-TIPS(8477) or submit a tip online via theUSMS Tips App.

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Sightings Of Double Murder Suspect Reported: Reward Offered - KPQ