Tag: Medicine

Doubling adult stem cells for bone marrow and immune system regeneration.

An international research team, led by scientists from Tel Aviv University and Sheba Medical Center, has unveiled an innovative method for activating adult stem cells from human bone marrow, enabling their expansion outside the body for use in bone marrow regeneration and the construction of a new blood and immune system.

The findings, published in the prestigious journal Nature Immunology, represent a breakthrough that could significantly improve transplant success rates for patients who have undergone intensive chemotherapy, suffer from genetic disorders, or require a bone marrow transplant but are unable to source a sufficient number of stem cells from a donor.

The study was led by Dr. Tomer Itkin from the Faculty of Medical and Health Sciences and the Sagol Center for Regenerative Medicine at Tel Aviv University, and the Neufeld Cardiac Research Institute at Sheba Medical Center, Tel Hashomer. The research also included contributions from leading medical institutions worldwide, including Weill Cornell Medical College and Hospital in New York, the Memorial Sloan Kettering Cancer Center (MSKCC), Mount Sinai Hospital, the University of Toronto Medical Center, and the Fred Hutchinson Cancer Research Center in Seattle.

Dr. Tomer Itkin.

Switching On Stem Cells

In the study, which is based on a comprehensive big data analysis of RNA sequencing and epigenetic DNA sequencing, the researchers identified a key protein—the Fli-1 transcription factor—that activates stem cells of the immune and blood system. These stem cells are highly active when sourced from umbilical cord blood but remain in a “dormant” and inactive state when obtained from adult bone marrow donors. Using modified mRNA technology—the same technology used to develop COVID-19 vaccines—the researchers successfully “awakened” the adult stem cells, allowing them to divide in a controlled manner without cancer risk. The activated cells were expanded on endothelial cells, which mimic the blood vessels that support stem cells in the bone marrow environment, demonstrating an enhanced ability to integrate and restore blood production under transplant conditions.

According to Dr. Itkin, “This new method significantly expands the available pool of stem cells for transplantation without relying on rare bone marrow donors. Additionally, the method can be used to treat patients whose stem cells have undergone genetic correction, such as those with thalassemia and hereditary anemia, as well as patients who have undergone multiple rounds of chemotherapy and have an insufficient number of stem cells for autologous transplantation“.

The key takeaway from the study is that activating stem cells through molecular programming, rather than arbitrary cell transplantation, substantially improves the success rates of regenerative treatments. The next stage of research involves testing the method in clinical trials to bring this groundbreaking technology into widespread therapeutic use. Furthermore, the researchers plan to apply the same therapeutic approach to regenerate additional tissues, including those without existing adult stem cells, such as the heart.

Is PTEN the key to advancing autism and cancer research?

A novel scientific method developed at Tel Aviv University promises to accelerate our understanding of the gene PTEN, a key player in cellular growth. This breakthrough will help scientists better understand how cells grow and divide, potentially leading to advancements in the treatment of various conditions, including developmental disorders and various forms of cancer.

The study, led by Dr. Tal Laviv in the Faculty of Medical and Health Sciences at Tel Aviv University, was published in the prestigious journal Nature Methods.

The research team explains that cells in the human body constantly adjust their size and rate of division to adapt to their environment throughout life. This process is crucial for normal development, as cells go through periods of precise growth regulation. When this process is disrupted, it can lead to severe diseases such as cancer and developmental disorders.

In the brain, regulating cellular growth is especially critical during early brain development, which occurs in the first years of life. Many genes are involved in this regulation, but one gene in particular—PTEN (Phosphatase and Tensin Homologue)—plays a central role. Mutations in PTEN are linked to a variety of conditions, including autism, epilepsy, and cancer.

PTEN’s Impact Explained

Dr. Tal Laviv explains: “Many studies have shown that PTEN is essential for regulating cell growth in the brain by providing a stop signal. This means PTEN activity is crucial for maintaining cells at their proper size and state. There is growing evidence that mutations in PTEN, which reduce its activity, contribute to diseases like autism, macrocephaly, cancer, and epilepsy. Despite the critical role PTEN plays in cellular function, scientists have had limited tools to measure its activity. For example, it wasn’t to directly measure PTEN activity in an intact brain, which would greatly help our understanding of its role in health and disease”.

Dr. Laviv and his research team, led by MD-PhD student Tomer Kagan, have developed an innovative tool that directly measures PTEN activity with high sensitivity in various research models, including in the intact brains of mice. This groundbreaking technology, which combines advancements in genetic tools and microscopy, will allow scientists to gain deeper insights into why PTEN is so crucial for normal brain development. It could also improve our understanding of how PTEN-related diseases, such as cancer and autism, develop.

The researchers predict that this new tool will enable the development of personalized therapeutics by monitoring PTEN activity in various biological settings. Additionally, it could help identify diseases at earlier stages, potentially leading to faster and more effective treatments.

.ADNP Protein Causes Different Brain Damage in Males and Females.

Researchers at Tel Aviv University, led by Prof. Illana Gozes, examined the effects of different mutations in the ADNP protein, which is essential for normal brain development and aging, on the brain cells of mice — distinguishing between males and females. To their surprise, they found that the defective protein affects completely different mechanisms in the two sexes: in males, the damage occurs in a mechanism that protects the structure of proteins, which in turn disrupts the process of neurogenesis — the production of new brain cells from stem cells — a process crucial for memory and learning. In females, on the other hand, the mechanism that regulates energy within the cell is impaired, preventing the brain from receiving sufficient energy. All of these processes are essential for maintaining memory and learning functions, and their disruption causes significant impairment in both sexes, leading to the development of incurable brain diseases such as Alzheimer’s, in which ADNP is also found to be defective.

The research was conducted by Prof. Illana Gozes, Dr. Gidon Karmon, and doctoral student Guy Shapira from theFaculty of Medical & Health Sciences and the Sagol School of Neuroscience at Tel Aviv University. Additional contributors to the study include Prof. Noam Shomron, Dr. Gal Hacohen-Kleiman, doctoral student Maram Ganaiem from the Faculty of Medical and Health Sciences, Dr. Shula Shazman from the Department of Mathematics and Computer Science at the Open University, and researchers from the University Hospital of Thessaloniki in Greece. The study was published in the prestigious journal Molecular Psychiatry from Nature.

Prof. Illana Gozes.

Prof. Gozes stated: “The ADNP protein was discovered in my lab, and we have been researching it for many years. We found that it is critical for brain development and plays a protective role in neurodegenerative diseases like Alzheimer’s. Additionally, it was found that defects in the ADNP gene cause ADNP syndrome, a rare genetic disorder associated with developmental delays, learning disabilities, and symptoms of autism. In parallel, we are developing the experimental drug Davunetide, which is based on a fragment of the ADNP protein. In this study, we aimed to examine whether ADNP is involved in the process known as ‘neurogenesis’ — the formation of new neurons from stem cells in the adult brain, a process essential for memory and learning. We focused on the hippocampus, a brain region crucial for memory, in adult mice”.

Using genetic engineering, the researchers established two mouse models reflecting different forms of ADNP syndrome: mice that express only half the normal amount of ADNP, with only one active allele in the DNA instead of two, which are typically inherited from both parents and mice with a mutation in the ADNP gene that truncates the protein production process, resulting in a shorter-than-normal ADNP protein.

The researchers note that the most severely affected children with ADNP syndrome are those with the mutation that produces the truncated protein. Additionally, neurogenesis was examined in a control group of healthy mice.

To track the course of neurogenesis, a substance was injected into the mice, staining the DNA of brain cells participating in the process. The data were analyzed using computational bioinformatics methods, proving that ADNP plays a crucial role in neurogenesis. Furthermore, a significant difference was found between how ADNP functions in males versus females. First, in healthy mice, neurogenesis was more active in males than females, while in male mice with an ADNP mutation, neurogenesis was reduced to the same level as in females. A fundamental difference between the sexes was also identified in an additional research method: RNA sequencing of all genes in the hippocampus of mice with the truncated ADNP protein.

How ADNP Protein Breaks Brains by Gender

Prof. Gozes explains: “There was almost no overlap. The damage to the ADNP protein affected completely different mechanisms in male and female brains. The explanation for this phenomenon is that in males, one of the functions of ADNP is to regulate a mechanism that maintains protein structure (unfolded protein response), which in turn regulates neurogenesis. The ADNP gene is a master regulator of this entire mechanism in male brains, and when it is defective, the process is significantly impaired. In females, however, the ADNP protein enters the mitochondria — the cell’s energy powerhouse — and when the mutation alters the protein’s structure, less ADNP can enter the mitochondria. As a result, energy production in the cell is likely impaired, disrupting brain function, which requires a large amount of energy”.

As part of the study, the researchers also tested the effectiveness of the experimental drug Davunetide, based on the NAP fragment of the ADNP protein, in treating affected mice. They observed a positive effect in all cases, with particularly significant neurogenesis recovery in the model where mice had only half the normal ADNP levels.

Promising Drug for ADNP and Beyond

Prof. Gozes concludes: “Our research shows that ADNP is closely linked to neurogenesis and that it functions differently in males and females — a finding that has also emerged in previous studies. Additionally, we found that Davunetide, the drug that we discovered and are developing, is effective. We aim to soon begin a clinical trial in children with ADNP syndrome (ADNP deficiency). We hope that in the future, the drug will also help Alzheimer’s patients — in whom we previously found sex-based differences — as well as other neurodegenerative diseases where ADNP is impaired. Notably, the rare and incurable disease Progressive Supranuclear Palsy (PSP), which has pathological similarities to Alzheimer’s disease, showed significant improvement in women treated with Davunetide in our previous clinical study”.

The pharmaceutical development is being carried out by ExoNavis Therapeutics Ltd under a licensing agreement with Ramot, Tel Aviv University’s technology transfer company. Prof. Gozes serves as Vice President for Drug Development at the company.

This gene-editing success from TAU could change cancer treatment forever.

Researchers from Tel Aviv University utilized CRISPR to cut a single gene from cancer cells of head and neck tumors – and successfully eliminated 50% of the tumors in model animals. This groundbreaking study was led by Dr. Razan Masarwy, MD, Ph.D. from the lab of  Prof. Dan Peer – a global pioneer in mRNA-based drugs, Director of the Laboratory of Precision Nanomedicine, VP for Research and Development and member of the Shmunis School of Biomedicine and Cancer Research – all at TAU. The findings were published in the prestigious journal Advanced Science.

A New Approach to Treating Head and Neck Cancers

“Head and neck cancers are prevalent, ranking fifth in cancer mortality”, says Prof. Peer. “These are localized cancers, typically starting in the tongue, throat, or neck, which can later metastasize. If detected early, localized treatment can effectively target the tumor. We aimed to use genetic editing of a single gene expressed in this type of cancer to collapse the entire pyramid of the cancerous cell. This gene is the cancer-specific SOX2, also expressed in other types of cancer and overexpressed in these particular tumors”.

Prof. Dan Peer.

Prof. Peer and his colleagues are global pioneers in developing mRNA-based drugs encased in synthetic lipid particles that mimic biological membranes. In this study, the researchers synthesized special lipids that encapsulate the delivered CRISPR system in an RNA format. An antibody targeting a receptor against a protein named EGF was attached to the surface of these particles.

“These tumors are highly targeted”, explains Prof. Peer. “We targeted EGF because the cancer cells express the EGF receptor. Using our nano-lipid delivery system, we injected the drug directly into the tumor in a tumor model and successfully took out the gene – cutting it out from the cancer cell’s DNA with the CRISPR ‘scissors’. We were happy to observe the domino effect we had predicted. Following three injections spaced one week apart, 50% of the cancerous tumors simply disappeared after 84 days – which did not happen in the control group”.

Prof. Dan Peer & research team.

TAU Pioneers CRISPR for Cancer Treatment

In 2020, Prof. Peer and his team were the first in the world to use CRISPR to cut genes from cancer cells in mice and a cell-specific manner, and this is the first time they have applied it to head and neck cancers.

“Generally, CRISPR isn’t used for cancer because the assumption is that knocking out one gene wouldn’t collapse the whole pyramid. In this study we demonstrated that there are some genes without which a cancer cell cannot survive, making them excellent targets for CRISPR therapy. Since cancer cells sometimes compensate with other genes, it’s possible that additional genes need to be cut out, or perhaps not. Theoretically, this approach could be effective against many types of cancer cells, and we are already working on additional cancer types, including myeloma, lymphoma, and liver cancer”.

This study was supported in part by the EXPERT project (European Union’s Horizon 2020 research and innovation programme (under grant agreement # 825828), and the Shmunis Fund for gene editing.

Potential new therapy for Crohn’s, colitis, and other inflammatory diseases.

Researchers at Tel Aviv University have achieved a breakthrough in drug delivery: they have successfully transported lipid nanoparticles encapsulating messenger RNA (mRNA) to the immune system of the small and large intestines — bypassing the liver upon systemic administration. By simply altering the composition of the nanoparticles, the researchers demonstrated that mRNA-based drugs can be directed straight to target cells, avoiding the liver.

The groundbreaking Tel Aviv University study was led by post-doctoral fellow Dr. Riccardo Rampado together with Vice President for R&D Prof. Dan Peer, a pioneer in the development of mRNA therapeutics and Director of the Laboratory of Precision Nano-Medicine at the Shmunis School of Biomedicine and Cancer Research. The study was published on the cover of the prestigious journal Advanced Science.

Prof. Dan Peer.

Targeting Drugs More Precisely with Lipid Nanoparticles

“Everything injected into the bloodstream eventually ends up in the liver — that’s just how our anatomy works”, explains Prof. Peer. “This poses two challenges. First, drugs intended to target specific cells in particular organs may be toxic to the liver. Second, we don’t want drugs to get ‘stuck’ in the liver. Ideally, the drug would reach the target organ first, and any remnants would then break down in the liver. We discovered that altering the proportions of lipids comprising the nanoparticles determines their destination in the bloodstream. This is a general phenomenon, meaning it works regardless of the specific lipids, which makes this a significant breakthrough”.

To demonstrate the concept, Prof. Peer and his team encoded the anti-inflammatory protein interleukin-10 into mRNA, encapsulated it in lipid nanoparticles with a composition different from those typically used (such as in mRNA COVID-19 vaccines), and successfully delivered it to the intestines of animal models with Crohn’s disease and colitis via intravenous injection.

“Not only were we able to deliver an mRNA-based anti-inflammatory drug directly to the inflamed intestine and improve all markers of colitis and Crohn’s disease, but we also transformed the immune cells in the intestine into factories for producing the anti-inflammatory interleukin-10”, Prof. Peer explains. “But this is just a proof of concept study. By tweaking the nanoparticle composition, we could deliver other RNA-based drugs to different organs. There’s a saying in American English: ‘It’s all in the formulation’. That’s exactly what this is about”.

Higher Phospholipids, Faster Delivery

In general, lipid-based drugs are encased in synthetic lipid nanoparticles, which mimic biological membranes. One of these lipids is phospholipid named phosphatidylcholine, a component found in all biological membranes. In vaccines like the COVID-19 vaccine, the mRNA is encapsulated in lipid particles containing about 10% of this phospholipid. Prof. Peer and his team increased the phospholipid ratio to 30% and demonstrated that this adjustment caused the particles to float through the bloodstream like oil on water.

“That’s the whole trick”, Prof. Peer concludes. “We adjusted the lipid composition and found that at 30% phospholipid, the drug is directed straight to the intestine. Of course, this wasn’t a blind trial-and-error approach. We understand the mechanism, at least partially, and recognize that this ratio more closely resembles a natural biological membrane, which intestinal cells are better suited to absorb. Now, we are exploring further adjustments to target the pancreas and other organs that can only be reached by fine-tuning the lipid nanoparticle composition. This direct delivery method for mRNA drugs opens up broad possibilities for developing new and more precise therapies than ever before”.

A breakthrough method delivers two drugs straight to the cancer site.

Researchers at Tel Aviv University have developed a new platform using polymeric nanoparticles to deliver drug pairs to specific cancer types, including skin and breast cancer. The researchers explain that having both drugs arrive at the tumor site significantly amplifies their therapeutic effects and safety profiles.

The study was led by Prof. Ronit Satchi-Fainaro and doctoral student Shani Koshrovski-Michael from the Department of Physiology and Pharmacology at Tel Aviv University’s School of Medicine, in collaboration with other members of Prof. Satchi-Fainaro’s lab: Daniel Rodriguez Ajamil, Dr. Pradip Dey, Ron Kleiner, Dr. Yana Epshtein, Dr. Marina Green Buzhor, Rami Khoury, Dr. Sabina Pozzi, Gal Shenbach-Koltin, Dr. Eilam Yeini, and Dr. Rachel Blau. They were joined by Prof. Iris Barshack from the Department of Pathology at Tel Aviv University’s School of Medicine, Prof. Roey Amir and Shahar Tevet from the School of Chemistry at Tel Aviv University, and researchers from the Israel Institute of Biological Research, Italy, Portugal, and the Netherlands. The study was published in the prestigious journal Science Advances.

Bringing Precision to Drug Partnerships

Prof. Satchi-Fainaro explains: “Currently, cancer treatment often involves a combination of multiple drugs that work synergistically to enhance their anti-cancer effect. However, these drugs differ in their chemical and physical properties – such as their rate of degradation, their circulation time in the bloodstream, and their ability to penetrate and accumulate in the tumor. Therefore, even if multiple drugs are administered simultaneously, they don’t arrive together at the tumor, and their combined effects are not fully realized. To ensure maximal efficacy and minimal toxicity, we sought a way to deliver two drugs simultaneously and selectively to the tumor site without harming healthy organs”.

The researchers developed biodegradable polymeric nanoparticles (which break down into water and carbon dioxide within one month) capable of encapsulating two different drugs that enhance each other’s activity. These nanoparticles are selectively guided to the cancer site by attaching them to sulfate groups that bind to P-selectin, a protein expressed at high levels in cancer cells as well as on new blood vessels formed by cancer cells to supply them with nutrients and oxygen.

The researchers loaded the platform with two pairs of drugs approved by the FDA: BRAF and MEK inhibitors used to treat melanoma (skin cancer) with a BRAF gene mutation (present in 50% of melanoma cases), and PARP and PD-L1 inhibitors intended for breast cancer with a BRCA gene mutation or deficiency. The novel drug delivery system was tested in two environments: in 3D cancer cell models in the lab and in animal models representing both primary tumor types (melanoma and breast cancer) and their brain metastases.

The findings showed that the nanoparticles, targeted toward P-selectin, accumulated selectively in primary tumors and did not harm healthy tissues. Furthermore, the nanoparticles successfully penetrated the blood-brain barrier, reaching metastases in the brain with precision without harming healthy brain tissue.

Additionally, the combination of two drugs delivered simultaneously was far more effective than administering the drugs separately, even at 30 times lower doses than prior preclinical studies. The nanoparticle treatment significantly reduced tumor size, prolonging time to progression by 2.5 times than standard treatments, and extended the lifespan of mice treated with the nanoparticle platform. Mice had a 2-fold higher median survival compared to those receiving the free drugs and a 3-fold longer survival compared to the untreated control group.

A New Approach to Cancer Treatment

Prof. Satchi-Fainaro summarized: “In our study, we developed an innovative platform using biodegradable polymeric nanoparticles to deliver pairs of drugs to primary tumors and metastases. We found that drug pairs delivered this way significantly enhanced their therapeutic effect in BRAF-mutated skin cancers and BRCA-mutated breast cancers and their brain metastases. Since our platform is versatile by design, it can transport many different drug pairs that enhance each other’s effects, thereby improving treatment for a variety of primary tumors and metastases expressing the P-selectin protein, such as glioblastoma (brain cancer), pancreatic ductal adenocarcinoma, and renal cell carcinoma”.

The project received competitive research grants from Fundación “La Caixa”, the Melanoma Research Alliance (MRA), the Israel Science Foundation (ISF), and the Israel Cancer Research Fund (ICRF). It is also part of a broader research effort in Prof. Satchi-Fainaro’s lab supported by an Advanced Grant from the European Research Council (ERC), ERC Proof of Concept (PoC), EU Innovative Training Networks (ITN), and the Kahn Foundation.

Researchers created an affordable, needle-free nasal spray COVID-19 vaccine.

A breakthrough in vaccine development: Prof. Ronit Satchi-Fainaro’s lab at TAU’s Faculty of Medical and Health Sciences collaborated with Professor Helena Florindo’s lab at the University of Lisbon to produce a novel nano-vaccine for COVID-19. The nano-vaccine, a 200-nanometer particle, trains the immune system against all common COVID-19 variants, just as effectively as existing vaccines. Moreover, unlike other vaccines, it is conveniently administered as a nasal spray and does not require a cold supply chain or ultra-cold storage. These unique features pave the way to vaccinating 3rd-world populations, as well as the development of simpler, more effective, and less expensive vaccines in the future. The revolutionary study was featured on the cover of the prestigious journal Advanced Science.

Prof. Ronit Satchi-Fainaro.

Prof. Satchi-Fainaro explains: “The new nano-vaccine’s development was inspired by a decade of research on cancer vaccines. When the COVID-19 pandemic began, we set a new goal: training our cancer platform to identify and target the coronavirus. Unlike Moderna and Pfizer, we did not rely on full protein expression via mRNA. Instead, using our computational bioinformatics tools, we identified two short and simple amino acid sequences in the virus’s protein, synthesized them, and encapsulated them in nanoparticles”. Eventually, this nano-vaccine proved effective against all major variants of COVID-19, including Beta, Delta, Omicron, etc.

“Our nano-vaccine offers a significant advantage over existing vaccines because it is needle-free and administered as a nasal spray,” notes Prof. Satchi-Fainaro. “This eliminates the need for skilled personnel such as nurses and technicians to administer injections, reducing contamination risks and sharp waste. Anyone can use a nasal spray, with no prior training”.

Room-Temperature Storage, Same Effectiveness

Another major advantage of the revolutionary nano-vaccine is its minimal storage requirements. Moderna’s sensitive mRNA-based vaccine must be kept at -20°C and Pfizer’s at -70°C, generating great logistic and technological challenges, such as shipping in special aircraft and ultra-cold storage – from the factory to the vaccination station. Prof. Satchi-Fainaro’s novel synthetic nanoparticles are far more durable and can be stored as a powder at room temperature. “There’s no need for freezing or special handling,” she says. “You just mix the powder with saline to create the spray. For testing purposes, as part of the EU’s ISIDORe (Integrated Services for Infectious Disease Outbreak Research feasibility program), we shipped the powder at room temperature to the INSERM infectious diseases lab in France. Their tests showed that our nano-vaccine is at least as effective as Pfizer’s vaccine”.

These important advantages—ease of nasal administration and regular storage and shipping — pave the way towards vaccinating at-risk populations in low-income countries and remote regions, which existing vaccines are unable to reach. Moreover, the novel platform opens the door for quickly synthesizing even more effective and affordable vaccines for future pandemics. “This is a plug-and-play technology,” explains Prof. Satchi-Fainaro. “It can train the immune system to fight cancer or infectious diseases like COVID-19. We are currently expanding its use to target a range of additional diseases, enabling the rapid development of relevant new vaccines when needed”.

The groundbreaking project has received competitive research grants from the Israel Innovation Authority and Merck under the Nofar program, as well as funding from Spain’s “La Caixa” Foundation Impulse as an accelerated program, and support from the ISIDORe feasibility program. It is also part of a broader vaccine platform development program at Professor Satchi-Fainaro’s lab, supported by a European Research Council (ERC) Advanced Grant.

TAU Researchers discovered a potential new target for developing effective treatments for Parkinson’s disease.

Researchers at Tel Aviv University discovered a new factor in the pathology of Parkinson’s disease, which in the future may serve as a target for developing new treatments for this terrible ailment, affecting close to 10 million people worldwide.

The researchers: “We found that a variant of the TMEM16F protein, caused by a genetic mutation, enhances the spread of Parkinson’s pathology through nerve cells in the brain”.

The study was led by Dr. Avraham Ashkenazi and PhD student Stav Cohen Adiv Mordechai from the Department of Cell and Developmental Biology at TAU’s Faculty of Medical and Health Sciences and the Sagol School of Neuroscience. Other contributors included: Dr. Orly Goldstein, Prof. Avi Orr-Urtreger, Prof. Tanya Gurevich and Prof. Nir Giladi from TAU’s Faculty of Medical and Health Sciences and the Tel Aviv Sourasky Medical Center, as well as other researchers from TAU and the University of Haifa. The study was backed by the Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease at TAU. The paper was published in the scientific journal Aging Cell.

Doctoral student Stav Cohen Adiv Mordechai explains: “A key mechanism of Parkinson’s disease is the aggregation in brain cells of the protein α-synuclein (in the form of Lewy bodies), eventually killing these cells. For many years, researchers have tried to discover how the pathological version of α-synuclein spreads through the brain, affecting one cell after another, and gradually destroying whole brain sections. Since α-synuclein needs to cross the cell membrane to spread, we focused on the protein TMEM16F, a regulator situated in the cell membrane, as a possible driver of this lethal process”.

α-synuclein spread in the mouse brain.

At first, the researchers genetically engineered a mouse model without the TMEM16F gene, and derived neurons from the brains of these mice for an in-vitro cellular model. Using a specially engineered virus, they caused these neurons to express the defective α-synuclein associated with Parkinson’s and compared the results with outcomes from normal brain cells containing TMEM16F. They found that when the TMEM16F gene had been deleted, the α-synuclein pathology spread to fewer healthy neighboring cells compared to the spread from normal cells. The results were validated in-vivo in a living mouse model of Parkinson’s disease.

TMEM16F Mutation Linked to Parkinson’s Risk in Ashkenazi Jews

In addition, in collaboration with the Neurological Institute at the Tel Aviv Sourasky Medical Center, the researchers looked for mutations (variants) in the TMEM16F gene that might increase the risk for Parkinson’s disease. Dr. Ashkenazi explains: “The incidence of Parkinson’s among Ashkenazi Jews is known to be relatively high, and the Institute conducts a vast ongoing genetic study on Ashkenazi Jews who carry genes increasing the risk for the disease. With their help, we were able to identify a specific TMEM16F mutation which is common in Ashkenazi Jews in general, and in Ashkenazi Parkinson’s patients in particular”. Cells carrying the mutation were found to secrete more pathological α-synuclein compared to cells with the normal gene. The researchers explain that the mechanism behind increased secretion has to do with the biological function of the TMEM16F protein: the mutation increases the activity of TMEM16F, thereby affecting membrane secretion processes.

Stav Cohen Adiv Mordechai: “In our study, we discovered a new factor underlying Parkinson’s disease: the protein TMEM16F, which mediates secretion of the pathological α-synuclein protein through the cell membrane to the cell environment. Picked up by healthy neurons nearby, the defective α-synuclein forms Lewy bodies inside them, and gradually spreads through the brain, damaging more and more brain cells. Our findings mark TMEM16F as a possible new target for the development of effective treatments for Parkinson’s disease. If, by inhibiting TMEM16F, we can stop or reduce the secretion of defective α-synuclein from brain cells, we may be able to slow down or even halt the spread of the disease through the brain”.

Dr. Ashkenazi emphasizes that research on the new Parkinson’s mechanism has only begun, and quite a number of questions still remain to be explored: Does inhibiting TMEM16F actually reduce the symptoms of Parkinson’s disease? Does the lipid composition of cell membranes play a part in spreading the disease in the brain? Is there a link between mutations in TMEM16F and the prevalence of Parkinson’s in the population? The research team intends to continue the investigation in these directions and more.