Tag: Medicine

The grant is for high-impact research using Data Science and Artificial Intelligence (AI) to combat the coronavirus

TAU researchers create a nanocarrier that selectively delivers two medications and releases them simultaneously at the malignant target

Researchers at Tel Aviv University, led by Prof. Ronit Satchi-Fainaro from the Department of Physiology and Pharmacology at the  Sackler Faculty of Medicine, developed an innovative nanotechnological drug delivery system that significantly enhances the effectiveness of treatment for the aggressive skin cancer melanoma. The nanocarrier is a biocompatible and biodegradable polymer, which comprises repeating units of glutamic acids (PGA- polyglutamic acid), packaging together two biological drugs belonging to different families with proven efficacy for the treatment of melanoma: BRAF inhibitors (Dabrafenib) and MEK inhibitors (Selumetinib, approved for use in children with NF1 – neurofibromatosis type I).

Prof. Satchi-Fainaro: “One of the major obstacles of the biological treatments is that after a while, the cancer cells develop resistance to the drugs. We assume that by precise delivery of two or more targeted drugs that will attack the cancer cells forcefully and simultaneously from different directions, we can delay or even prevent the acquisition of this drug-resistance.”

The research group included PhD students Evgeni Pisarevsky, Dr. Rachel Blau and Yana Epshtein from Prof. Satchi-Fainaro’s research laboratory at TAU’s Sackler School of Medicine. The paper was published as the cover article of the August 2020 issue of Advanced Therapeutics.

Prof. Satchi-Fainaro: “In this project, we looked for a solution to a problem often associated with drug cocktails: Today, most oncological treatments are administered in the form of cocktails of several medications; However, despite the fact that all drugs are administered to the patient simultaneously, they do not reach the tumor at the same time, due to differences in basic parameters – like how long they survive in the bloodstream (i.e. half-life), and the time it takes each drug to reach the tumor tissue. Thus, in most cases, the medications do not work concurrently, which prevents them from attaining optimal synergistic activity.”

Responding to these challenges, the researchers developed an innovative, efficient and biodegradable drug delivery system. Two biological drugs, known to be effective for the treatment of melanoma, Dabrafenib and Selumetinib, (inhibiting two different components – BRAF and MEK respectively – in the biological pathway which is over-activated in melanoma), were chosen, with the intention of delivering them jointly to the tumor by using a nanocarrier. The drug nanocarrier chosen for the task was PGA, a polymer of glutamic acid – one of nature’s most common amino acids. Developed in Prof. Satchi-Fainaro’s lab several years ago, the nanocarrier has already been tested successfully for treating pancreatic, breast and ovarian cancer in animal models.

In search of an optimal ratio

First, the researchers determined the optimal ratio between the two medications – based on levels and types of toxicity, as well as the resistance mechanism developed by cancer cells for each medication – to ultimately ensure maximum effectiveness, minimal toxicity and optimal synergistic activity. Another important advantage of joint delivery is reduced dosage: a much lower dose is required compared to each drug when administered independently.

The next step was using chemical modifications to enable bonding between the polymeric carrier and the chosen drugs. This combined system can travel through the body with total safety, inflicting no damage to healthy tissues. Upon reaching the cancer cells, the nanocarrier encounters proteins of the cathepsins enzyme family, which are highly activated in malignant tumors. The proteins degrade the polymer, releasing the drugs which become active and join forces to attack the tumor. Prof. Satchi-Fainaro: “It’s like several passengers riding in one cab and getting off together at the same address. They all arrive at the same destination, right at the same time.”

Promising results

Tested on a mouse model of melanoma, the new treatment showed promising results: The nanocarrier delivered the two drugs to the tumor and released them there simultaneously in quantities about 20 times greater than those that reach the tumor when similar doses of the same medications are administered independently. In addition, the therapeutic effect achieved by the drugs delivered by the nanocarrier lasted much longer – 2-2.5 times compared to control group and the group treated with free medications. According to the researchers, this means that the new platform enables much lower dosages – about one third of the dose required in regular drug cocktails, and the treatment as a whole is both safer and more effective. Also, if needed, the new approach allows for dosages that are much higher than the maximum dosage permissible in current methods, thereby enhancing the effectiveness of the treatment even further.

Prof. Satchi-Fainaro: “In this project, we developed an innovative drug delivery system for treating melanoma, delivering two proven medications and releasing them simultaneously at the tumor site. The treatment proved both safer and more effective than the same medications administered as a cocktail. Moreover, our new platform is highly modular and can be used for delivering a vast range of medications. We believe that its potential for enhancing therapeutics for different diseases is practically endless.”

The study was funded by the Israel Cancer Research Fund (ICRF), the European Research Council (ERC), Israel’s Ministry of Health (EuroNanoMed-II program), the Melanoma Research Alliance, the Morris Kahn 3D BioPrinting for Cancer Research Initiative and the Israel Science Foundation (ISF).

Featured image: Prof. Ronit Satchi-Fainaro

Grantee Professor Jonathan Gershoni aims to block the coronavirus by targeting its most vulnerable spot

Science-based technology company 3M has awarded a significant philanthropic research grant of $400,000 (1.36 million NIS) to the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University to advance scientific knowledge in the global response to the COVID-19 pandemic. The grant from 3M, which bases its Israel operations in Herzliya, is part of a $5 million initiative to support research programs with a focus on treatments and vaccine development for COVID-19 at leading educational establishments around the world. TAU secured the funding through an international competitive process; this reflects the high esteem in which the University’s scientific research programs are held. The grant was disbursed via 3M’s grant-making partner, GlobalGiving, to ensure thorough vetting, due diligence and reporting. The research project is being led by Professor Jonathan Gershoni, a renowned expert in viral pathogens, who said: “Publication of the SARS CoV2 genome on January 9, 2020, launched the race for a COVID-19 vaccine. Tens of vaccine candidates have already entered clinical trials, the leaders of which are actively recruiting thousands of volunteers worldwide for phase III efficacy trials. All these efforts use the viral spike protein as their vaccine’s active ingredient. This relatively large protein is made up of 1200 amino acids arranged in groups of three, decorating the virus with a crown-like appearance. “The spike protein presents many targets that have evolved to confuse and distract our immune system and to steer us away from the virus’ most vulnerable soft spot, its receptor-binding motif (RBM). In order for the virus to successfully infect us and cause COVID- 19, it must first latch onto a unique protein, the ACE2 receptor, which is present on the surface of our lung cells. For this, the viral RBM, a tiny but highly complex structure, must detect ACE2, bind to it and mediate infection. A vaccine that exclusively targets the RBM should be extremely potent in affording maximal protection against SARS CoV2 by stimulating our immune system in the most efficient and cost-effective way. “We have developed a novel patented technology to ‘surgically’ isolate the RBM from the rest of the spike protein. This grant from 3M will significantly enhance our efforts to produce a highly focused, potent and especially safe vaccine for COVID 19,” he added. ^{Prof. Gershoni’s Lab team (Photographer: Moshe Bedarshi)} This study is anchored in more than 30 years of research on the interaction of RNA viruses with their receptors and the immune response against them, noted Professor Tal Pupko, Head of the Shmunis School at TAU. “The 3M grant will dramatically accelerate the pace of research for overcoming COVID-19,” said Professor Pupko, adding that Tel Aviv University was particularly proud to be included in this important global initiative by 3M. “Science is at the heart of 3M and we are committed to advancing the rapid study of this virus as part of our continued effort to combat the COVID-19 pandemic,” said Isabelle Zadikov-Carp, 3M Israel Country Leader. “It’s important that 3M holds true to its core values by supporting our communities and improving lives. We hope that the grant to TAU will facilitate the development of an effective vaccine and we will be keenly following the progress and outcomes of Professor Gershoni’s research with interest.” Featured image: Professor Jonathan Gershoni (Photographer: Moshe Bedarshi)

Recent Shmunis School achievements:

• The Gershoni Lab was awarded a US patent for a novel vaccine against the coronavirus
• The Stern Lab‘s genetic sequencing of the coronavirus tracked the spread of COVID-19 in Israel
• The Ehrlic Lab is developing virus-based immunotherapies for cancer ​
• The Lederkremer Lab developed a therapeutic approach for Huntington’s disease, for which no treatment exists

Participating in online sports programs during the COVID-19 pandemic improves adolescents’ psychological resilience

The school, funded by a generous endowment from the Shmunis Family, aims to research and improve treatments for cancer, COVID-19 and other diseases

Innovative method to convert waste into disinfectant is a pandemic game-changer

Tel Aviv University Researchers Discover Alzheimer’s-Like Traits in Autistic Child’s Brain

An extensive international study led by Tel Aviv University, headed by Prof. Illana Gozes of the Department of Human Molecular Genetics and Biochemistry, found deposits of the tau protein typically found in Alzheimer’s patients in tissues taken from the postmortem brain of a 7-year-old autistic child. The child suffered from the ADNP syndrome, an ADNP mutation that causes a deficiency/malfunctioning of the ADNP protein which is essential for brain development. The ADNP syndrome child was characterized by severe developmental delay, intellectual disability, and autism. In light of these findings, the researchers tested an experimental drug called NAP – originally developed for Alzheimer’s disease – on nerve cells in a model of ADNP syndrome with the mutation inducing Alzheimer’s-like symptoms. The experiment was a success, with the damaged nerve – like cells returning to normal function.

The study was conducted in close collaboration with researchers from the Blavatnik School of Computer Science at Tel Aviv University, Sheba Medical Center, and a variety of research institutions across Europe, including the biotechnology institute BIOCEV in the Czech Republic, the Aristotle University of Thessaloniki in Greece, the University of Antwerp in Belgium, and the University Hospital Centre in Zagreb, Croatia. The article was published in July 2020 in the journal Translational Psychiatry printed by the Nature Publishing Group.

Prof. Gozes explains that the current study is based on tissues taken from the brain of a 7-year-old boy with ADNP syndrome who died in Croatia. “When we compared the postmortem ADNP syndrome brain tissues to tissue from the brain of a young person without ADNP syndrome, we found deposits of the tau protein in the ADNP child, a pathology that characterizes Alzheimer’s disease.”

The researchers then “treated” damaged nerve-like cells carrying an ADNP mutation, similar to the deceased child mutation with a drug candidate called NAP, which is developed in Prof. Gozes’s laboratory and originally intended to be used to help treat Alzheimer’s disease. “NAP is actually a short active fragment of the normal ADNP protein,” says Prof. Gozes. “When we added NAP to the nerve cells carrying an ADNP mutation, the tau protein bound to the nerve cell skeleton properly, and the cells returned to normal function.”

Prof. Gozes: “The fact that NAP treatment has been successful in restoring the normal function of neuronal-like cell models with impaired ADNP raises hopes that it may be used as a remedy for ADNP syndrome and its severe implications, including autism. Moreover, because other genetic disorders related to autism are characterized by tau pathologies in the brain, we hope that those suffering from these syndromes will also be able to benefit from NAP treatment in the future.” It is important to note that NAP (also called CP201) has been classified as an “orphan drug” by the US Food and Drug Administration, and is currently in the preparatory stages of a clinical trial in children with ADNP syndrome through the company Coronis Neurosciences.

In another phase of the study, the researchers sought to broaden their understanding of the effects of the mutation that causes ADNP syndrome. To do this, they extracted the genetic material mRNA (messenger RNA) from the tissues of the deceased child, and performed an expression analysis of about 40 proteins in the same child, encoded by the mRNA. Full genetic sequencing was also performed to determine protein expression in white blood cells taken from three other children with ADNP syndrome. An in-depth study was carried out on all of the data obtained in the genetic sequencing using advanced bioinformatics computational tools. The data were compared to online databases of protein expression data from healthy individuals, revealing a variety of characteristics that were common to the children with the syndrome, but very different from the normal appearance of these proteins.

Prof. Gozes concludes that “the significance of these findings is that the mutation that causes ADNP syndrome damages a wide range of essential proteins, some of which bind to, among other things, the tau protein, and impair its function as well. This creates various pathological effects in the brains (and other tissues) of children with ADNP syndrome, one of which is the formation of tau deposits, known to be a characteristic of Alzheimer’s disease. The vast and in-depth knowledge we have accumulated through the present study opens the door to further extensive and diverse research. We hope and believe that we will ultimately reach the goal of developing a drug or drugs that will help children with autism resulting from genetic mutations.”

Featured image: Prof. Illana Gozes

Immune System Stimulating Treatment to Reduce Psychological and Physiological Stress Prevents Metastases and Can Save Cancer Patients’ Lives

In a breakthrough research published recently in Nature magazine, Tel Aviv University researchers found that the short time period around the tumor removal surgery (the weeks before and after surgery), is critical for prevention of metastases development, which develop when the body is under stress.

According to the researchers, to prevent development of metastases after the surgery, patients need immunotherapeutic treatment along with treatment to reduce inflammation, and physical and psychological stress. The research was conducted by Prof. Shamgar Ben-Eliyahu from the School of Psychological Sciences and Sagol School of Neuroscience at Tel Aviv University and Prof. Oded Zmora from Assaf Harofe Medical Center.

Immunotherapeutic treatment is a medical treatment activating the immune system. One such treatment, for example, is injecting substances with similar receptors to those of viruses and bacteria into the patient’s body. The immune system recognizes them as a threat and activates itself, thus it can prevent a metastatic disease.

Prof. Ben-Eliyahu explains: Surgery for the removal of the primary tumor is a mainstay in cancer treatment, however the risk of developing metastases after surgery is estimated at 10% among breast cancer patients, at 20%-40% among colorectal cancer patients, and at 80% among pancreas cancer patients.

According to Prof. Ben-Eliyahu, when the body is under physiological or psychological stress, such as a surgery, groups of hormones called prostaglandin and catecholamine are being produced in large quantities. These hormones suppress the immune system cells’ activity, and thus indirectly increase the development of metastases. Additionally, these hormones help tumor cells left after the surgery to develop into life threatening metastases. Thus, exposure to those hormones cause tumor tissues to become more aggressive and metastatic.

“Medical and immunotherapeutic intervention to reduce psychological and physiological stress, and activate the immune system in the critical period before and after the surgery, can prevent development of metastases, which will be discovered months of years later,” stresses Prof. Ben-Eliyahu.

Prof. Ben-Eliyahu adds that anti-metastatic treatment today skips the critical period around the surgery, thus leaves the medical staff to face the consequences of treating progressive and resistant metastatic processes, which are much harder to stop. Prof. Ben-Eliyahu’s research contradicts the assumption, widespread in the medical community, according to which, just like in chemo and radiotherapy, it is not recommended to give cancer patients immunotherapeutic treatment in the month before and after the surgery.

Dan Yamin can detect any kind of contagious outbreak