37 innovations from Bar-Ilan University, available for licensing, co-investment, or spin-out through BIRAD.
Barda-saad Mira
The immune system employs intricate regulatory mechanisms to ensure that immune cells distinguish foreign invaders from healthy tissues via the ‘education’ process. Natural Killer (NK) cell education is of crucial interest due to its upcoming role in adaptive immunity. In individuals, 13%±6% of the NK cells do not express classical inhibitory receptors as killing inhibitory receptors (KIRs) superfamily and NKG2A. These dysfunctional cells, termed ‘anergic’ NK cells, have relatively lowered cytotoxic potential and reduced pro-inflammatory cytokine secretion. Most research has focused on the role of NK cell education, but the molecular framework underlying NK cell anergy or hypo-responsiveness phenotype remains unknown. Re-programming these cells and enhancing their functional role has great potential for cancer immunotherapy. Here we decipher the underlying molecular mechanism and identify key intrinsic regulators such as EGR2 and DGKα governing NK cell anergy. Together, reinforced by transcriptome analysis, we profile the anergic vs. responsive signature. Furthermore, we demonstrate that silencing these intrinsic regulators revokes NK functionality (cytotoxicity) , thus serving as markers for anergy or hypo-responsiveness and acting as a potential target to reverse dormancy. This newfound approach to “reprogram” them in situ via intrinsic regulators is of high clinical relevance for future NK anti-tumor immunotherapeutic approaches.
Margel Shlomo
In this research, nano/micro-particles and thin coatings on different polymeric films were prepared in order to impart disinfectant properties on the film’s surface. The particles and coatings are based on silane polymers containing urea functional groups. The coatings divided into 4 types that release different biocide chemicals: activated chlorine, hydrogen peroxide, essential oils and metallic ions. All types of coatings illustrated biocidal effects against microorganisms and decrease/prevent biofilm formation. Synergetic anti-microbial effects were achieved by combining different types of coatings. The following diagram describes the four types of coatings prepared in the present work. Similar nano/micro-particles were also prepared.
Cohen Haim
Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels and its beneficial effects are mediated by the gasotransmitter H2S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, specifically preventing the aging-dependent H2S reduction, and elevation of the methyl donor, SAM. Sirt6-dependent acetylome analysis of old liver revealed differential acetylation of most of the one-carbon enzymes. Sirt6-dependent Matα1 K235 deacetylation reduces SAM production activity and Cbs binding, thereby reducing its activation of Cbs-dependent H2S production. In addition, Sirt6 downregulates xCT expression in a Sp1-dependent manner, decreasing cystine uptake and increasing Cgl H2S production activity. The net outcome is H2S and SAM levels similar to those observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.
Levanon Erez
Recent findings suggest that ICIs fail to invoke an immune response when the tumors lack potent immunogenic peptides called “neoantigens”. The majority of mutations in cancer result in only slightly modified peptides that are unlikely to serve as neoantigens and trigger an immune response – despite checkpoint inhibitor treatment. To overcome this limitation, we developed a computational framework that aids the design of synthetic polymers, called antisense oligonucleotides (ASOs), that manipulate the splicing process in tumor cells to offset protein synthesis machinery and force production of entirely new peptides. Smart, computationally driven, choices of potential targets, will result in highly immunogenic peptides. We expect the combination of our technology with current checkpoint inhibitors, to offer a new and effective strategy in cancer therapy.
Cohen Cyrille
In this invention, we have identified a gene involved in amino acid metabolism that when over-expressed in primary human lymphocytes, enhances T-cell function
Ayal Hendel
Tumor-Infiltrating Lymphocyte (TIL) therapy has emerged as an effective personalized treatment for advanced melanoma. However, several obstacles hinder its optimal implementation in clinical practice. The advent of CRISPR gene editing presents a promising avenue for enhancing TIL therapy by improving the ability of lymphocytes to target tumors more effectively. By making precise modifications to immune cells, it is possible to boost significantly their efficacy in combating cancer. Specifically, the simultaneous targeting of CBL-B and CBL immune checkpoints in CRISPR-modified TILs has demonstrated increased production of cytotoxic molecules and cytokines, thereby enhancing their capability to eradicate cancer cells directly. This innovative approach has the potential to lead to improved clinical outcomes for a broader range of patients with melanoma.
Cohen Cyrille
In this invention, we have identified several genes that are part of the glucose metabolism that when expressed in primary human lymphocytes, enhance T-cell function
Cohen Haim
This invention relates to a method for diagnosing Covid-19 virus in biological samples. Specifically, this invention relates to a method for detecting SARS-CoV2 viral RNA using a fluorescently labeled complementary DNA probe according to a phenomenon known as Microscale Thermophoresis (MST). MST is a physical phenomenon where biomolecules migrate differently along a temperature gradient according to properties such as size, hydration shell and charge. These different migration patterns resulting in a separation along the gradient which can be quantified for scientific studies. Since binding events are predicted to affect thermophoretic migration, MST is used to detect biological interactions such as protein-protein and protein-ligand interactions with high accuracy and low sample consumption. In a typical MST measurement an infra-red laser (I.R) is used to create the temperature gradient for a limited time and one of the binding partners is fluorescently labeled and being monitored during the total time of the experiment. The ratio between the florescence signal before and during the temperature gradient is calculated and represents the thermophoretic migration. The present invention is directed to utilize this phenomenon, prior MST measurement RNA is extracted from a biological sample using guanidinium thiocyanate phenol-chloroform extraction technique. Then, under strict conditions to ensure maximum specificity it is allowed to hybridize with a fluorescently labeled SARS-CoV2 DNA probe. If the viral RNA is present in the sample, a RNA:DNA hybrid is formed and the difference between the thermophoretic migration of a free probe and the hybrid is measured using an MST instrument. For more details and proof of concept’ please see figure 1-4. The method of this invention allows a detection time of 3 seconds for 1 sample, meaning a theoretical capacity up to 58,000 samples per day for 1 MST instrument (depends on the model in used). The invention is also further applicable for the diagnosis of other viruses and bacteria.
Yissachar Nissan
The invention relates to the identification and use of a unique gut microbes configuration that inhibits tumor growth and enhances the efficacy of immune checkpoint inhibitors (ICIs) in metastatic melanoma patients. By utilizing specific gut bacterial strains with immunomodulatory properties - it is possible to predict clinical response prior to immunotherapy, enhance anti-tumor immune responses, overcome treatment resistance, and improve therapeutic outcomes in patients with resistant cancers. Specifically, the invention focuses on a defined consortium of bacterial strains identified through a series of experiments conducted in our laboratory (by analyzing intestinal responses to patients microbiota samples using our unique gut organ culture system). This microbial mix includes Barnesiella intestinihominis, Ruminococcus callidus, Ruminiclostridium siraeum, and additional strains predicted to induce pro-inflammatory immune responses that potentiate enhanced anti-tumor immunity. The invention further comprises a novel experimental pipeline for identifying beneficial gut bacterial strains from among the thousands found in patient microbiome samples, aimed at boosting immune system activity and improving the success of anti-cancer treatments.
Gerber Doron
We have invented a microfluidic mechanism that allows us to take any ELISA/antibody based detection assay and improve its sensitivity 2-3 orders of magnitude. This means that we can work with very small samples or discover for example blood markers that are very scarce.
Meital Gal-Tanamy
We have constructed novel monoclonal neutralizing antibodies for Hepatitis C virus that correlates with infection outcome. We have isolated 7 neutralizing antibodies from phage display library that we have constructed from samples obtained from spontaneously cleared HCV infections and 3 neutralizing antibodies from phage display library that we have constructed from samples obtained from chronic HCV infections. Two antibodies isolated from spontaneously cleared infections were improved by generating and analyzing HCV B-cell repertoires. These two antibodies are uniue to cleared infections and show high binding specificity to HCV E2 envelop protein and neutralize all 7 HCV genotypes thus show high neutralization breath.
Shamay Meir
Distal cis-regulatory elements, such as enhancers and silencers, dictate tissue-specific complex transcriptional repertoire in an orientation- and position-independent manner. Herpesviruses show programmed latent and lytic gene expression based on the infected tissue and physiological cell state. In a recent study we systematically identified the enhancers within the Kaposi’s Sarcoma-associated Herpesvirus (KSHV) genome. Here, we present ENHAvir, an NLM-based tool that can successfully predict the enhancers in a viral genome. We used the DeBERTa v3 language model56 in our framework. DeBERTa v3 is an encoder-style language model, making it a suitable candidate for extracting representations that could be used for new tasks. ENHAvir successfully identified known and novel enhancer elements in the herpesviruses, namely, EBV, HSV1, HSV2, VZV, HCMV, HHV-6, HSV-7, and MHV68. ENHAvir learned the minute patterns of previously published KSHV enhancers and their adjacent sequences responsible for enhancer looping. The activity of the predicted enhancers was validated by cloning the ENHAvir predicted sequences on the EBV genome downstream to the luciferase gene in a reporter plasmid with a weak promoter and performing dual-luciferase reporter assays in EBV-infected and uninfected cell lines. Interestingly, ENHAvir also precisely identified enhancers with the human genome, and examples for Fos, Jun, DPPA3, and Myc genes are presented. The ability of ENHAvir to predict both viral and cellular enhancers, provides an additional layer to the complex gene regulation via viral enhancers but also points out the evolutionary conservation of enhancer micro-signatures between a virus and its host.
