17 innovations from Bar-Ilan University, available for licensing, co-investment, or spin-out through BIRAD.
Gonen, Nitzan
Males and females differ drastically in many traits including organ development, behaviour, prevalence of diseases and responses to drugs. It is believed that this difference stem from sex chromosome composition (XY/XX) or sex hormones (Testosterone/ Estrogens). It is impossible to distinguish between the two under normal conditions. We have developed a system of mice that enables to segregate between sex chromosomes and sex hormones and hence understand what are the mechanisms leading to sexual dimorphisms between males and females.
Meital Gal Tanamy
Vaccines based on live attenuated viruses are the most effective strategy for controlling infections, since they elicit long-lasting natural and effective immune response, but entail challenges as safety and virulence. Hepatitis C Virus (HCV) is a major global health problem, causing liver diseases and liver cancer, with millions infected each year and hundreds of thousands of annual fatalities; but no vaccine is currently available for the virus. Here we present a novel computational approach for the accurate predication of virus attenuation. The approach is based on a rational design of weakened virus variants by insertion of high number of synonymous mutations to disrupt the viral RNA’s secondary structure and regulatory sequences important for the viral life cycle. By measuring RNA levels and virus spread in HCV infection model, we showed that these variants have lower viral fitness relative to the wild-type virus, with gradient of attenuation in concordance with the prediction model. Deep sequencing of replicating viruses demonstrated genomic stability of the attenuated variant. Differential expression analysis and evaluation of cancer-related phenotypes revealed that the variants have a lower pathogenic influence on the host cells, compared to the WT virus. These rationally designed variants may be further considered as a promising direction for a viable HCV vaccine. Importantly, the computational approach described here is based on the most fundamental viral regulatory motifs and therefore may be applied for almost all viruses as a new strategy for vaccine development.
Albeck Amnon
development of protein-protein interaction inhibitors, whose activity is calcium concentration dependent. Thus, at low calcium conc. the inhibitors will be active (preventing the interaction between the two proteins), but at high concentration they will not interfere with the biological activity.
Piran Ron
The progressive loss of insulin-producing β-cells is central to the pathogenesis of all diabetes types, yet strategies for their regeneration remain limited. Here, we describe the successful implementation of a mathematical prediction we developed: inhibition of somatostatin (Sst) expression enabled robust, glucose-responsive β-cell regeneration and restored insulin independence in diabetic models. Genetic Sst knock out (SstKO) mice spontaneously recovered from chemically induced diabetes. We then rediscovered Cysteamine (Cys), an FDA-approved drug, as a pharmacological inhibitor of Sst production in mouse and human primary islets. Mechanistically, Sst suppression released a brake on intrinsic regenerative pathways within the islet. In diabetic wild-type mice, Cys reproduced the regenerative phenotype of SstKO animals. Importantly, in autoimmune-prone NOD mice, Cys treatment restored β-cell function and insulin independence. Together, these findings identify Sst inhibition as both a regenerative and therapeutic axis for β-cell regeneration, and nominate Cys as a safe, clinically translatable candidate for diabetes therapy
Shokhen Michael
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Ayal Hendel
We have developed a machine learning based approach for analysing treatment vs control multiplexing-PCR and Next-generation sequencing data to infer and quantify CRISPR genome editing off-target activity. Our methods are now well developed and we are in the final stages of writing a full manuscript. The main contributions of this project are the tool and the statistical modelling approach behind it, which lead to improved performance as we demonstrate. Moreover - we observed that using this type of data also allows us to infer translocation/fusion adverse events. These are not addressed by any of the existing approaches (e.g CRISPResso (1 and 2) and ampliCan). We apply our inference methods to experimental data (5 different on-target loci, in different technical configurations and with a total of 230 off-target sites examined) and demonstrate unique findings that also shed a light on translocation mechanisms related to CRISPR genome editing.
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.
Gonen, Nitzan
We have generated testis organoids from embryonic and neonatal mouse testicular cells. We use transwell inserts and well defined media for this. The organoids can be maintained for 9 weeks in vitro and preserve all main testicular cell types. They also display gene expression profiles that are highly similar to the real testis as well as spatial organisation that resemble the testis. We also developed 2 defined media compositions that enable to support the immature versus mature testis states.
Louzoun Yoram
We have developed a novel machine learning for microbiome based classification. The method is based on the translation of samples into images and applying CNN to these images
Louzoun Yoram
The effect of microbes on their human host is often mediated through changes in metabolite concentrations. As such, multiple tools have been proposed to predict metabolitc profiles from microbial taxa frequencies, assuming a direct relation between the gut microbiome composition and blood metabolite concentrations. However, the microbiome-metabolite relation may depend on host demographics or condition. We show that the relation between microbiome and metabolites is best predicted at the log concentration level. We further develop LOCATE (Latent Of miCrobiome And meTabolites rElations), a machine learning (ML) tool based on latent representation which predicts the log normalized metabolites composition based on the log normalized microbiome composition. LOCATE has a higher overall accuracy than all current state-of-the-art predictors in both 16S rRNA gene and shotgun gene sequencing. The accuracy of LOCATE and all other predictors significantly decreases when predicting on one dataset and testing on a different dataset, or on a different condition in the same dataset, especially in 16S rRNA gene sequence based data. We propose an intermediate representation between the microbiome and the metabolite concentrations and show that this representation can be used to predict the host phenotype better than either the microbiome or the metabolome. This representation is strongly correlated with host demographics, including age, gender and diet and can be used to improve ML predictions of host phenotypes in comparison with either microbiome or metabolome using a large microbiome sample combined with a small number of metabolome samples (~ 50)
Qvit Nir
Protein-protein interactions (PPIs) play a key role in a variety of critical processes and in many human diseases including cardiovascular diseases (CVDs) and are therefore highly relevant potential therapeutic targets. Peptides have emerged as a promising approach to targeting PPIs, as they demonstrate more rapid clearance than antibodies and higher specificity than small molecules. Recently, mitochondrial dysfunction has emerged as one of the main pathogenic mechanisms underlying an increasing number of diseases, including CVDs. The membrane-associated RING-CH-type finger (MARCH) 5, a mitochondrial ubiquitin ligase plays a crucial role in mitochondrial homeostasis. However, its significance in cardiomyocytes under physiological and pathological conditions remains unclear. MARCH5 was demonstrated to interact with and ubiquitinate mitofusin2 (Mfn2) which is thought to be involved in its intracellular localization and/or activation. To further determine the significance of MARCH5/Mfn2 PPI significant in mitochondrial quality and function, we: (1) Developed a peptide, CVP-220, that targets MARCH5/Mfn2 PPI; (2) Demonstrated that the peptide is specific to MARCH5/Mfn2 PPI and does not inhibit other MARCH5 PPIs; and (3) Shown that CVP-220, is cardioprotective in cardiomyocytes. Taken together, our findings suggest that CVP-220 might be a promising lead for the treatment of diseases with mitochondrial dysfunction.
