38 innovations from Bar-Ilan University, available for licensing, co-investment, or spin-out through BIRAD.
Piran Ron
Latent autoimmune diabetes in adults (LADA) is a relatively new defined diabetes type. It has a strong autoimmune component, making it similar to type I diabetes (T1D), while its onset is at a later age (30’s or older), making it similar to type II diabetes (T2D). It is still unclear how prevalent LADA is in the general population, as most LADA patients are erroneously diagnosed with T2D receiving imprecise treatment. It is estimated that most lean T2D patients are LADA patients. Therefore, it is estimated that the percentage of LADA patients out of the T2D patients is 10%. Considering that T2D is 90% of all diabetic patients and that T1D is about 8%, making LADA more abundant than T1D (10*90/100=9% of total diabetic patients). All diabetes types eventually end in pancreatic β-cell loss and thus results in the loss of insulin secretion, which causes overproduction and a decreased cellular uptake of glucose. Therefore, developing novel strategies aiming to protect, regenerate, and restore β-cells would represent a promising therapeutic alternative for all patients with diabetes. Researches have identified several drugs which possibly stimulate β-cell proliferation and enhance their function. Among these are γ-Aminobutyric acid (GABA), dipeptidyl peptidase IV inhibitors (DPP-4i) such as Sitagliptin (SIT), or proton pump inhibitors (PPI) like Omeprazole (OMP). We found that the combined treatment (CT) administration demonstrated a significant improvement in diabetic symptoms compared to untreated mice and mice that received GABA, GABA+SIT, GABA+OMP, or SIT+OMP. Moreover, ~30% of the mice that were given CT were COMPLETELY CURED of diabetes and showed normoglycemia for 7 weeks after the last drug administration, an unprecedented achievement for this irreversible disease. We have clear indications that similar success rates also recapitulate in human LADA patients. The challenge was to differentiate the 30% cured from CT unresponsive mice. Thus, we repeated the CT experiment, this time taking blood samples from all mice after diabetes onset but before starting treatment. After the experiment, we returned to the blood samples and arranged them according to the cured/unresponsive. We identified circulating RNA markers that predict 100% response to CT, enabling the successful identification of candidates for CT.
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 several genes that are part of the glucose metabolism that when expressed in primary human lymphocytes, enhance T-cell function
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. Dynamin-related protein 1 (Drp1), a mitochondrial GTPase plays a crucial role in mitochondrial homeostasis. Drp1 was demonstrated to interact with Fission protein 1 (Fis1) leading to excessive fission, resulting in mitochondrial damage. To further determine the significance of Drp1/Fis1 PPI significant in mitochondrial quality and function, we: (1) Developed a library of peptides and macrocycles, and identified CVP-350 and CVP-354, that target Drp1/Fis1 PPI; (2) Demonstrated that the peptides are specific to Drp1/Fis1 PPI; and (3) Shown that CVP-350 and CVP-354, are cardioprotective in cardiomyocytes. Taken together, our findings suggest that CVP-350 and CVP-354 might be promising leads for the treatment of diseases with mitochondrial dysfunction.
Knisbacher Binyamin
The invention presents methods for customizing chronic lymphocytic leukemia (CLL) treatment through the use of a detailed biomarker panel and specific agents, based on the patient's biomarker profile. This method aims to match patients with treatments likely to be effective, according to various markers from distinct categories (e.g., gene expression, protein expression, mutations, clinical features, disease subtypes), aiming to improve treatment precision and outcomes in CLL management. The approach suggests a shift towards personalized treatment, leveraging molecular characteristics to inform therapeutic choices in oncology. The results are, at least in part, based on dynamic BH3 profiling experiments, which were used in a comprehensive drug screen that tested 42 different FDA approved drugs on samples taken from dozens of CLL patients.
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.
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.
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.
Fischer Bilha
Calcium pyrophosphate deposition (CPPD) is associated with osteoarthritis and is the cause of a common inflammatory articular disease. Nucleotide pyrophosphatase/phosphodiesterase1 (eNPP1) is the major ecto-pyrophosphatase in chondrocytes and cartilage-derived matrix vesicles (MVs). Thus, eNPP1 is a principle contributor to extracellular pyrophosphate levels and a potential target for interventions aimed at preventing CPPD. Recently, we synthesized and described a novel eNPP1-specific inhibitor, SK4A, and we set out to evaluate whether this inhibitor attenuates nucleotide-pyrophosphatase activity in human osteoarthritis cartilage. Cartilage tissue, chondrocytes and cartilage-derived MVs were obtained from donors with osteoarthritis undergoing arthroplasty. OA chondrocytes express eNPP1 in early passages. Similarly, significant nucleotide-pyrophosphatase activity was detected in early-passage chondrocytes. The eNPP1 inhibitor, SK4A, was not toxic to chondrocytes and stable in culture medium and human plasma. SK4A effectively inhibited nucleotide-pyrophosphatase activity in whole cartilage tissue, in chondrocytes and in cartilage-derived MVs and reduced ATP-induced CPPD formation, as visualized and quantified with Alizarin red S staining. Next we developed second generation drug candidates exhibiting improved NPPase inhibition in human chondrocytes.
Mandel Yossi
The invention relates to novel proteinoid-based nanocapsules (NCs) designed for non-invasive drug delivery to the retina via topical administration (eye drops). The nanocapsules are synthesized from tailored amino acid–based polymers that self-assemble into hollow nano-sized particles capable of encapsulating therapeutic agents. These biodegradable, non-toxic, and customizable nanocapsules enable penetration across ocular barriers and delivery of drugs to posterior eye tissues, including the retina and choroid, thereby potentially replacing invasive intravitreal injections. The invention includes specific proteinoid compositions optimized for enhanced retinal penetration, safety, and drug-loading capacity.
Gil Hava
The invention consists of (i) discovery that tumor metastasis of breast and other forms of cancer can be prevented by inhibiting the interaction between cortactin and the non-receptor tyrosine kinase Pyk2, (ii) a 19-mer peptide derived from the Pyk2 sequence is an inhibitor of this interaction, (iii) administration of this peptide significantly reduces metastasis in malignant cell-lines and in immune-competent mice, and (iv) additional peptides with improved inhibition profiles were derived in a structure-based approach.
Cohen Haim
Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Here, we characterized age-related changes in chromatin accessibility in the murine liver. We found that aging leads to increased chromatin accessibility. These changes were accompanied by upregulation of inflammation-related pathways and downregulation of metabolic pathways. Remarkably, SIRT6 overexpression reversed these changes, reducing inflammation and enhancing metabolic function. Notably, ETS family members were enriched in regions with increased accessibility during aging, while liver-enriched transcription factors (LETFs) were enriched in regions with reduced accessibility. H3K9ac and H3K56ac ChIP-seq analyses showed that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging and that SIRT6 can reverse this effect. Furthermore, an viral system of AAV-mediated SIRT6 overexpression experiment in aged mice demonstrated that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state. This highlights the potential of SIRT6 based therapy to rejuvenate aged tissues and mitigate age-related dysfunction.
