43 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.
Major Dan Thomas
This invention relates to an integrated computational platform — EnzyDock-RxnNet — that combines automated reaction-network enumeration (RxnNet) with mechanistic molecular docking (EnzyDock) to predict, rank, and rationally engineer the product selectivity and promiscuity of terpene synthase enzymes. The platform operates on a quantum-chemistry foundation, parametrizes reactive carbocation intermediates automatically, and scales to full biosynthetic reaction networks encompassing hundreds of intermediates.
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.
Qvit Nir
Protein-protein interactions (PPIs) play a key role in a variety of critical biological processes and are involved in many human diseases, including cardiovascular diseases (CVDs), making them attractive therapeutic targets. Peptides have emerged as a promising strategy for targeting PPIs due to their higher specificity compared to small molecules and more rapid clearance than antibodies. Recently, mitochondrial dysfunction has been recognized as a major pathogenic mechanism underlying numerous diseases, including CVDs. Optic atrophy 1 (Opa1), a mitochondrial dynamin-like GTPase, and PTEN-induced kinase 1 (Pink1) are central regulators of mitochondrial quality control and homeostasis. Dysregulation of the Opa1/Pink1 interaction pathway has been associated with impaired mitochondrial function and cellular damage. To further investigate the significance of Opa1/Pink1 PPI in mitochondrial quality and function, we: (1) developed a library of peptides and identified CVP-026, which targets the Opa1/Pink1 PPI; (2) demonstrated that the peptide is selective for the Opa1/Pink1 interaction; and (3) showed that CVP-026 exerts cardioprotective effects in cardiomyocytes and (4) demonstrated protective effects in myocardial infarction (MI) animal models. Taken together, our findings suggest that CVP-026 may represent a promising lead compound for the treatment of diseases associated 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.
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.
Meital Gal Tanamy
Hepatitis C virus (HCV) is a major public health concern, with about 60 million people infected worldwide, who are at risk for developing life-threatening liver disease. No vaccine is available, and immunity against the virus is not well understood. HCV usually causes chronic infections. However, 20-40% of infected individuals experience spontaneous recovery, suggested to be mediated by HCV-specific immunity. Therefore, comparing immune responses between spontaneous clearer (SC) and chronically infected (CI) individuals may identify mechanisms governing successful viral clearance and lead to designing effective vaccines. It is now widely accepted that broad neutralizing antibodies that cross neutralize heterogeneous viral isolates play a key role in HCV clearance. However, since most of the HCV-neutralizing antibodies developed and characterized to date were isolated from CIs, the nature and epitope specificities of nAbs in SC HCV infections are not well understood. We recently revealed novel distinct epitopes that are associated with infection clearance. To identify the linear immunodominant epitopes associated with viral clearance, we employed an unbiased approach. We screened a phage-display library presenting random peptides to detect binders to antibodies in serum samples from SC and CI HCV infections. This methodology enabled us to capture a comprehensive view of the various immunodominant epitopes in each patient group and compare between them. We identified three SC-unique epitopes that were synthetically synthesized as peptides and validated that these are immunodominant neutralization epitopes specifically in SCs. Importantly, we showed that these epitopes may be efficiently represented by linear peptides, an important observation considering that most of the HCV neutralization epitopes are conformational. by in vivo experiments were we immunized mice with these peptides, we validated their ability to elicit an anti-HCV antibody-mediated immune response. Importantly, we showed that SC-unique epitopes induced a broader and stronger neutralization response compared to other known epitopes. The mixed-peptides sera exhibited the highest neutralization capacity across almost all HCV genotypes. Therefore, this rational design of anti-HCV peptide vaccine induces a broad and efficient antibody immune response.
Shamay Meir
Kaposi’s sarcoma-associated herpesvirus (KSHV, HHV-8) is associated with several human malignancies. Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma that is universally associated with KSHV. The lack of optimized therapy combined with the aggressive nature of PEL results in a short median survival of only 6 months. We have found that the interaction between the viral protein LANA and the cellular protein MeCP2 is essential to maintain viral latency. We designed a peptide that disrupts this interaction. We confirmed that the peptide disrupts the recruitment of LANA by MeCP2. Treatment of PEL cells with the peptide inhibited cell proliferation. We propose this peptide as a treatment for KSHV-associated malignancies, such as PEL.
