CF is the most common autosomal recessive disorder in western countries, affecting approximately 30,000 people in the US alone. A major risk in CF arises from chronic bacterial lung infections, affecting 80% of CF patients by the age of 25. Bacterial lung infections are also of major clinical...
CF is the most common autosomal recessive disorder in western countries, affecting approximately 30,000 people in the US alone. A major risk in CF arises from chronic bacterial lung infections, affecting 80% of CF patients by the age of 25. Bacterial lung infections are also of major clinical importance in patients with chronic obstructive pulmonary disease (COPD), trauma, burn wounds, sepsis, or in patients requiring ventilation. The infections are currently treated with antibiotics, which rapidly become inefficient as resistant bacteria strains arise. The present technology suggests a novel therapeutic approach for the prevention and treatment of bacterial lung infection in susceptible populations, especially CF patients
Alternative treatment for bacterial lung infections.
A prophylaxis for patients susceptible to bacterial lung infections
A novel therapeutic approach to prevent or cure bacterial lung infection.
The new therapy is based on reinforcement of the physiological innate immunity rather than on antibiotics.
The new therapy can be easily administered, via inhalation.
FTY720, a SPH analog, is already in clinical use for treating multiple sclerosis.
Sphingosine (SPH), a natural bactericidal agent which acts as a part of the human innate immune system in the skin, was found to be an effective treatment and prophylaxis for bacterial lung infections in cystic fibrosis (CF) mice. The new technology is based on the discovery that both CF human patients and CF mice display reduced rates of SPH in the airways. Moreover, normalizing SPH levels by inhalation prevents or cures the infections in CF mice, thus rendering SPH and its analogs a potent therapeutic agent for CF patients, an alternative to antibiotics.
Organophosphates are toxic compounds found in chemical warfare agents, such as nerve gases, and insect pesticides.Use of volatile nerve gas agents by terrorist organizations is a key concern of governments around the world. V-type nerve agents (e.g. VX, RVX, and CVX) are particularly toxic nerve gases...
Organophosphates are toxic compounds found in chemical warfare agents, such as nerve gases, and insect pesticides. Use of volatile nerve gas agents by terrorist organizations is a key concern of governments around the world. V-type nerve agents (e.g. VX, RVX, and CVX) are particularly toxic nerve gases, with an exceptionally high potency. Although not as lethal as nerve agents, organophosphate insecticides can be harmful in large or prolonged doses. The standard therapy has limited efficacy, carry risks of serious adverse effects and have relatively short shelf life in field conditions. Bioscavengers represent a preferred to rapidly detoxify organophosphates in the blood, before they had the chance to reach its physiological targets and cause damage, but usually require the use of very high doses. The present invention provides genetically modified phosphotriesterase (PTE) variants, which serve as catalytic bioscavengers for V-type nerve agents, with exceptional detoxification activity at low doses, and improved stability.
Prophylactic or post exposure treatment for nerve gases attack, in particular V-type agents
Treatment for pesticides poisoning
High catalytic activity allow high efficacy at low doses
Reduced effective doses allows to reduce adverse effects
High stability increasing shelf life
Compatible with both prophylaxis and post exposure
Compatible for both surface decontamination and administration to patients
Researchers at Prof. Tawfik lab use directed evolution to drive protein mutagenesis towards desired traits. Appling this approach, using the actual threat agents, the present inventors generated recombinant phosphotriesterase (PTE) variants with improved catalytic efficiencies towards V-type nerve agent hydrolysis. Serving as catalytic bioscavengers, these recombinant PTE variants hydrolyze organophosphates without being consumed and thus can be applied at low doses (catalytic efficiency (kcat/KM) greater than 3.106 M-1min-1). Importantly, PTE is efficient both as a prophylactic agent that may be given several hours prior to exposure as a preventive measure, and as post exposure antidote, even days after in a single or multiple-doses. It is compatible with both decontamination of surfaces and detoxification administrated to a patient by standard routes such as orally or injectables. Finally, some PTE variants show superior stability properties, retaining at least 50% of their catalytic activity at 50?C, indicating extended shelf life. This may be especially critical in field conditions, where the risk for nerve agent exposure is high.
Dysregulation of the immune system is the underlying cause of potentially fatal conditions such as sepsis and severe allergic reactions. Adequate therapies are currently absent or lacking. There is therefore an unmet medical need for therapies that would target the underlying causative immune pathways...
Dysregulation of the immune system is the underlying cause of potentially fatal conditions such as sepsis and severe allergic reactions. Adequate therapies are currently absent or lacking. There is therefore an unmet medical need for therapies that would target the underlying causative immune pathways. Anti-microbial peptides (AMPs) possess promising anti-inflammatory activities, however, are commonly toxic. In a series of newly synthesized peptides, the outlined invention provides a method to modify naturally occurring AMPs to possess both potent therapeutic anti-inflammatory activity and minimal toxicity in-vitro and in-vivo. The resulting series of peptides were shown to remarkably inhibit severe allergic reaction as well.
Novel Therapy for sepsis and severe allergic reactions
Very potent anti-inflammatory and anti-allergenic agents
Targeted against the underlying cause of both indications, which is an improper and uncontrolled immune response
Diversity elucidating the parameters that control efficiency and toxicity allows to modify the basic formula to optimally fit different systems
With natural AMPs properties in mind, Prof. Shai and his team characterized the key modifications that underline anti-inflammatory activity and toxicity. A series of peptides with variable degrees of hydrophobicity, length, charge, position of charge and amino acid chirality were tested for their LPS neutralizing activity. It was found that ~20mer peptides under the formula Kn(AL)mKn (wherein n et each occurrence is independently 0-2, and m is 6-9) demonstrate anti-inflammatory activities at nanomolar concentrations as evident by inhibition of TNF? secretion from macrophages, following LPS induction. Furthermore, a single dose of an exemplary peptide was able to inhibit septic shock in mice induced by purified LPS or by whole heat-killed E.coli. In contrast to previous attempts, which focused on increasing hydrophobicity, the core of the present invention is the designation of an optimal hydrophobicity that is necessary for high activity and low toxicity. Additional important features for LPS neutralizing were found to be ?-helical structure and strong oligomerization ability. Surprisingly, the present peptides were shown to contain highly potent anti-allergenic activity as well. In-vitro inhibition of Fc?RI-mediated degranulation was recapitulated in-vivo
An efficient and selective decomposition of plant biomass carbohydrates to their basic components, carbon monoxide and hydrogen, for use as syngas.Terrestrial plants contain about 70% hemicellulose and cellulose, which constitute a significant renewable bio-resource with potential as an alternative to...
An efficient and selective decomposition of plant biomass carbohydrates to their basic components, carbon monoxide and hydrogen, for use as syngas. Terrestrial plants contain about 70% hemicellulose and cellulose, which constitute a significant renewable bio-resource with potential as an alternative to petroleum feedstock for carbon-based fuels. Traditional conversion of biomass to liquid fuels has been in the form of ethanol and bio-diesel, but this process is inefficient and much of the starting material is unusable and ultimately becomes waste. Additionally, use of ethanol or bio-diesel is not universal to all engines as vehicles require specialized components to run on these fuels. The presented technology allows for significantly greater efficiency in use of starting material, and the versatile final product of syngas, which can be a fuel itself or used as a fuel precursor in the well-known Fischer-Tropsch process to create hydrocarbons. Alternatively, in a hydrogen economy scenario, this method can also be used to convert carbon monoxide to hydrogen via the water-gas shift reaction. Advantageously, both processes allow for the polyoxometalate (POM) catalyst to be reused without the need for recovery, which enables continuous use in a refinery setting.
Liquid hydrocarbon fuel synthesis from syngas
Entry into a new market hydrogen production from biomass
Efficient and complete breakdown of starting biomass material
Possible to produce hydrogen or syngas as product
The technology allows for preparation of syngas by reaction of a carbohydrate with a POM catalyst in the presence of a concentrated acid under anaerobic conditions, to yield carbon monoxide, followed by electrochemical release of hydrogen. This two-step process allows for easy separation and storage of the desired products. An alternative application of the same POM catalyst relates to a method for preparing formic acid in a similar method, but in a solvent consisting of a mixture of alcohol and water. This reaction is based on the unexpected finding that POM catalysts, such as H5PV2Mo10O40, catalyze plant biomass derived polysaccharides of general form (CnH2nOn)m, with high selectivity and efficiency under mild conditions. Formation of CO occurs through an intermediate formation of formic acid and formaldehyde, and transformation of these transition compounds in concentrated acid results in the desired CO product. During this process, hydrogen atoms are stored on the POM catalysts as protons and electrons. Hydrogen gas is subsequently electrochemically released from the POM catalyst, which returns the catalyst to its original oxidized state and allows for continued reuse.
A new computer graphics tool for the efficient and robust deformation of 2D images was developed by the group of Prof. Lipman. Space deformation is an important tool in graphics and image processing, with applications ranging from image warping and character animation, to non-rigid registration and...
A new computer graphics tool for the efficient and robust deformation of 2D images was developed by the group of Prof. Lipman.
Space deformation is an important tool in graphics and image processing, with applications ranging from image warping and character animation, to non-rigid registration and shape analysis. Virtually all methods attempt to find maps that possess three key properties: smoothness, injectivity and shape preservation. Furthermore, for the purpose of warping and posing characters, the method should have interactive performance. However, there is no known method that possesses all of these properties.
Previous deformation models can be roughly divided into meshbased and meshless models. Mesh-based maps are predominantly constructed using linear finite elements, and are inherently not smooth, but can be made to look smooth by using highly dense elements. Although the methods for creating maps with controlled distortion exist, they are time-consuming, and dense meshes prohibit their use in an interactive manner. On the other hand, meshless maps are usually defined using smooth bases and hence are smooth themselves. Yet we are unaware of any known technique that ensures their injectivity and/or bounds on their distortion.
The new method presented here bridges the gap between mesh and meshless methods, by providing a generic framework for making any smooth function basis suitable for deformation.
Computer graphics and animation
Image registration for medical imaging, satellite imaging and military applications
Robust, fast, efficient and scalable
Generic, can be applied to various scenarios
Possesses smoothness, injectivity and shape preservation with interactive performance
Deformation od 2D images is accomplished by enabling direct control over the distortion of the Jacobian during optimization, including preservation of orientation (to avoid flips). The method generates maps by constraining the Jacobian on a dense set of collocation points, using an active-set approach. Only a sparse subset of the collocation points needs to be active at every given moment, resulting in fast performance, while retaining the distortion and injectivity guarantees. Furthermore, a precise mathematical relationship between the density of the collocation points, the maximal distortion achieved on them, and the maximal distortion achieved everywhere in the domain of interest is derived.
A novel therapy for Triple Negative Breast Cancer (TNBC) using mAbs combinationBreast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) representing about 15% of all breast cancer cases, is the deadliest form of all breast cancer subtypes, and tends to affect...
A novel therapy for Triple Negative Breast Cancer (TNBC) using mAbs combination Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) representing about 15% of all breast cancer cases, is the deadliest form of all breast cancer subtypes, and tends to affect women at a younger age. Unfortunately TNBC cannot be treated with the common receptor targeted therapies since it does not express these targets, the estrogen, progesterone and Her2/neu receptors. Therefor systemic treatment options are currently limited to cytotoxic chemotherapy. The lack of effective targeted therapies, resistance to chemotherapy, and early metastatic spread have contributed to the poor prognoses and outcomes associated with TNBC. The current technology offers a novel therapeutic strategy for TNBC. The application of two novel, noncompetitive antibodies against EGFR, achieves a robust degradation EGFR resulting in tumor inhibition.
Novel and unique antibody targeted therapy for TNBC.
The novel anti EGFR antibodies can cooperate synergistically with the currently marketed EGFR antibodies.
A promising therapeutic scenario to treat TNBC.
Enhanced EGFR degradation and improved anti-tumor activity, in contrast to clinically approved anti-EGFR mAbs, which display no cooperative effects.
Lysosomal EGFR degradation pathway induced by epitope-distinct antibody mixture may potentially lead to improved therapeutic outcome, and reduced resistance.
Prof. Yosef Yarden and his team demonstrated that a combination of novel antibodies that target distinct regions on the human EGF receptor resulted in its robust and synergistic down-regulation, leading to pronounced tumor growth inhibition. Furthermore, the combined mAbs induced lysosomal degradation of EGFR, while avoiding the recycling route. Such irreversible mode of EGFR degradation may potentially increase response rate or delay the onset of patient resistance. Conversely, combining cetuximab and panitumumab, the mAbs routinely used to treat colorectal cancer patients, did not improve receptor degradation because they are both attracted to the same epitope on EGFR.
Heart failure is the leading cause of death in the western world. Existing treatments fail to compensate the irreversible loss of functional cardiomyocytes (CM), thus presenting a major medical unmet need. Inducing native CM replacement is one approach being tested as regenerative treatment, with the...
Heart failure is the leading cause of death in the western world. Existing treatments fail to compensate the irreversible loss of functional cardiomyocytes (CM), thus presenting a major medical unmet need. Inducing native CM replacement is one approach being tested as regenerative treatment, with the advantage of a more straightforward methodology over cell transplantation approaches. In a multidisciplinary study, headed by Prof. Eldad Tzahor from the Weizmann institute of Science, the tyrosine kinase ERBB2 was shown to be both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials. Thus, potentiation of ERBB2 signalling in adult CMs might represent a promising therapeutic approach for CM replacement in heart failure.
Induction of cardiomyocytes replacement therapy following heart injury.
Straightforward methodology Avoids complications associated with the requirement for cell transplantation.
Include several optional targets - both ERRB2 and its downstream effectors serve as potential targets for therapeutic agents, which may be administrated in combination, to increase chances for successes.
The ligand-receptor network consisting of NRG1, and its tyrosine kinase receptors ERBB4, ERBB3 and ERBB2, plays critical roles during heart development. In a multidisciplinary study, headed by prof. Eldad Tzahor from the Weizmann institute of Science, ERBB2 was shown to be necessary and limiting for NRG1-induced CM proliferation in the neonate. Inspired by this finding, the team examined the possibility to use ERBB2 as a target for induced cell proliferation and regeneration in adult hearts. Using loss- and gain-of-function genetic experiments in mice, they reveal that NRG1/ERBB2 signalling is both essential for CM proliferation and heart integrity in the neonatal period, and sufficient to prolong the postnatal proliferative and regenerative windows. Regeneration was shown to be a result of increased CM dedifferentiation and proliferation accompanied by neovascularization and followed by redifferentiation, tissue replacement with reduced scar formation and restoration of function. Thus, these finding highlight ERBB2 as a strong target for heart regeneration treatments as well as its downstream effectors.
A new image processing tool for transient detection was developed by the group of Prof. Gal-Yam, originally for time-domain observational astronomy.Image sequences are used in various fields, including medical imaging and satellite/airborne imaging. The comparison between images taken at different...
A new image processing tool for transient detection was developed by the group of Prof. Gal-Yam, originally for time-domain observational astronomy. Image sequences are used in various fields, including medical imaging and satellite/airborne imaging. The comparison between images taken at different conditions (e.g. equipment or configuration, angles, weather and wavelength) can be a highly non-trivial problem, as subtraction artifacts can outnumber real changes between images. The existing remedy for this problem includes highly complex solutions using machine learning algorithms to narrow the sea of candidates. In some cases, human interpretation of images cannot be avoided, resulting is very long processing times. The new method presented here provides a proven solution for the subtraction of images taken at varying conditions. The tool can be applied for any type of imaging, allowing fast processing and accurate results.
Fast and automatic
Generic, can be applied to various imaging scenarios
Easily implementable into existing systems
The new method is used for processing at least two N-dimensional data-measurements (DMs) of a physical-property for detecting one or more new-objects and/or a transition of one or more known-objects, in complex constant-background DMs. Generally, the
the method includes: (1) generating a filtered-new-DM by match-filtering a new-DM, respective to impulse response of a reference-DM (2) generating a filtered-reference-DM by match-filtering the reference-DM, respective to impulse response of the new-DM (3) generating an N-dimensional object-indicator (OI) by subtracting the filtered-reference-DM from the filtered-new-DM, or vice versa and (4) generating an N-dimensional data score from the N-dimensional OI, where each of the scores is a probe for existence of an object at a specific N-dimensional location.
Our technology provides a new type of oxidative cleavage reaction of organic compounds with highly selective product formation.Polyoxometalate (POM) catalysts have become well-known for their utility and diversity in specific reactions. Through the elucidation of POM catalytic pathways, greater...
Our technology provides a new type of oxidative cleavage reaction of organic compounds with highly selective product formation. Polyoxometalate (POM) catalysts have become well-known for their utility and diversity in specific reactions. Through the elucidation of POM catalytic pathways, greater versatility has been achieved. This technology is one such application of a novel POM catalyst and is exploited to cleave carbon-carbon double bonds in alkenes (olefins) through an aerobic oxidation reaction. Oxidation reactions are of particular interest because they are difficult to achieve on an industrial scale while maintaining green chemistry practices. 
--------------------------------------------------------------------------------  Green Chem., 2007, 9, 717-730
As a novel catalyst in industrial organic chemistry processes
Sold as a stand-alone catalyst for laboratory or individual use
Environmentally friendly oxidation reaction
Easy catalyst regeneration
Our approach is motivated by societal considerations that demand environmentally benign and sustainable solutions for oxidative reactions. As such, we have developed a scheme to react NO2 with a transition-metal-substituted POM which yields a metal-nitro intermediate that is competent for forming the precursors for oxidation with molecular oxygen, O2, to have a final product of ketones and/or aldehydes, and regenerate the POM catalysts. This method has preference towards di/tri-substituted alkenes. High yields of ketones or aldehydes have been produced and the POM catalyst is regenerated without further oxidation to carboxylic acids, as is typical with other oxidative catalysts. The selective cleavage of carbon-carbon double or triple bonds with metal-nitro or metal-nitrito compound has not been reported. This exciting new discovery could lead to a wide variety of organic reactions not previously possible, along with revolutionary green oxidative chemistry techniques.
--------------------------------------------------------------------------------  J. Am. Chem. Soc., 2014, 136(31), pp10941-10948
Lower collateral toxicities allow for greater flexibility in treatment dosage.
Enhanced patient survival rate.
More favorably considered as a line of therapy due to decreased side effects.
Utilization of well-characterized compounds alleviates safety and toxicity considerations.
ER stress, elicited by chemotherapeutic agents such as doxorubicin, 5FU, vincristine and bortezomib, or statins such simvastatin, triggers cell death at least in part through generation of leukotriene C4 (LTC4), which induces ROS accumulation, DNA damage and subsequent cell death. LTC4 can be produced by two parallel pathways. Cells of hematopoietic origin express C4 synthase (LTC4S) and secrete their LTC4 load, thereby affecting nearby tissues. In contrast, as discloses by the present invention, non-hematopoietic cells generate LTC4 by the enzyme MGST2 (an isoenzyme of LTC4S), and retain it to act internally leading to their demise. This difference is the basis for the present invention. Thus, LTC4 receptor antagonists (montelukast, pranlukast, etc.) will alleviate the toxicity of chemotherapy towards non-hematopoietic tissues and cells, but retaining the therapeutic effectiveness of chemotherapy on lymphocytic leukemia, lymphoma and myeloma patients. In conjuction, it was found that pranlukast attenuated cell death triggered by a broad range (0.5-4 µg/ml) of simvastatin (a statin) concentrations.
For patients with AML, identification of their specific subtype and genetic background is crucial for predicting their outlook and decision of treatment. Therefore, understanding the molecular characteristics of specific subtypes of AML can lead to novel therapeutics and improve patient survival. The...
For patients with AML, identification of their specific subtype and genetic background is crucial for predicting their outlook and decision of treatment. Therefore, understanding the molecular characteristics of specific subtypes of AML can lead to novel therapeutics and improve patient survival. The present invention relates to a unique vulnerability of AML subtypes, in which specific chromosome abnormalities result in the dependence of the cancer cells on the activity of native RUNX1. Selective inhibition of RUNX1 under these genetic backgrounds results in killing of the cancer cells. Thus, the methods described in this innovation may lead to the development of novel AML therapeutics.
Specificity targets a signaling vulnerability which is unique to AML and does not occur in healthy cells.
Critical impact the inhibition of RUNX1 in addicted cells induces irreversible killing of the cancer cells by apoptosis rather than just inhibiting their proliferation.
Targeting RUNX1 in the addicted AML subtypes can potentially improve patient survival and also be used as a therapy for patients which developed secondary resistance in response to conventional chemotherapy.
The RUNX1 transcription factor is a frequent target of various chromosomal translocations. The t(8;21) and inv(16) AML subtypes create oncoproteins which interfere with RUNX1 activity in a dominant-negative manner. While RUNX1 is frequently inactivated in other forms of AML, an active RUNX1 allele is maintained in both t(8;21) and inv(16) AML patients, underscoring the medical significance of native RUNX1 in A-E and C-S mediated leukemogenesis. Knockdown (KD) of RUNX1 in cell culture models for A-E and C-S showed that these cells are physiologically dependent on RUNX1 activity for their survival and inhibition of RUNX1 in these cells leads to apoptotic cell death. This apoptosis is triggered by decreased expression of key mitosis-regulatory gene. Therefore, AML subtypes associated with an altered RUNX1 activity or expression are addicted to native RUNX1 for their survival. Targeting RUNX1 in these patients is expected to activate apoptosis and compromise leukemogenesis. Thus, the genetic addiction described in the current innovation can be used for the development of novel targeted therapies for AML.
Improved magnetic resonance imaging (MRI) for cardiac fibrosis and other fibrotic diseases.Myocardial fibrosis is associated with worsening ventricular systolic function, abnormal cardiac remodeling, and increased ventricular stiffness, significantly increasing the risk of adverse cardiac outcomes....
Improved magnetic resonance imaging (MRI) for cardiac fibrosis and other fibrotic diseases. Myocardial fibrosis is associated with worsening ventricular systolic function, abnormal cardiac remodeling, and increased ventricular stiffness, significantly increasing the risk of adverse cardiac outcomes. Hypertension and diabetes elicit fibrotic processes in the heart, placing a high percentage of the western world population at risk, yet the early identification of fibrotic development in high-risk patients is hindered by lack of adequate fibrosis imaging modalities. This in turn leads to increased morbidity and additional financial burden to health care services. The current standard method to assess myocardial fibrosis employs the usage of MRI coupled with intravenous infusion of Gadolinium contrast agent. However, this method suffers from considerable drawbacks including reduced sensitivity (that permits diagnosis only at advanced stages of disease), lengthy scan times and toxicity of the contrast agent, which excludes a significant subset of patient populations from diagnosis. Thus, the capacity to diagnose myocardial fibrosis in its early stages would allow successful therapeutic intervention, and may also create a platform for the non-invasive study of fibrotic development, thereby facilitating the design of targeted therapies. The current invention is comprised of a novel cardiovascular magnetic resonance method with enhanced sensitivity, without the need for contrast agent administration.
Detection of cardiac fibrosis due to various pathologies, including hypertension, diabetes and heart failure.
The method can be applied to detect fibrotic tissues in a broad range of disorders including cancer, renal fibrosis and pathologies related to skeletal muscles.
A platform for the clinical study of targeted therapies that may prevent or arrest fibrotic diseases.
Monitoring the efficacy of treatment tailored to target fibrotic tissue development.
The method relies on magnetization transfer to provide contrast, and therefore obviates the need for any extrinsic, toxic contrast agent such as Gadolinium.
Improved sensitivity over current contrast agent-based cardiac MRI methods.
The method can be readily applied to existing MRI clinical imaging systems.
A team of researchers at the Weizmann Institute has developed a novel approach for detection of myocardial fibrosis using magnetization transfer contrast (MCT) MRI cardiac imaging technology. The method was tested in vivo on animal models of heart failure and proved highly sensitive for detection of scar tissue formation and monitoring of fibrotic development. One prominent advantage of the present technology over current cardiac imaging modalities is that it eliminates the requirement for extrinsic contrast agents, thereby circumventing potential adverse toxic side effects.
The spatial distribution of proteins inside the cell is under tight regulation. This regulation is necessary to ensure proper functioning of the cell, and is of particular importance when extracellular stimulation is applied. Upon stimulation, many signaling proteins rapidly and dynamically change...
The spatial distribution of proteins inside the cell is under tight regulation. This regulation is necessary to ensure proper functioning of the cell, and is of particular importance when extracellular stimulation is applied. Upon stimulation, many signaling proteins rapidly and dynamically change their location. Today, there is a widely recognized need to identify novel sequences which regulates nuclear translocation. Recently, Prof. Zeger and his team discovered a new level of regulation to stimulated transcription. They showed that ?-like importunes are central mediators of nuclear translocation of signaling proteins. Furthermore they identified the site of interaction and designed accordingly a peptide which was found to prevent nuclear translocation. This technology presents peptides with the potential of treating inflammatory and immune disease by regulating (prevent or promote) the translocation of proteins into the nucleus.
The researchers found that ?-like importins play a key role in JNK and p38 translocation. They also found that the translocation of these MAPKs is mediated by the formation of either Imp3/Imp7/MAPK or Imp3/Imp9MAPK heterodimers. Most importantly, the researchers identified the site in p38 that mediate the interaction with Imp7 and Imp9 and showed that the important sequence lies within residues 20-30 of p38?. Subsequently they synthesized a 14 amino acid myristoylated peptide based on the sequence of residues 21-34 of p38?. When it was applied to HeLa cells prior to stimulation, it prevented the nuclear translocation and Imp7/9 interaction of the MAPKs. Since the peptides of this technology are able to specifically inhibit the nuclear activities of p38 (such as inflammatory activities) without modulating their cytoplasmic activities, these peptides may serve as a therapeutic agent for inflammatory and apoptosis related diseases without having side effect.
Novel immunosupressive peptides, derived from the TM domain of the HIV protein gp41, with high selectivity towards distinct immune cell populations.Uncontrolled activity of immune cells is an underlying cause of both autoimmune and inflammatory diseases. One of the major challenges in the field is to...
Novel immunosupressive peptides, derived from the TM domain of the HIV protein gp41, with high selectivity towards distinct immune cell populations. Uncontrolled activity of immune cells is an underlying cause of both autoimmune and inflammatory diseases. One of the major challenges in the field is to develop therapeutics that would target specific populations of immune cells, in order to avoid immune-deficiencies that would leave patients exposed to infections. The present invention provides novel peptides, based on Immunosupressive regions within the TM domain of the HIV gp41 fusion protein. These peptides were shown to specifically and efficiently inhibit T-cells and TNF? secretion from inflammatory macrophages. Importantly, these peptides were shown to have particular inhibitory effects towards T cells that are activated in a multiple sclerosis model.
Selective therapy towards T cell mediated autoimmune diseases (e.g. multiple sclerosis)
Selective therapy towards TNF?-associated inflammatory disorders
Specific towards defined cell populations avoids general immune suppression
Significant efficiency towards MS-associated T-cell activation
The present invention takes advantage of the potent immune evasion mechanisms that are utilized as part of the HIV virus pathogenesis. Gp41, a component of the virus envelop, is a transmembrane glycoprotein that mediates viral entry into cells of the immune system. In addition to its role in mediating the actual fusion event, gp41 has been shown to contain immunosuppressive activities that are attributed to its N terminus. Using biochemical and biophysical approaches, Prof. Shai and his team from the Weizmann institute, reveal yet another immunosuppressive activity of gp41, exerted via its transmembrane domain. Importantly, this immunosupressive activity was shown to be specific for T cell activation (mediated through binding to CD3/TCR complex) and Toll-Like Receptor (TLR)-mediated activation of macrophages. The present inventors generated synthetic peptides that derive from the gp41 trasmembrane domain and demonstrated their suppressive activity in both in-vitro and in-vivo models. Significantly, T-cell activation was inhibited following activation with a peptide associated with the propagation of multiple sclerosis (MOG 35-55), proposing a specific inhibitory activity towards MS-generating mechanisms. Macrophages inhibition was shown to significantly compromise the secretion of pro-inflammatory factors, predominantly TNF?, following LTA (lipotechoic acid) activation.
MTCH2 as a novel target for the treatment of obesity.Obesity is an escalating public health problem with an increasing prevalence worldwide, and a primary contingency of many life-threatening diseases, as well as early mortality. In the U.S. alone, more than one-third of adults are obese. Obesity-...
MTCH2 as a novel target for the treatment of obesity. Obesity is an escalating public health problem with an increasing prevalence worldwide, and a primary contingency of many life-threatening diseases, as well as early mortality. In the U.S. alone, more than one-third of adults are obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death. Physicians and patients alike consider the weight-loss efficacy of the current therapeutics to be unsatisfactory. Therefore, there is an unmet need for innovative options that are at once safe and efficacious, and allow the patient to maintain weight loss. The present invention describes the identification of Mitochondrial Carrier Homolog 2 (MTCH2) as a novel player in muscle metabolism and the therapeutic potential of inhibiting MTCH2 for the treatment of diet-induced obesity and diabetes.
A fresh approach for targeting weight-related disorders
Direct effect on metabolism instead of indirect mechanisms of current therapeutics which target appetite modulation.
Protection from diet-induced obesity can be used as a prevention treatment for people with a tendency for weight gain.
MTCH2 functions as a receptor-like protein for the pro-apoptotic BID protein in the mitochondria. MTCH2 was identified as one of six new gene loci associated with Body Mass Index (BMI) and obesity in humans suggesting that MTCH2 may also play a role in metabolism. MTCH2 was recently shown by the Grosss lab to also function as a repressor of mitochondria oxidative phosphorylation (OXPHOS) in the hematopoietic system. Deletion of MTCH2 in skeletal muscle increases mitochondrial OXPHOS and mass, and increases capacity for endurance exercise. In addition, loss of MTCH2 increases mitochondria and glycolytic flux in muscles as measured by monitoring pyruvate and lactate levels. MTCH2 knockout mice are protected from diet-induced obesity, hyperinsulinemia, and are more prone to weight loss upon caloric restriction. Therefore, the association of MTCH2 with mitochondrial function offers a potential novel target for muscle metabolism modulation in the fight against metabolic disorders such as obesity and diabetes.