Biomass production by plants and other photosynthetic organisms involves carbon fixation, the process of incorporating inorganic carbon dioxide into organic compounds. Currently carbon fixation by plants and other photosynthetic organisms is the limiting factor in biomass production. Improvement in the...
Biomass production by plants and other photosynthetic organisms involves carbon fixation, the process of incorporating inorganic carbon dioxide into organic compounds. Currently carbon fixation by plants and other photosynthetic organisms is the limiting factor in biomass production.
Improvement in the metabolic pathway related to carbon fixation would have great value in increasing crop yields, synthesizing high value compounds in algae, and developing means in removing CO2 from the atmosphere to combat climate change.
The present technology is an engineered E. coli with a carbon fixation pathway. The unique innovation can be used to efficiently screen the activity of RuBisCO, the most abundant carbon fixing enzyme on earth, which is further applicable to improving biomass production in different photosynthetic organisms such as plants and algae.
·Powerful platform for screening and improving various enzymes in the carbon fixation process.
·Unique metabolic pathway for use in Synthetic Biology applications.
·Possible Carbon Credits for developing improved means of carbon fixation.
·E. coliis fast growing and easily manipulated by various genetic tools.
·Novel source of biomass production.
·Potentially low cost R&D system.
The technology functions by the recombinant insertion of two enzymes from the Calvin-Benson-Bassham (CBB) into E. coli, kinase prk and the carboxylating enzyme RuBisCO. With further modifications, the engineered E. colis metabolism was divided into two subsections. First a carbon fixing metabolism that can incorporate inorganic CO2 into sugar production, the second subsection consumes organic pyruvate to produce energy to drive the aforementioned carbon fixing cycle. Subsequently the technology is overall carbon neutral, but is an inexpensive and fast platform for screening improvements in the CBB carbon fixation pathway.
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.
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.
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.
Neuropathic Gauchers (nGD), is a rare but very severe manifestation of the disease, with a varying degree of involvement of the central nervous system, in addition to systemic symptoms. As of today, there is no cure for these severe conditions. The search for such cure is tremendously hindered by the...
Neuropathic Gauchers (nGD), is a rare but very severe manifestation of the disease, with a varying degree of involvement of the central nervous system, in addition to systemic symptoms. As of today, there is no cure for these severe conditions. The search for such cure is tremendously hindered by the unmet need for a reliable biochemical biomarker for nGD. The present invention identifies the glycoprotein non-metastatic B (GPNMB) as a potential powerful nGD biomarker for use in early diagnosis, determination of disease severity, as well as a straight forward readout in clinical and preclinical experiments.
Diagnosis and drug development for neuropathic GD
Straight forward diagnostic tool based on standard biochemical assays Relatively simple clinical procedure samples are collected from CSF and not brain High sensitivity for the diagnosis of disease severity Compatible with preclinical experiments
Prof. Futerman and his team preformed a quantitative global proteomic analysis (using LC-MS/MS) of cerebrospinal fluid (CSF) samples from four patients with Type 3 GD, to identify mis-regulated proteins, compared with healthy subject. Glycoprotein non-metastatic B (GPNMB), a protein that was previously associated with several lysosomal storage disorders, exhibited very high levels (a 42-fold increase) in the CSF of type 3 GD patients. Two peptides were identified from GPNMB, both located in the non-cytosolic domain, suggesting that GPNMB is cleaved and secreted into the CSF from the brain. LC-MS/MS results were validated by ELISA and by western blot analysis in CSF and in human brain samples. Several proof of principle experiments were conducted in order to prove the validity of using GPNMB as a biomarker for monitoring disease state and treatments efficacy in neuropathic GD in patients and mouse models: GPNMB levels were shown to be correlated with the severity of type 3 Gauchers disease patients, as measured by lower IQ score and lower score in Purdue Pegboard test, assessing eye-hand coordination. In addition, using conduritol b epoxide (CBE)-injection based mouse model that simulate different severities and recovery periods, it was shown that GPNMB levels rapidly rise or decline to reliably reflect progress/remission states of the diseases.
A novel method to revert human iPSC to a fully naive state, retaining stable pluripotency. The feasibility for the existence of ground state naive pluripotency in human embryonic stem cells (hESC) has long been researched. This innovative technology supplies the composition of chemically defined...
A novel method to revert human iPSC to a fully naive state, retaining stable pluripotency. The feasibility for the existence of ground state naive pluripotency in human embryonic stem cells (hESC) has long been researched. This innovative technology supplies the composition of chemically defined conditions required for derivation and long term maintenance of such cells, without genetic modification. Human naive pluripotent cells can be robustly derived either from already established conventional hESC lines, through iPSC reprogramming of somatic cells, or directly from ICM of human blastocysts. The new human pluripotent state was isolated and characterized; it can open up new avenues for patient specific disease relevant research and the study of early human development.
Reprogramming kits - Somatic cells to iPSC at near 100% efficiency (7days), iPSC to fully naive state.
Deterministic iPSC reprogramming with no genetic modification required.
Stable pluripotency, with low propensity for differentiation
Reagents available off-the-shelf.
Hallmark features of rodent naive pluripotency include driving Oct4expression by its distal enhancer, retaining a pre-inactivation state of X chromosome in female pluripotent cell lines amongst others. Naive mouse ESCs epigenetically drift towards a primed pluripotent state; while human embryonic stem cells (hESCs) share several molecular features with naive mESCs (e.g. expression of NANOG, PRDM14 and KLF4 naive pluripotency promoting factors), they also share a variety of epigenetic properties with primed murine Epiblast stem cells (mEpiSCs). These observations have raised the question of whether conventioal human ESCs and induced pluripotent stem cells (iPSCs) can be epigenetically reprogrammed into a different pluripotent state, extensively similar with rodent na?ve pluripotency. Researchers at the Weizmann Institute discovered that supplementation of certain chemically defined conditions, synergistically facilitates the isolation and maintenance of pluripotent stem cells that retain growth characteristics, molecular circuits, a chromatin landscape, and signaling pathway dependence that are highly similar to naive mESCs, and drastically distinct from conventional hESCs.
Cancer is a leading cause of death in the developed countries. It is a highly heterogeneous disease even among patients with the same type and grade of cancer. Thus, drug development for cancer is extremely challenging. However there are some consistencies; most tumor cells exhibit genomic instability...
Cancer is a leading cause of death in the developed countries. It is a highly heterogeneous disease even among patients with the same type and grade of cancer. Thus, drug development for cancer is extremely challenging. However there are some consistencies; most tumor cells exhibit genomic instability with an increased expression of oncogenes and inactivation of tumor suppressor genes. P53 is a key tumor suppressor that is mutated in more than half of the human cancers. Over the years several mouse models were developed in order to study p53 mutations. Interestingly it has been shown that mice homozygous for mutant p53 are viable, and develop malignant tumors only in adulthood. Prof. Rotter and her team revealed the mechanism by which embryos are protected from mutant p53-induced transformation. They found, using embryos stem cells (ESCs), that the conformation of mutant p53 in ESCs is stabilized to a WT conformation. They further identified the network of proteins that may shift p53 transformation to its WT form. This technology presents methods (compositions and kits) of stabilizing mutant p53 in ESCs by interacting proteins, thus propose a novel cancer therapy.
Targeted for p53
The researchers hypothesized that cellular factors in the pluripotent cells contribute the stabilization of the WT conformation of p53. They used a mass spectrometry (MS)-based interactome analysis to examind the interaction network of the different conformations of p53 in WT and Mut ESCs compared with somatic cells from the spleen. They immunoprecipitated WT and Mut conformation of p53 and used p53 KO cells as controls for background binding. Importantly, they identifies chromatic-specific proteomic network that is suggested to bind p53 and act as a stabilizer of Mut p53 into a WT conformation. This network (59 proteins) includes the CCT complex, USP7, Aurora kinase, Nedd4, and trim24. Interactions with this network enables the activation of WT activity of p53 and eliminates the gain-of function Mut activities, despite the p53 mutation. Overall this is a proposed mechanism of rescuing ESCs cells from transformation which sets the basis for future p53-targeted cancer therapeutics.
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.
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.
Optimal growth and metabolic activities of Lactic Acid Bacterial (LAB) starters are critical for assuring high-quality fermentation in the manufacturing process of numerous dairy products. Despite extensive efforts, phage infection of starter cultures for dairy processing remains the most common cause...
Optimal growth and metabolic activities of Lactic Acid Bacterial (LAB) starters are critical for assuring high-quality fermentation in the manufacturing process of numerous dairy products. Despite extensive efforts, phage infection of starter cultures for dairy processing remains the most common cause of slow or incomplete fermentation and product downgrading. Standard anti-phage measures (sanitation, culture handling) fail to provide sufficient protection, exposing the production process to massive economic setbacks. Extensive R&D efforts have led to the discovery of phage resistance systems, however many phages can circumvent these systems, and in addition not all LABs can accommodate them. Therefore, there is a strong need for additional defense systems that could naturally protect LABs against phages. The Sorek laboratory at the Weizmann Institute of Science has recently identified hundreds of novel functional toxin/antitoxin systems in bacterial genomes. These systems were discovered using analysis of data from millions of shotgun cloning experiments across 388 bacterial species. Acting as an abortive infection agent to prevent phage spread, some of these systems were already validated as conferring resistance against phage infection upon introduction to E.coli cells. In another novel technology, researchers at Dr. Rotem Soreks lab identified a novel anti phage gene cassette, termed BREX (Bacteriophage Exclusion), which confers complete or partial resistance against phages spanning a wide phylogeny of phage types, including lytic and temperate ones.
Tools for conferring anti-phage traits to bacterial starters.
Provides efficient phage-resistance features.
Robust: confers resistance to a broad range of phages, including both lytic and temperate ones.
General: the same defense system may be applied in various cultures, not confined to specific strains.
Novel systems, provides a fresh approach to the field of phage resistance
Toxin/antitoxin (TA) modules, composed of a toxic protein and a counteracting antitoxin, are proposed to function in phage defense via abortive infection. The two genes, which reside on the same operon, code for small proteins where inhibition of the toxin is carried out through protein-protein interaction. Upon a specific signal (phage infection) the antitoxin degrades rapidly by one of the housekeeping bacterial proteases, resulting in either bacteriocidic (cell-killing) or bacteriostatic (growth-inhibiting) effects, thus protecting the colony against phage spread. The inventors took advantage of the concept that toxins could only be cloned when the neighboring antitoxin was present on the same clone to systematically reveal active TA pairs. Following extensive statistical and experimental validations, 8 novel families of TA pairs that are likely to play a role in phage defense were identified. By introducing these systems into new bacteria, the inventors showed that the toxin/antitoxin pairs could protect the engineered bacteria from phage infection. BREX is a novel cassette of six genes that confers protection against a wide range of phages, including virulent and temperate ones. This cassette is composed of genes not typically found in other defense systems, and hence employs a novel mechanism of anti-phage protection. Scientists at the Sorek lab further uncovered the mode of action of this novel system. It was shown that the system is not an abortive infection system (i.e., does not lead to suicide of the infected cell), and that it allows phage adsorption but blocks phage replication in a DNA degradation independent manner.
L-DOPA is a high value compound used in the treatment of Parkinsons disease and a precursor for other high value compounds. Current industrial methods for producing L-DOPA are problematic in terms of complexity, yield, or toxic byproducts.Betalains are robust, flavorless, natural water soluble dyes,...
L-DOPA is a high value compound used in the treatment of Parkinsons disease and a precursor for other high value compounds. Current industrial methods for producing L-DOPA are problematic in terms of complexity, yield, or toxic byproducts. Betalains are robust, flavorless, natural water soluble dyes, in the color ranges of both red-violet and yellow-orange. Currently there is no natural quality source for water soluble natural yellow dyes, with present natural yellow dyes being water insoluble. The present technology offers an alternative method that is simple, does not produce side-products, and is non-toxic with Tyrosine being the only feedstock. The technology produces L-DOPA and natural water soluble yellow and red Betalain dyes, both within yeast and in different plant species.
Production of L-DOPA for use in pharmaceuticals or dietary supplements.
Synthesis of water soluble yellow and red natural dyes for use as colorants, antioxidants, and food supplements.
Altering coloration of ornamental plants by inserting the metabolic pathway.
One-step reaction for L-DOPA synthesis from Tyrosine.
Non-toxic and non-hazardous synthesis.
Ecologically friendly - no waste management issues.
Multiple colors can be produced with yellow, red, or orange if pathways combined.
Flavorless - avoid influencing the taste of different products.
Flexibility in biosynthetic production - multiple possible host systems.
The present technology takes advantage of the Betalain biosynthetic pathway to selectively produce L-DOPA and natural Betalain dyes. A newly discovered, specific, cytochrome P450-CYP76AD6 begins the pathway, with the capacity to convert Tyrosine to L-DOPA. Then L-DOPA is converted to Betalamic acid via DOPA 4, 5-dioxygenase. With the Betalamic acid intermediate, the biosynthetic pathway diverges to make either Betaxanthins (yellow dyes) or Betacyanins (red dyes). In the production of yellow dyes an amine (e.g. amino acid) spontaneously reacts with Betalamic acid. In the case of red dyes, cycloDOPA (generated by the enzyme CYP76AD1 modifying Tyrosine and L-DOPA) and a Betalain-related glucosyltransferase react with Betalamic acid. Furthermore the two pathways can be done in parallel to produce an orange color.
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
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.