NEW HAVEN, CT, United States
NEW HAVEN, CT, United States

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Patent
L2 Diagnostics, Llc | Date: 2014-09-18

Described herein are compositions and methods for diagnosing or monitoring type 1 diabetes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 595.41K | Year: 2013

DESCRIPTION (provided by applicant): Lyme disease is the most common arthropod-borne disease in the United States, with over 38,000 confirmed and probable cases reported in 2009. The causative agent of Lyme disease is the spirochete Borrelia burgdorferi, which is transmitted by the tick of the Ixodes scapularis tick. The number of Lyme disease cases has tripled over the past fifteen years. The disease is sometimes difficult to diagnose in its early stages, leading to delayed treatment. Patients who are nottreated in a timely fashion may suffer from severe, long lasting symptoms, and fail to respond to antibiotic therapy. Control measures designed to prevent contact with ticks are not sufficient to prevent the disease. We propose to develop a vaccine to control Lyme disease in human populations. After being injected into the skin of a mammalian host, Borrelia bacteria multiply locally before disseminating to other organs. We have now for the first time been able to isolate sufficient amounts of bacteria fromthe skin of infected mice in order to identify proteins expressed at high levels in the skin. We believe that immunization against these proteins, which are expressed in the early acute phase of Lyme disease, will be highly effective in preventing bacterial proliferation and dissemination. Fifteen membrane proteins identified in the skin of infected mice will be produced in recombinant form using standard bacterial expression systems. These proteins are conserved among strains of Borrelia, which should ensure that our vaccine is effective against all strains of circulating Borrelia. Each antigen will then be administered to C57Bl/6 mice in the presence of an adjuvant. We will demonstrate that this immunization protocol results in the appearance of anti-Borrelia antibodies. Immunized animals will then be challenged with 104 live Borrelia spirochetes. Twenty-one days after challenge we will collect tissue samples to determine whether they contain live Borrelia. We will also quantitatively detect the presence ofBorrelia DNA in these samples. A protein antigen will be considered protective (1) if spirochetes cannot be cultured from the tissues of immunized mice after challenge or (2) if the bacterial load, determined from the amount of DNA detected, is reduced byat least 50%. At the conclusion of these experiments we will select up to four antigens for further study. Phase II experiments will determine the optimal formulation and method of delivery. We will also examine whether antigens can be combined to providefull protection against Borrelia. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Lyme disease is a bacterial disease transmitted by ticks. It is very common in the Northeast and the Midwest of the United States. The disease is sometimes difficult to diagnose, leaving patients exposed to more severe and long lasting symptoms. We propose to develop a vaccine that would prevent Lyme disease in human populations.


Grant
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase II | Award Amount: 996.93K | Year: 2013

Flaviviruses, and dengue viruses in particular, are significant human pathogens. No vaccine or specific therapeutic agent is available against West Nile and dengue viruses. Our goal is to develop peptide-derived therapeutics active against West Nile virus, dengue viruses, and other flaviviruses. In Phase I of this project, we identified several candidate tetrapeptides able to neutralize multiple flaviviruses in in-vitro assays. These very short peptides have a molecular weight below 500, affording them the favorable drug characteristics of small molecules. In Phase II, we will further investigate and optimize these hit peptides against flaviviruses. We will systematically vary the composition of our initial hits to obtain variants with greater efficacy. We will also confirm the mechanism of action of the antiviral peptides by verifying that they block the entry of viruses into host cells. Successful completion of these Phase II experiments will place us in an excellent position to initiate testing in animal models of flavivirus diseases during Phase III of this project.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 250.30K | Year: 2014

DESCRIPTION (provided by applicant): Over 34 million people are currently living with HIV/AIDS. Combination antiviral therapies have significantly reduced the morbidity and mortality of the disease; however, there is currently no cure for the disease. Discovery that a naturally occurring variant of CCR5, the delta32 mutation, renders cells resistant to HIV infection has led to efforts by several academic laboratories and biotech companies to find gene therapy approaches to mimic the delta32 mutation. This project will demonstrate the feasibility of using peptide nucleic acids (PNAs) as a therapeutic to genetically truncate the CCR5 protein in CD34+ stem cells and block HIV cell entry. Preliminary experiments that modified the CCR5 gene used a targeting PNA with a donor DNA sequence to induce a stop codon near the delta32 mutation. In this Phase I project, we will develop a novel strategy for PNA-induced CCR5 gene modification to increase the CD34+ mutation frequency to clinically useful levels. Specific


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 694.52K | Year: 2016

Abstract The long term product goal of this project is a small molecule rheumatoid arthritis RA therapeutic which acts by reducing the inflammatory response triggered by the pro inflammatory cytokine macrophage migration inhibitory factor MIF The therapeutic benefit of MIF inhibition in RA disease models has been well established by small molecules that bind to a catalytic site of the MIF trimer that mediates the cytokineandapos s vestigial non physiological tautomerase activity However allosteric binding of inhibitors in regions outside the tautomerase pocket to date remains ill investigated as a therapeutic approach to blocking MIFandapos s cytokine activities Our research project focuses on therapeutic development of such allosteric MIF inhibitors Through structure based drug design we have obtained a unique class of compounds which as revealed by crystallography bind on the surface of the MIF trimer directly above the tautomerase pocket and overlap the MIFandapos s CD receptor binding site that is central to MIF function In vitro tautomerase CD binding and bioassays revealed that these allosteric inhibitors not only blocked the activities of MIF but also those of D dopachrome tautomerase D DT or MIF the MIF homolog in humans whose simultaneous inhibition in MIF related diseases appears necessary for therapeutic benefit These preliminary results support further development of this class of allosteric MIF inhibitors as leads for MIF directed RA therapy Our hypothesis is that this class of MIF D DT allosteric inhibitors will reduce the inflammatory responses triggered by these cytokines and therefore will prove beneficial in treating RA In this project building from our extensive preliminary data we propose to use medicinal chemistry guided by structural studies to modify the inhibitors for improved MIF and D DT inhibition in an effort to obtain molecules that are efficacious in the RA mouse model The work proposed in the three specific aims of our project focuses on modifying the inhibitors to obtain a structure activity relationship introducing functional groups to gradually improve their target binding and potency in MIF mediated tautomerase and bioassays and evaluating efficacy in the mouse model of collagen induced arthritis These efforts are expected to yield a lead compound suitable for further development towards an orally bio available small molecule MIF directed therapeutic for RA Public Health Significance The long term goal of this project is a novel small molecule drug for rheumatoid arthritis RA a debilitating joint disease that affects million people in the US and for which there is no cure This drug will block the activity of macrophage migration inhibitory factor MIF the cytokine responsible for inflammation that leads to ultimate joint destruction Since MIF acts early in the inflammatory cascade inhibition of its activity by the novel drug is expected to treat RA more effectively than existing therapies


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 298.96K | Year: 2016

DESCRIPTION provided by applicant Hepatocellular carcinoma HCC is the most prevalent cancer in human population and will lead to over deaths in the United States this year alone However the molecular mechanisms driving hepatocellular carcinoma HCC growth and metastasis remain elusive and there is a huge unmet medical need to find new therapeutic targets We performed an unbiased genome wide RNA interference RNAi screen to identify factors that are necessary for the epigenetic silencing of a HCC tumor suppressor Hedgehog Interacting Protein HHIP The RNAi screen was based on the rationale that factors necessary for epigenetic silencing of HHIP in HCC cells could in principle promote HCC tumor growth The RNAi screen identified three new drivers of HCC B cell lymphoma BCL histone deacetylase HDAC and CDC like kinase CLK RNAi based knockdown of these genes significantly inhibited HCC cell growth in culture and in a mouse model of HCC tumorigenesis Remarkably we found that these three genes are overexpressed in patient derived samples of HCC Furthermore their overexpression correlates with liver fibrosis and microvascular invasion both of which are markers of poor prognosis For this Phase I project we have chosen to develop small molecule inhibitors of BCL because it is a novel therapeutic target currently not exploited for HCC Our hypothesis is that pharmacological inhibition of BCL will suppress the HCC malignant phenotype Aim experiments will use two existing but therapeutically limited small molecule inhibitors to demonstrate the utility of this new HCC epigenetic therapeutic strategy using appropriate in vitro and in vivo models The inhibitors will be tested for inhibition of HCC cell growth in soft agar assays a surrogate assay for mouse tumorigenesis Cell based assays will also determine whether BCL inhibitors modulate HCC cell HHIP expression and expression of other downstream effectors such as cyclin D p and PIM A BCL inhibitor with efficacy in a mouse model of lymphoma will be tested for efficacy in an orthotopic xenograft based mouse model of HCC tumorigenesis Concurrently in Aim we will utilize our medicinal chemistry capabilities to create a focused library of up to new candidate BCL small molecule inhibitors that retain the beneficial inhibitory pharmacophore features of two existing structurally distinct inhibitors but add or eliminate other chemical features to address their off target effects and pharmacokinetic structural liabilities Structural activity relationships for these new merged pharmacophore compounds will be assessed by inhibition of BCL SMRT binding and by their ability to block HCC cell growth in soft agar assays In Aim we will proceed to in vivo efficacy testing of the top five candidates in a BCL dependent mouse xenograft model of HCC A successful Phase I project will reveal new and effective HCC therapeutic strategies and provide novel BCL inhibitors for Phase II medicinal chemistry to optimize efficacy and drug like properties The long term project goal is to develop a novel epigenetic therapy to significantly improve treatment of HCC patients PUBLIC HEALTH RELEVANCE Hepatocellular carcinoma HCC is the most prevalent cancer in human population It is universally and rapidly fatal leading to over deaths every year in the United States alone We discovered that BCL is necessary for HCC cells to form tumors in vivo in mice The goal of this project is to identify novel BCL inhibitors to serve as leads fo development of new drugs to effectively treat HCC patients


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2016

DESCRIPTION provided by applicant The goal of this STTR is to identify novel small molecule compounds targeting the nitrogen respiration pathway of Pseudomonas aeruginosa This pathway is crucial to the pathogenesis of P aeruginosa in vivo but has not yet been exploited for antimicrobial drug discovery There is a clear need for new treatments to combat P aeruginosa infections Antibiotic resistance is exhibited by most clinical isolates and has a marked negative impact on our ability to treat and cure such infections in patients In addition hospital acquired multi drug resistant Gram negative infections are estimated to increase per patient costs andgt $ Our preliminary results show that genetic or chemical inhibition of nitrogen respiration in P aeruginosa prevents anaerobic growth limits biofilm formation and decreases fitness of P aeruginosa in murine models of pulmonary infection indicating the potential of small molecule inhibitors of nitrogen respiration as strong candidates for a new type of antimicrobial agent In addition our preliminary analysis of the crystal structure of the Escherichia coli nitrate reductase NAR which has high sequence homology to the not yet crystallized P aeruginosa enzyme suggests opportunities for small molecule binding and inhibition We have developed a whole organism high throughput screening assay that measures inhibition of nitrogen respiration We plan to screen compounds from libraries at the ICCB facility at Harvard Medical School in this Phase I project Control assays will be performed to exclude false positives Our team of chemists will analyze data from the screen to identify and prioritize hits with drug development potential Hits will be purchased and or resynthesized for follow up studies to confirm inhibition of anaerobic growth and positive hits will then be screened for inhibition of biofilm formation Compounds will also be screened for cytotoxicity in human cell lines At the end of this Phase I project we expect to have or lead compound series to move forward into further drug development i e increasing potency selectivity and drug like properties in a Phase II proposal PUBLIC HEALTH RELEVANCE Pseudomonas aeruginosa leads to chronic infections that are resistant to many antibiotic treatments The goal of this STTR project is to develop a new class of small molecule therapeutics for P aeruginosa that targets the nitrogen respiration pathway a novel mechanism of action not currently exploited by commercially available drugs and therefore expected to be effective against drug resistant P aeruginosa infections


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.70K | Year: 2014

ABSTRACT The long-term product goal of this project is a small molecule therapeutic for choroidal neovascularization (CNV, the hallmark of wet age-related macular degradation), an abnormal growth of blood vessels in the choroid layer of the eye that results in damage to the retina and consequent blindness. Our lead compound is the natural product sterculic acid, which has been shown to inhibit CNV in animal models. The main current treatment options for CNV involves intravitreal injection of anti-VEGF agents such as ranibizumab (Lucentis), aflibercept (Eylea) and (in off-label use) bevacizumab (Avastin) which, while often slowing disease progression, have a number of side-effects associated with the method of administration. A small molecule therapeutic which might be administered topically would present obvious advantages. Sterculic acid has very recently been shown to mitigate the induction of CNV in a rat model and to antagonize the inflammatory effects of 7- ketocholesterol (7KCh) in cultured human re


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 271.24K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 297.30K | Year: 2015

DESCRIPTION provided by applicant The long term product goal of this project is a small molecule therapeutic to prevent or treat Type diabetes T D Our objective is to reduce the inflammatory response triggered by the pro inflammatory cytokine macrophage migration inhibitory factor MIF Under physiological conditions MIF is secreted by cells and regulates their function but during immunoinflammatory events the pancreatic islets secrete high amounts of MIF that mediate islet apoptosis Immunoneutralization or genetic deletion of MIF in mouse models of T D has correlated with halting the progression of T D or completely preventing the disease Since MIF is an upstream regulator of the inflammatory cascade small molecule therapeutics targeting MIF activity are expected to provide effective treatment for T D which currently afflicts million people in the US alone and for which there is no curative therapy To this end we have identified novel small molecule MIF inhibitors Our lead proprietary small molecules F and A block MIF driven cellular activation pathways that are associated with the immunopathology of T D including apoptosis and production of proinflammatory mediators F and A are minimally cytotoxic and are structurally unique possessing functional groups that have not been previously associated with MIF inhibitory activity The immediate objectives of the Phase I is to demonstrate the therapeutic efficacy of L andapos s proprietary F and A small molecules to reverse or prevent T D in the well established T D non obese diabetic NOD mouse model NOD mice which are the mainstay of preclinical diabetes research as they share similarities with human T D will be treated with our lead compounds and controls in a time and dose dependent manner Therapeutic efficacy will be monitored by measuring blood glucose levels and cell death by our recently developed novel droplet digital PCR In addition we will perform cellular assays measuring Th Th and T regulatory cytokine levels as well as apoptosis to determine the effects of the F and A on MIF driven inflammatory process All of these efforts are expected to yield a lead compound suitable for further development towards a small molecule therapeutic for T D PUBLIC HEALTH RELEVANCE Type diabetes is characterized by an autoimmune destruction of cells of the pancreas The long term goal of this project is to develop a novel type diabetes therapeutic drug that blocks the action of the pro inflammatory cytokine macrophage migration inhibitory factor

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