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NEW HAVEN, CT, United States

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

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

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

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 268.21K | Year: 2012

DESCRIPTION (provided by applicant): This is a proposal to test the feasibility of using triplex molecules for use as a therapeutic to correct Hurler Syndrome (HS). Lysosomal storage diseases (LSDs), such as HS, represent a diverse collection of monogenicdisorders that have devastating clinical features. LSDs are caused by mutations in genes that encode lysosomal enzymes and other proteins that are critical for lysosomal function. HS is caused by mutations in the -L-iduronidase gene (IDUA). For many LSDs, treatment consists of enzyme replacement therapy and supportive care. However, enzyme replacement therapy costs from 90,000 to 565,000 per patient. Alternatively, allogeneic hematopoietic stem cell transplantation (HSCT) represents a highly effective treatment. However, allogeneic HSCT requires an HLA-matched donor, is associated with significant morbidity and mortality and is expensive, about 200,000 per patient. Genetic modification of autologous HSCT, using CD34+ cells, is emerging as a viable therapeutic alternative to allogeneic HSCT. Autologous HSCT is preferred because it is far less expensive and safer than allogeneic HSCT. One emerging approach to targeted genome modification in CD34+ cells is the use of triplex molecules, either in the formof triplex-forming oligonucleotides or peptide nucleic acids. These molecules bind to duplex DNA in a sequence-specific manner and stimulate recombination when combined with donor DNA molecules. Gene modification occurs via recruitment of the cells own DNArepair machinery, without the need for viral vectors. Viral vectors have proven problematic in such therapies. Our Specific Aim is to test the feasibility of using triplex molecules to correct one of the most prominent gene mutations in the IDUA gene, W402X. For this technology to be viable as a commercial therapy, we must demonstrate that we can achieve a success rate of at least 3% for correction of our gene target in CD34+ cells. Next, we must demonstrate that we can generate a sufficient number of monocytes from these stem cells to be utilized as part of a bridging therapy to wholesale HSCT. In Phase II, we will carry out in vivo studies to demonstrate in vivo efficacy and work on developmental and IND enabling studies to move this technology toward clinical studies. PUBLIC HEALTH RELEVANCE: Hurler Syndrome (HS), a devastating genetic disease that results in multiple organ failure with progressive deterioration in the central nervous system, is caused by mutations in a single gene that is involved in the processing of large sugar molecules within compartments in our cells. L2 Diagnostics LLC is proposing to develop a therapeutic gene targeting protocol to correct one of the most prominent mutations responsible for HS. Our protocol would repair this mutation in isolated blood stem cells from HS patients and then reintroduce the corrected cells back into the patient with the potential of having a significant impact on the symptoms of the disease.

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

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

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