RTP, NC, United States
RTP, NC, United States
SEARCH FILTERS
Time filter
Source Type

Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 289.93K | Year: 2013

DESCRIPTION (provided by applicant): Characterization of human tumor samples and cell lines in combination with inhibitor studies in animal models has established a central role for the Hh pathway in a vast array of cancer types, including small-cell lung, pancreatic, oesophageal, prostate, breast, colon, liver and ovarian cancers. Hh signaling is now implicated in approximately 20-25% of all cancers. GLI1 is the downstream effector in the Hh signaling pathway, and has emerged as a valid therapeutic target. It has been suggested that due to the complexity of signaling inputs in the Hh pathway, targeting GLI1 may provide a more comprehensive strategy for treating both canonical and noncanonical Hh-pathway dependent cancers. This is especially true in light of the acquired resistance to inhibitors of SMO in patients. Screens utilizing GLI1-dependent transcriptional reporter cell-based assays have yielded inhibitors targeting the Hh pathway downstream of SMO including small molecule and natural product compounds that act by targeting GLI1 through differing mechanisms of action. Targeting at the level of GLI1 with small molecules has been effective in a number of cancer model systems including colon, CLL and breast cancer. However, these compounds have only micromolar potencies in vitro, and a subset (GANT61 and ATO) has shown only modest efficacy in in vivo cancer models. These studies suggest that GLI1 is pharmacologically targetable, and that the use of GLI1 inhibitors is a valid and promising approach for targeting GLI1-dependent cancers. Unfortunately, current GLI1 inhibitors are hampered by low potency and a lack of in vivo efficacy and hence are not viable clinical candidates. There are no GLI1-targeted inhibitors in the clinic. Using a novel high throughput, high content cell-based imaging platform, we will screen a diverse collection of small molecules to identify potent inhibitors of GLI1 (Aim 1). Compounds that show inhibitory activity will be further validated in a focused panel of cell-based assays which will incorporate cells derived from primary human breast tumors. These assays will also examine selectivity of the compounds as well as their effects on motility/invasiveness (Aim 2). Promising compounds discovered in Aims 1 and 2 will be subjected to extensive structure-activity relationship to optimize the novel GLI1 inhibitors (Aim 3). PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: A central role for the Hedgehog (Hh) pathway has been established in a vast array of cancer types and it hasbeen implicated in approximately 20-25% of all cancers. GLI1 is a downstream mediator of Hh signaling, making GLI1 a very attractive therapeutic target. A limited number of small molecule inhibitors of GLI1 have been identified; however none of them are clinically viable. In this application we describe a highly innovative cell-based drug screen that will be applied to identifying novel, potent and selective inhibitors o GLI1 as potential cancer therapeutics.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 462.39K | Year: 2012

DESCRIPTION (provided by applicant): Diabetes and diabetes-related co-morbidities are at epidemic proportions and an enormous burden to our healthcare system. Although there has been significant progress in defining the causative factors and molecular mechanisms involved in both type 1 and type 2 diabetes, it remains an overwhelming challenge to identify efficacious therapeutic modalities. Novel approaches and tools to accelerate research and development of additional therapeutics are urgently needed. Although the mechanisms are distinct, in both type 1 and type 2 diabetes there is a loss of pancreatic islet resident ?-cells or??-cell function, resulting in a complete or significant reduction in insulin production. Human islets are currently the most physiologically relevant system for the validation of potential therapies that modulate the metabolic regulation of insulin production and factors that regulate growth, differentiation, and apoptosis of??-cells. Biotech and pharmaceutical companies are in urgentneed of novel approaches and tools to accelerate their drug development programs that require human islets and islet-derived cells. ZenBio has recently launched a human islet program in which we are obtaining human islets from Prodo Labs and are offering islet cell-based assays in low throughput platforms. We have received numerous requests for cell based contract research services utilizing both human and porcine islets and islet-derived cells. In our discussions with these companies it became evident thathigher throughput platforms using human islets were essentially non- existent, yet highly desirable. In this application we propose to establish cGLP-assays through adapting human islets and islet-derived ?-cells to a robust, reproducible and validated high throughput screening platform. This strategy will allow ZenBio to increase screening capacity in an efficient and reliable format providing a much needed accelerant in diabetes drug discovery. We foresee a significant commercial opportunity for the company in providing these services. PUBLIC HEALTH RELEVANCE: Diabetes is a significant worldwide healthcare problem. Novel tools and approaches are urgently needed in effort to accelerate development of therapies to treat diabetes. This proposal describes a plan to adapt human islets and islet-derived cells to high throughput drug screening platforms; and integrate these assays to our current suite of contract research capabilities.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.32K | Year: 2015

DESCRIPTION provided by applicant The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP driven adaptive thermogenesis Expression of mitochondrial UCP uncouples oxidative phosphorylation resulting in accelerated substrate oxidation but low ATP production The resulting dissipation of energy is associated with plasma triglyceride clearance a key factor in weight loss The brown adipose depot has long been known to exist in rodents as well as in human infants However recent evidence has demonstrated the existence of active brown adipose tissue in human adults These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the andquot browningandquot of white adipose tissue a phenomenon wherein UCP mediated mitochondrial uncoupling is induced by stimuli Studies using rodent models have demonstrated that brown fat activation or induction of browning can promote beneficial metabolic effects and promising therapeutic targets have been identified However the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model Therefore there is a pronounced need to validate existing therapeutic targets in the human system ZenBio will address this need by providing both a primary and immortalized human brown adipocyte cell culture system to the research community and will utilize these tools to establish a screen to identify activators of human brown adipogenesis The principal goal of this project is to generate and characterize a human adult brown adipocyte cell system We will achieve this in a stepwise fashion beginning with an initial feasibility study focused on human fetal brown adipocytes Aim I will use functional and genomic analyses to generate a widely available fetal brown adipocyte model which will be used as a tool to establish the adult cell system The fetal model will be developed first due to the comparative ease of detecting fetal brown adipose tissue and its ready availability through existing procurement agencies The second aim is to generate and characterize an immortalized fetal brown adipocyte system for high throughput high content screening These cells will circumvent the limited material and lifespan of primary cells and allow for the development of a high throughput screening platform to identify novel targets of brown adipocyte activation Phase I will be expanded in Phase II with the goal of characterizing and commercializing the human adult brown adipocyte system from donors of differing BMI age gender and diabetic state These studies will generate both primary and immortalized human adult adipocyte cells which will be used to identify novel targets of brown adipocyte energy expenditure for the treatment of obesity PUBLIC HEALTH RELEVANCE The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases We will generate human brown adipocyte systems that can be used to discover and validate novel therapeutic modalities


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.90K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

DESCRIPTION provided by applicant Acne Vulgaris is a common skin disorder that affects of the population typically teenagers and young adults Over million people in the US are affected by acne generating a $ billion market for acne treatments of which is derived from prescription medications Although acne is not a life threatening condition it still has a hih psychosocial impact resulting in depression anxiety anger suicidal thoughts physical scarring and decreased quality of life The primary causes of acne are the overproduction of sebum by sebaceous glands hyperkeratinization of follicular epithelium P acnes proliferation and inflammation Unfortunately the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics Retinoids have been used for more than years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne However because of serious concerns regarding the teratogenic properties of retinoids their use is now part of an FDA mandated registry program In addition isotretinoin has been linked to serious side effects including clinical depression inflammatory bowel disease and sensitive skin There is a clear need for safe and efficacious treatments that target sebum production in sebocytes We have identified a novel compound class in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis Initial SAR studies surrounding this parental compound are promising and justify screening the additional derivatives to establish proof of concept for these compounds as acne therapeutics The aims of this phase I project are to use our existing cell based human sebocyte screening platform ex vivo skin models and in vivo Syrian hamster model to identify lead compounds in this class for further development in Phase II studies PUBLIC HEALTH RELEVANCE Acne Vulgaris is a common skin disorder that affects of the population including over million people in the US the majority of which are teenagers and young adults A primary cause of acne is excess sebum production by sebocytes Unfortunately current treatments while effective have severe side effects including birth defects We have identified a novel compound class through a phenotypic screen that inhibits sebum production from human primary sebocytes These compounds will be further developed as safe and effective acne therapeutics


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 363.20K | Year: 2010

DESCRIPTION (provided by applicant): Diabetes affects the lives of hundreds of millions of people worldwide and the incidence rate is continuing to rise. About 8% of the US population is estimated to have Type 1 or Type 2 diabetes, with the prevalence of Type 2 diabetes increasing with the rise in obesity. Even though the etiology of Type 1 and Type 2 diabetes is different, the end stages show a similar reduction or loss of pancreatic insulin secretion. This is caused by destruction of the pancreatic beta cells which produce and secrete insulin in response to serum glucose levels. Current diabetes therapies do not offer the degree of metabolic control needed to prevent the progression of the disease to the serious complications and mortality that occur when glucose control is lost. The potential for excellent, long-term glycemic control offered by a beta-like , insulin producing cell is the rationale for our proposal. This cell would release insulin in a physiologically controlled, glucose-dependent manner, responding minute-to-minute to acute changes in blood glucose levels. In this situation, diabetes would be completely controlled. We have obtained significant preliminary data suggesting that adipose-derived stem cells can be differentiated in culture to beta-like insulin producing cells, and propose to develop applications of these cells for use in cell therapy and drug development. It is our goal to identify and characterize an optimized adult stem cell population from human adipose tissue that has the therapeutic potential for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: Current diabetes therapies do not offer the degree of metabolic control needed to prevent the progression of the disease to the serious complications and mortality that occur when glucose control is lost. Our objective is to identify and characterize an adult stem cell population from human adipose tissue that has the therapeutic potential to differentiate into insulin-secreting pancreatic beta-like cells. If successful, this work would offer the possibility for cell treatment and possible cure of type 1 and type 2 diabetes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.29M | Year: 2010

DESCRIPTION (provided by applicant): Breast cancer is the second most common cancer among women. Roughly 190,000 women in the U.S. will be diagnosed with breast cancer in 2009, and 40,000 will die. The majority of breast cancers originate in the lobular or ductal cells of the milk-producing glands. In these structures, there are two main cell types: the inner luminal cells surrounded by basal myoepithelium. These cells types are distinct and are the precursors to various forms of breast cancer. As such, it is it is important to study these cell populations independently as well as in co-culture models systems. There are no commercial sources of quality-controlled, matched basal and luminal cells (from individual donors), forcing researchers to isolate and characterize the cells on their own. This process is time-consuming, requires access to human tissue, and introduces variation in the preparation and characterization of the cells. Primary cultured human mammary-derived cells are an ideal model currently used to investigate the genesis and understanding of human breast cancer. Because a consistent commercial source of primary human cultured breast-derived luminal and basal cells is unavailable, Zen-Bio, Inc. will address this need by providing a well characterized system to the research community. Phase I of this project focused on generating an optimized primary human mammary-derived basal/luminal cell system from non-diseased tissue. Isolation and propagation of normal human basal and luminal mammary epithelial cells was achieved. Based on the successful completion of Phase I, we are eager to extend our research in Phase II by focusing on making this cell system commercially available. Additionally, we will expand the cell system to include basal and luminal mammary epithelial cells from breast tumor tissue. Aim 1 of this project is to continue detailed characterization of normal basal and luminal cells focusing on quality control and release criteria for commercialization. Aim 2 is to establish isolation and propagation procedures and detailed characterization of human breast cancer tumor derived cells building on our existing capabilities. Aim 3 is to perform comparative analyses between normal and malignant human cells to establish quality control criteria for commercialization and additional contract assay services at Zen-Bio. Multiple product offerings are expected from this proposal: matched, primary human mammary cell systems from non- diseased and malignant tissue, support media and reagents, contract assay services, and kits for breast cancer research. PUBLIC HEALTH RELEVANCE: At the completion of this project, a fully characterized human primary mammary-derived basal/luminal cell system from normal and malignant breast tissue will be commercially available to researchers. These systems will provide a currently unavailable opportunity to investigate the etiology of breast cancer and to identify potential cures.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 777.91K | Year: 2016

Project Summary The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP driven adaptive thermogenesis Expression of mitochondrial UCP uncouples oxidative phosphorylation resulting in accelerated substrate oxidation but low ATP production The resulting dissipation of energy is associated with plasma triglyceride clearance a key factor in weight loss The brown adipose depot has long been known to exist in rodent models as well as in human infants However recent evidence has demonstrated the existence of active brown adipose tissue in adult humans These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the browning of white adipose tissue a phenomenon wherein UCP mediated mitochondrial uncoupling is induced by stimuli Multiple studies using rodent models have demonstrated that activation of brown fat or induction of browning can promote beneficial metabolic effects and promising therapeutic targets have been identified However the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model Therefore there is a pronounced need to validate existing therapeutic targets in the human system ZenBio will address this need by providing a well characterized human brown adipocyte cell culture system to the research community and will utilize this tool to screen potential candidates for stimulation of human brown adipogenesis The overarching goal of this project is to generate and characterize an adult human brown adipocyte cell system Aim is intended to build on our successful establishment of a human fetal brown adipocyte system in Phase and use molecular and functional characterization to generate a widely available adult human brown adipocyte system This includes establishing conditionally immortalized adult brown preadipocyte lines for use in cell number intense research and screening The second Aim will expand the adult system to include donors from a wide range of demographics This Aim will also establish a database of molecular and functional characterization from this donor set that will be available to the research community Aim will establish a robust high content high throughput screening platform capable of multiplexing molecular and function al assays in a well format This platform will be able to screen for brown fat modulators and activators as well as validating therapeutic targets The goal of these three Aims is to characterize and commercialize the adult human brown adipocyte system from donors of differing BMI age gender and diabetic state and validate their use to identify novel targets of brown adipocyte differentiation for the treatment of obesity These studies will result in innovative targets for human brown adipocyte activation a crucial step for anti obesity therapeutics Project Narrative The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases We will generate an adult human brown adipocyte system and screening platform that can be used to discover and validate novel therapeutic modalities


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 350.68K | Year: 2011

DESCRIPTION (provided by applicant): Metabolic diseases such as type 2 diabetes (T2D), obesity and their related co-morbidities have reached epidemic proportions worldwide. While progress continues to be made into the molecular mechanisms involved in bothobesity and T2D, the identification and development of safe, efficacious therapeutic modalities is significantly limited. There is an urgent need for innovative medicines to combat both obesity and diabetes. Recent data along with our preliminary data strongly suggest that pharmacological intervention of Fyn kinase provides an excellent target and novel approach for the discovery of new drugs to treat metabolic disease. In preliminary high throughput screens we have identified a promising selective inhibitor of Fyn kinase. This proposal describes an approach for further development and identification of additional analogs of our lead compound. This will include SAR based on novel chemistries, characterization in human cell-based assays for glucose and fattyacid metabolism as well as biochemical assays centered on potential mechanism of action. PUBLIC HEALTH RELEVANCE: Metabolic diseases such as type 2 diabetes, obesity and their related co-morbidities have reached epidemic proportions worldwide. Thereis an urgent need for innovative medicines to combat both obesity and diabetes. This proposal focuses on further development and identification of lead small molecule drug for the treatment of metabolic disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 251.14K | Year: 2011

DESCRIPTION (provided by applicant): Skeletal muscle wasting is a serious condition prevalent in the aging population (sarcopenia) and in a variety of specific diseases. This condition results in loss of muscle function through impaired muscle regeneration, resulting in an increase in falls and injuries, a loss of independence, and a reduced quality of life. These changes produce a large health care burden estimated in the year 2000 to be 18.5 billion in the aged population. Since the morbidity and mortality rates are directly correlated to the mobility of elderly subjects, new medicines that promote muscle regeneration should lower health care costs through less hospitalization and nursing home care. Muscle regeneration is controlled by the satellite cell,an adult muscle stem cell. When muscle is injured, the satellite cell becomes activated to proliferate and subsequently differentiate to terminally committed myoblasts. The overall objective of this application is to establish a human satellite cell-basedsystem that can support: 1) identification of the signaling pathways and agents that control the proliferation of satellite cells, 2) studies of the alterations that underlie muscle wasting, and 3) drug discovery programs on muscle regeneration. In Aim1 using human muscle biopsy material, we will establish a satellite cell assay in a 384-well format that can determine the capacity of the cells to proliferate, maintain their satellite cell phenotype and allow measurement of the effects of different agents on these properties. This platform will establish a robust screening system that can be used in Phase II work to identify agents that modify the cells' capacity to replicate and differentiate. Efforts in Aim 2 will validate the assay by examining a set of agents with known effects on skeletal muscle. The utility of the assay will be demonstrated by screening small libraries of highly annotated compounds. Importantly, this work will be the first step toward identifying novel mechanisms and molecules that promote muscle regeneration. The screening assay will become part of Zen Bio's contract assay service when it is refined by work in Phase II, allowing pharmaceutical, biotech and academic institutions to profile the actions of compounds and biological agents on human satellite cells. Phase II efforts will also help Zen Bio develop an intellectual property portfolio that covers chemical and target-driven information on muscle regeneration. PUBLIC HEALTH RELEVANCE: Muscle wasting is a major problem in theelderly and in a variety of specific diseases (e.g. chronic obstruction pulmonary disease, cancer related cachexia, end stage renal disease). This application describes the generation of a cell-based assay system using the human satellite cell, an adult stem cell that controls skeletal muscle regeneration. This assay will provide a method for determining the controls that regulate human satellite cell proliferation, examine the cause of the poor muscle regeneration seen in various states such as elderly subjects and the disease states mentioned above, and facilitate the identification of new drugs that can reverse the age and disease-related decline in muscle mass and function.

Loading Zen-Bio, Inc. collaborators
Loading Zen-Bio, Inc. collaborators