Research Project
7805608
DESCRIPTION (provided by applicant): Fibrosis can be defined as an uncontrolled wound healing response that results in organ dysfunction. Fibroproliferation leads to the over production and increased deposition of extracellular matrix, particularly collagen, eventually replacing normal tissue with scar tissue. Typically this is a slow process occurring over many years, often resulting in organ failure or death. Fibrosis is a cause of morbidity and mortality in multiple conditions and chronic fibrotic disorders have been estimated to be the cause of over 45% of deaths in the developed world [6]. Currently there are no effective therapies for this large group of fibrotic diseases, representing a major unmet medical need. The slow turnover and chronic nature of these disorders is the main obstacle to evaluating the effectiveness of anti-fibrotic therapies using standard techniques. Collagen is the main extracellular matrix protein that accumulates in fibrosis. KineMed has developed a proprietary technology, using stable isotope labeling and mass spectrometric analysis, to accurately measure changes in tissue collagen synthesis in vivo in humans and animal models. The goal of this research is to apply this technology to the measurement of collagen synthesis in patients with fibrotic disorders and thereby evaluate drug candidates for their effectiveness as anti-fibrotic agents. The specific aims of our Phase I research were to develop and validate a high through-put kinetic method for the simultaneous detection of cell proliferation, mitochondrial biogenesis and fibrogenesis (measured as collagen synthesis rate), for use as readouts of hepatic toxicity. We achieved these goals by developing sensitive assays for liver cell proliferation and collagen synthesis in vivo models of hepato-toxicity. These assays were then validated against conventional methods. Stable isotope detection of cell proliferation and collagen synthesis proved highly sensitive and reproducible in several models of drug and chemical exposure. Our Phase II specific aims are, 1) to use measurements of collagen synthesis rates to identify a lead anti-fibrotic drug from a series of candidates in preclinical animal models of fibrosis;2) to demonstrate the feasibility of stable isotope labeling to measure collagen synthesis in human skin and liver biopsies;and 3) to determine the effects of fibrotic diseases on the rate of collagen synthesis in patients with active fibrotic disease. The application of this technology to quickly and accurately quantitate disease progression and assess drug efficacy in humans could in principle allow us to identify anti-fibrotic drugs more rapidly and accelerate the clinical processes required to bring these candidates to clinic in a patient population that is currently severely lacking effective therapies. PUBLIC HEALTH RELEVANCE: Fibrotic diseases are responsible for significant morbidity and mortality in association with a large number of diseases. The development of effective pharmacological therapeutics for these individuals has been hindered by a number of factors. Firstly, fibrogenesis is a slow process, often taking years to develop, so assessing changes in fibrosis over a small period of time is difficult and makes clinical trials long and expensive. Secondly, the current methods for measuring fibrosis are insensitive and qualitative rather than quantitative. The goal of this work addresses both of these problems. Translating our collagen kinetic biomarker from rodents to humans will give us an assay for the rapid and accurate detection of disease progression in patients. In turn, this will allow us to rapidly evaluate and develop therapeutic agents for this significantly underserved patient population.
