Noninvasive urinary monitoring of NASH by activity based nanosensors

Project Summary Abstract Nonalcoholic steatohepatitis NASH is dubbed the stealth epidemic and in the U S alone percent of the million people who are estimated to have NASH will progress and develop life threatening conditions including fibrosis cirrhosis hepatocellular carcinoma and liver failure By the year NASH is projected to be the leading indication for liver transplantation surpassing hepatitis C virus HCV and alcoholic related cirrhosis and by the total NASH pharmaceutical market size is estimated to reach $ billion Currently the liver biopsy is the gold standard for diagnosing and monitoring NASH yet it is invasive expensive $ and associated with significant patient morbidities Importantly a single biopsy provides only an instantaneous `snapshotandapos of tissue architecture and is unable to identify NASH patients who are `rapid progressorsandapos and thus urgently require treatment or those on therapy that are `respondersandapos As a result of these limitations liver biopsy remains the key bottleneck in the safe accurate diagnosis and monitoring of NASH This proposal aims to develop the Glympse liver test GLT a noninvasive urine diagnostic that detects the activity of hepatic proteases that drive NASH GLT consists of an injectable panel of nanosensors that detect proteases involved with inflammation and fibrosis and produce signals that are detected in urine The detection signals are amplified by enzymatic action in the liver and then concentrated in the patientandapos s urine for quantification by mass spectrometry Because enzyme activity is measurable at the molecular level before microscopic changes are evident by biopsy the test is thus both ultrasensitive and predictive We will demonstrate the feasibility of formulating GLT nanosensors on an inert polymer scaffold to sense matrix metalloproteinases MMPs a key family of enzymes that are involved in NASH progression and regression We will then validate the ability of GLT to predict disease progression and regression in a mouse model of NASH and conduct preclinical toxicology studies in preparation for an IND submission The GLT will offer clinicians a rapid determination of the state and trajectory of the patientandapos s liver without the morbidity of biopsy reduce cost of diagnosis from $ to $ and raise sensitivity by The benefit to the healthcare system per patient is estimated to be $ in reduced biopsy associated costs and $ in drug costs over a patientandapos s lifetime saving more than $ billion annually for the of NASH patients with progressive disease alone The impact of the adoption of GLT will reach across multiple constituencies increasing patient care and comfort improving physician decision making accelerating pharmaceutical drug trials and lowering healthcare costs Project Narrative Nonalcoholic steatohepatitis NASH is a deadly type of fatty liver disease that progresses to liver cancer and liver failure yet the biopsy remains the diagnostic standard despite its invasiveness and limited predictive power We will develop a new noninvasive urine diagnostic that can predict NASH progression and regression to transform the care of NASH patients