Core D: Therapeutics & Screening

Hepatorenal fibrocystic diseases (HRFD)s are among the most common inherited disorders. Since only supportive care is available to patients with any form of HRFD, this group of disorders causes a major burden to individual patients and society. However, molecular pathways highly relevant to pathobiology of several specific HRFD have been recently identified. This raises hope that pharmacological targeting of druggable components of these pathways may attenuate HRFD progression. Since similar level of disease knowledge triggered identification of FDA-approved treatments for other inherited disorders (e.g., cystic fibrosis or Fabry disease), we believe that comparable success can be achieved for at least some forms of HRFD. To help facilitate this goal, we established the Therapeutics Development and Screening Resource to provide essential tools, models and technologies, along with an integrated plan for their use in lead compound optimization and preclinical development. Core D is fully integrated into the UAB HRFD Core Center that has, thanks to its broad user base, already catalyzed seminal discoveries that will inform design of HRFD therapeutics. While major advances occurred at the stages of HRFD drug target identification and target validation, evaluation towards translation of these discoveries to clinical care has been hindered by the lack of HRFD-specific technical resources and absence of an integrated therapeutics development plan. The central objective of the Core is to address these impediments by developing key reagents and provide easy access to services that accelerate preclinical stages of HRFD drug discovery. This objective will be accomplished through three aims:

Specific Aims

Aim 1: Develop in vitro predictive assays to identify and characterize HRFD lead compounds. Availability of a relevant cell line model often represents a corner stone of a successful drug discovery, retesting-based target confirmation and characterization. To allow use of similar strategies in HRFD, the Core is developing a tractable model to identify and study lead compounds in assembled and well characterized collection of cell lines with known HRFD mutations (e.g., Core B engineered mutations in hTERT-immortalized epithelial cells from Core C or differentiated iPS cells from genetically annotated HRFD patients). Coupling of such cell-based resource with relevant reporter assays (e.g, for intracytoplasmic Ca++ or cAMP) offers innovative and robust tool for identification of HRFD lead compounds and for discovering molecular determinants of in vitro drug sensitivity - a first step towards defining mechanisms and biomarkers of drug response in HRFD patients.

Aim 2: Develop in vivo predictive translational HRFD models to enhance efficacy assessment in preclinical testing. To improve success rates of selected candidate compounds entering a clinical testing phase, we will develop predictive in vivo HRFD assays that will allow efficient standardized longitudinal monitoring of drug effects on established and newly developed biochemical and imaging markers of the disease progression in an assembled collection of animal HRFD models (in part generated by Core B.

Aim 3: Develop advanced HRFD-specific toxicology and safety screens. To complement enhanced efficacy testing and to improve likelihood of FDA approval of clinical testing and its safe outcome, we will design HRFD model-based in vitro and in vivo toxicology and safety screens to unmask potential HRFD-specific toxicities of candidate compounds in in vitro and in vivo HRFD models.

Contact Dr. Michal Mrug ( to discuss potential projects utilizing the Therapeutics Development and Screening Core