There is no FDA-approved therapy for any form of HRFDs. However, molecular pathways highly relevant to pathobiology of several specific HRFD have recently been 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), we believe that comparable success can be achieved for at least some forms of HRFD. To help facilitate this goal, we have established the Therapeutics Development and Screening Resource (Core D) to provide essential tools, models and technologies, along with an integrated plan for their use in lead compound optimization and preclinical development. Specifically, (i) to address lack of predictive in vitro assays that can be used to identify and characterize HRFD lead compounds, Core D will develop a tractable model for lead compound identification consisting of a well characterized panel of cell lines with known HRFD mutations. Coupling of such cell-based resource with HRFD relevant reporter assays offers innovative and robust tool for identification of HRFD lead compounds and for characterization of functional HRFD protein domains that are potentially targeted with a single drug. (ii) To improve assessment of drug efficacy, Core D will develop in vivo predictive models for standardized longitudinal monitoring of drug effects in animal HRFD models using established and newly developed markers of the disease progression. (iii) To enhance preclinical safety assessment of prioritized drugs, Core D will develop HRFD-specific toxicology and safety screens. In summary, to advance development of HRFD therapeutics, Core D will establish innovative drug discovery and standardized drug efficacy screening systems. These newly developed resources will be made available to the HRFD Core Center Investigator Base to advance discovery and evaluation of new HRFD therapeutics. In addition, a standardized strategy for drug efficacy testing in HRFD models will help to solidify emerging hypotheses by providing cost-effective in vivo evaluation of specific HRFD progression modulating effects. Therefore, we anticipate that Core D will also catalyze development of HRFD therapeutics indirectly by attracting additional funding to HRFD research by enhancing quality of HRFD grants and manuscripts and by attracting new non-HRFD investigators to this field.
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