Development of a Targeted Identification Platform of Small Molecule Inhibitors for Rare and Orphan Diseases Öffentlichkeit

Abstract

Rare and orphan diseases are often under-researched due to their limited financial incentive to pharmaceutical companies. Drug repurposing provides a unique, beneficial approach which reduces costs, leverages small patient populations, limited resources, and lowers other barriers in rare and orphan disease drug discovery and development. This project aimed to establish and optimize a screening platform and workflow for rare and orphan diseases by evaluating therapeutic agents for their ability to serve as treatments or reversals of phenotypes. Multisystem Proteinopathy 1 (MSP-1) was the model disease for this development, with a therapeutic approach to employ candidates aiming to reverse phenotypes driven by harmful levels of protein aggregation. Candidates were screened for efficacy, toxicity, impact on various diseases markers, and reversal of phenotypes that drive disease in vivo. Future directions include pursuit of advanced efficacy platforms and expanding the scope of the project to other diseases or full classes of diseases, with a streamlined goal of selection of repurposed agents to expedite the path to the clinic with a robust, informed preclinical package.

Table of Contents

Introduction  2

Background. 4

Disease History 4

Clinical Manifestations  6

Role of VCP/p97 in MSP1. 6

VCP Function in Protein Clearance    8

Relationship between Autophagy and the Ubiquitin Proteasome System   9

Therapeutic Approach           10

Methods        12

Initial Cell Culture      12

MTS Assay      16

Reactive Oxidative Species (ROS) Detection & Optimization 17

Autophagy Assay       17

Results 18

Toxicity Screening      18

ROS Detection 25

Autophagy Studies     20

Discussion & Future Direction           32

Toxicity Studies          32

ROS Detection 33

Autophagy Studies     32

Rare and Orphan Disease Drug Discovery     34

References     36

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, General Health Sciences, Pharmacology
Stichwort	Drug Discovery
Committee Chair / Thesis Advisor	Christina Gavegnano , Emory University
Committee Members	Dennis Liotta, Emory University Eric Miller, Emory University

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