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Title:DNA/RNA-targeted therapeutic approaches for myotonic dystrophy type 1
Author(s):Lee, JuYeon
Director of Research:Zimmerman, Steven C
Doctoral Committee Chair(s):Zimmerman, Steven C
Doctoral Committee Member(s):Kalsotra, Auinash; van der Donk, Wilfred; Huang, Raven H
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):DNA/RNA-targeted therapeutics, myotonic dystrophy type 1, DM1, small molecules targeting DNA/RNA
Abstract:New discoveries showing the key role of RNAs in diseases such as cancer and neurodegenerative disorders have led to a paradigm shift in drug discovery. At the same time, transcriptome analyses combined with the structural information provided by X-ray crystallography and NMR spectroscopy have further accelerated progress in the field of RNA-targeted therapeutics. Myotonic dystrophy type 1 (DM1) is an excellent disease for developing RNA-targeted therapeutics because the pathogenesis involves a toxic RNA gain-of-function. DM1 is an incurable multisystemic and neurodegenerative disease that originates in an aberrantly expanded CTG trinucleotide repeat in the 3’-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Healthy individuals have 5-37 CTG repeats, whereas DM1 patients have expanded repeats ranging from 50 to > 2000 repeats. The repeat length directly correlates with the age of onset and severity of the disease. The corresponding expanded transcript, r(CUG)exp, causes toxicity through multiple pathways including muscleblined-like protein 1 (MBNL1) sequestration, repeat-associated non-ATG (RAN) translation, and reduction of myocyte enhancer factor 2 (Mef2). Chapter 1 reviews the background of DM1 including the pathogenesis and therapeutic approaches that target both the DM1 RNA and DNA. The regular and repetitive structure of r(CUG)exp provides a good target to develop finely tuned multivalent ligands. The rationally designed multivalent ligand and its biological activities will be discussed in Chapter 2. The multivalent ligand contains key features of cell penetrating peptide mimics, allowing carrier-free entry to cells and their nucleus. The ligand regulated r(CUG)exp both at the transcriptional and post-transcriptional level, recovering DM1 molecular features in DM1 cells and in a DM1 liver mouse model. Although the therapeutic strategies regulating r(CUG)exp can recover DM1 symptoms to some extent, the origin of the disease in DNA is not addressed by this approach. Furthermore, d(CTG)exp progressively expands throughout the patient’s lifetime as well as across generations. Chapter 3 discusses the development of a small molecule to modify the repeat instability. This ligand was rationally designed to recognize and alkylate the characteristic structure at d(CTG)exp. By creating a covalent adduct with d(CTG)exp, the ligand functioned as a transcription inhibitor as well as a dCTG repeat modulator. The biological activities in DM1 model cells and DM1 patient cells will be discussed.
Issue Date:2018-04-18
Rights Information:Copyright 2018 JuYeon Lee
Date Available in IDEALS:2020-08-27
Date Deposited:2018-05

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