Abstract Details

Title Abrogation of Phenotype by Small Molecule Read-Through Compounds in a Human Model of Ataxia Telangiectasia

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 048

Objective

Background BACKGROUND: Ataxia Telangiectasia (A-T) is an early onset progressive neurodegenerative disease caused by loss of function mutations in ATM. ATM protein is a kinase that plays a crucial role in cellular response to double stranded-DNA break. Thus far, animal models of A-T have failed to show many aspects of the disease, including progressive cerebellar ataxia, the most debilitating symptom in A-T patients.

Design/Methods DESIGN/METHODS: Using lenti-virus that harbors reprogramming Yamanaka factors, we reprogrammed A-T patient's fibroblasts into induced pluripotent stem cells (iPSC). These iPSCs were characterized for their pluripotency by immunostaining and teratoma assay. These iPSCs were then differentiated into neural lineages, including neuroprogenitor and neurons. These neural derivatives were subjected to gamma irradiation to induce double-stranded DNA break. ATM activity was measured by the degree of ATM phosphorylation using immunofluoresence. Response to DNA damage was monitored by the presence of gamma-H2AX, a histone variant involved in DNA repair. The neural derivatives were treated with small molecule read through (SMRT) compounds that induce misread mRNA around termination codons. The effect of SMRT compounds on ATM activity by ATM phosphorylation and double stranded DNA repair measured by gamma-H2AX were evaluated.

Results RESULTS: This model resembles several key aspects of the disease in neural progenitor cells and neurons. Furthermore, we show that small molecule read through (SMRT) compounds that induce misread mRNA around termination codons, restore ATM activity and improved response to DNA damage.

Conclusions CONCLUSIONS: This in vitro model, therefore, allows for efficient screening of novel compounds, identify target effects, and preclinical testing on relevant cell types for the study and treatment of A-T.

Authors/Disclosures
Peiyee Lee, MD, PhD PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Darren Tayama, MD (Genentech)	No disclosure on file
Douglas L. Arnold, MD, FAAN (Montreal Neurological Institute, McGill Univ)	Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Frequency Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xfacto communications. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Find therapeutics. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Idorsia. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kiniksa. Dr. Arnold has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Clario.
	No disclosure on file
	No disclosure on file
Susan L. Perlman, MD (UCLA)	Dr. Perlman has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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