Optimizing Small Molecule Read-Through Compounds for Treating AtaxiaTelangiectasia

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PROJECT SUMMARY Ataxia-Telangiectasia (A-T) is a rare (~ 1 in every 100,000) but catastrophic and deadly disease that causes progressive loss of motor function and death between the ages of 10 and 30 years. In about one-third of A-T cases, the cause is a nonsense mutation in the ATM (Ataxia-Telangiectasia mutated) gene that encodes a premature termination codon (PTC). No effective treatments are available. However, our group has been developing and testing a series of compounds that effectively readthrough PTCs in the transcribed mRNA. Published and unpublished studies demonstrate the capability of these “SMRT” compounds (for Small Molecule ReadThrough) to readthrough PTCs and restore translation of functional ATM protein in in vivo and ex vivo experiments. The rationale to further develop SMRT compounds is strengthened by promising therapeutic results in mouse models for Duchenne muscular dystrophy and hereditary pulmonary arterial hypertension by our collaborators. However, success in these models does not ensure success in a multisystem, neurological disorder like A-T, in part because A-T uniquely requires the compound to cross the blood-brain barrier in adequate amounts. We have made considerable progress in our preclinical studies. We present data indicating that SMRT compounds elicit synthesis of full-length functional protein that penetrates the brain. We also recently solved a major hurdle in the field of A-T research: lack of an animal model that faithfully reflects clinical disease. In NINDS-supported studies, we used a double hit strategy to generate a mouse harboring both a clinically relevant PTC in the ATM gene and a knockout of a related DNA repair gene called aprataxin (Aptx). Characterization of this mouse model, including the profound, progressive ataxia that is a hallmark of A-T is complete. Now, we move to next logical phase: to use a rationalized and comprehensive approach to optimize our top candidate SMRT compound via medicinal chemistry. In AIM 1 we will develop and validate a novel potency assay specifically designed to evaluate potency across the 10 most common A-T causing nonsense mutations. In AIM 2 we will develop and validate an assay designed to confirm ATM function in human cells taking advantage of our unique repository of A-T patient derived cell lines. Finally, in AIM 3, these assays (along with those already standard in our labs to assess solubility, protein binding, blood brain barrier permeability, and toxicity) will be utilized to conduct a medicinal chemistry optimization campaign to generate a small set of candidate compounds with properties that maximize their chances of success in follow-on efficacy studies in our new A-T mouse model. Our work represents the first real hope for kids suffering from A-T's devastating effects.