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Published and unpublished studies demonstrate the capability of these “SMRT” compounds (for Small Molecule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.