One major challenge in biomedical research is to leverage advances in genome sequencing into lead therapeutic modalities to treat human disease. This precision medicine approach holds great promise to advance patient-specific therapeutics and to provide highly selective chemical probes of function to study disease biology. In this proposal, we describe an innovative precision therapeutic approach to custom synthesize highly selective and potent lead therapeutics in only disease-affected cells and tissues by using a disease-causing gene product as a catalyst. That is, the disease-affected cell serves as a reaction vessel and a disease-causing RNA as a catalyst to allow for the synthesis of its own treatment. This is in contrast to traditional precision medicine approaches in which both healthy and disease-affected cells are exposed to the therapeutic, potentially causing toxicity due to binding off-targets. Our technology will be applied to develop compounds to treat and study microsatellite disorders that affect millions of people worldwide and have no known cure. Microsatellite disorders are caused by expanded repeating sequences located in both coding and non-coding regions, with the RNA being a key pathogenic agent. We have previously shown that repeating transcripts are most effectively targeted with multivalent compounds. However, as the compounds increase in valency, their molecular weights increase and their drug-likeness decreases. We therefore recently developed an innovative strategy to synthesize multivalent compounds, from their monovalent components, in cellulo using a disease-affected cell as a reaction vessel and a toxic, disease-causing RNA as a catalyst. We will take these exciting results in new directions and apply them to other debilitating microsatellite disorders including Huntington?s disease, various forms of muscular dystrophy, the genetic defect that causes fragile X syndrome (the only known single gene cause of autism), fragile X-associated tremor ataxia syndrome, and a common mutation that causes amyotrophic lateral sclerosis and frontal temporal dementia (ALS/FTD). Since defects in the brain and the nervous system are observed in these diseases, devising methods to transform brain-penetrant compounds into highly potent, selective inhibitors of disease would be truly transformative. Specifically, we will: (i) synthesize precise medicines/chemical probes in disease-affected tissues and animal models of microsatellite disease; and (ii) develop imaging agents for disease-causing RNAs in their native contexts in cellular and animal models of disease.
Herein, we propose to leverage genome-sequencing data to develop precise medicines to treat and study human neurological disease. In particular, we will custom synthesize highly selective and potent lead therapeutics in only disease-affected cells and tissues by using a disease-causing gene product as a catalyst, potentially allowing low molecular weight compounds to cross the blood-brain barrier and transform into potent, oligomeric inhibitors in disease-affected brain. Further, these compounds can be used to study disease pathology and image the disease-causing agent directly in cells and tissues of live animals.
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