Friday, May 30, 2025
5/30/2025
AI/ML and iPSC-Derived Organoids for Myotonic Dystrophy Drug Discovery - PROJECT SUMMARY/ABSTRACT Drug discovery for rare diseases is often limited by the lack of relevant preclinical models that adequately capture the complexity and diversity of patients affected. Furthermore, clinical trials are burdened with challenges in patient recruitment and stratification to assess the safety and efficacy of a drug candidate. The ability to use in vitro cellular data for efficacy assessment will create drug development opportunities for rare diseases that were previously considered too challenging due to the small number of patients. To enable the use of data from relevant cellular models to replace, reduce or refine clinical trials for rare diseases, this proposal will leverage human induced pluripotent stem cells (iPSCs), a well-established tool for patient-specific and disease-specific modeling in vitro, to advance the concept of “clinical trial in a dish” to accelerate, de-risk, and streamline drug discovery for rare diseases. Additionally, we combine iPSC technology with artificial intelligence and machine learning (AI/ML) to discover novel therapeutic compounds that are predicted to have significantly improved safety and efficacy. Here, we leverage our expertise in myotonic dystrophy type 1 (DM1) as a rare disease with unmet needs to apply our iPSC-AI/ML drug discovery platform. DM1 is a monogenic rare disease affecting nearly 1 in 2,100 in the general population and is the most common adult form of muscular dystrophy. It is a progressive multi-systemic disease with cardiovascular complications being the second leading cause of death behind respiratory failure. To date, there is no treatment for the heart in DM1 and no pharmacological treatments available for the prevalent arrhythmias. The main standard of care for DM1 patients at risk of arrhythmias and sudden cardiac death is an implantable cardioverter defibrillator (ICD). Specific Aim 1 will utilize AI/ML to identify safe and novel compounds with high binding affinity to RNA structures formed by expanded CUG repeats in the RNA from the DMPK gene, which is the underlying cause of the disease. Specific Aim 2 will then evaluate these drugs in iPSC-derived cardiac organoids and in DM1 mouse model. The outcome of this project will inform the development of general standards, quality control criteria, and best practices for in vitro models to be used for rare disease safety and efficacy assessment for clinical trial readiness.
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