Brain-targeted delivery of therapeutic molecules by exosomes derived from engineered human iPS cells: a potential therapeutic approach for Huntington's disease

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PROJECT SUMMARY Huntington’s disease (HD) is a devastating neurodegenerative disease caused by a CAG repeat expansion in the gene huntingtin (HTT). The CAG repeat is translated into a polyglutamine (polyQ) tract in the mutant HTT protein that has neurotoxic properties. Current therapeutic efforts are focused at suppressing the expression of the mutant HTT protein or targeting downstream pathways of neurotoxicity. We and others have shown that CAG repeat-targeting phosphorodiamidate morpholino oligomers (PMOs) and neurotrophic protein BDNF have therapeutic benefits for HD. However, PMOs and BDNF do not usually cross the blood-brain barrier (BBB), hindering the translation of clinical application. Therefore, more efficient delivery vehicles capable of BBB penetration are critical for the development of effective therapies for HD and other neurodegenerative disorders in general. Exosomes (Exo) are cell-secreted extracellular vehicles with BBB penetration potential, capable of delivering exogeneous therapeutic molecules. iPSCs have been considered as one of the best sources for Exo manufacture, based on high Exo yield, availability of cGMP-compatible clinical-grade manufacture platform for iPSC production and Exo manufacture, and feasibility to perform genome editing to establish engineered iPSCs that produce modified Exo for more efficient brain targeting. We therefore propose to develop strategies to produce brain-targeting Exo from engineered iPSCs as delivery vehicles for PMOs as well as BDNF, and further rigorously study the therapeutic efficacy of the brain-targeting Exo loaded with PMOs and BDNF in a panel of HD neuron and mouse models. Success of this project will set the stage for future larger scale investigations aimed at using huma iPSC-derived Exo for targeted delivery of therapeutic molecules (such as PMOs, chemical compounds and neurotrophic factors) for various neurodegenerative disorders.