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

Award Number: R21NS125350
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $204,302 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/14/2023	NON-COMPETING CONTINUATION	$204,302
														Subtotal = $204,302

Issue Date FY: 2023 ( Subtotal = $260,959 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/13/2023	NEW	$260,959
														Subtotal = $260,959

Grand Total All Awards = $465,261

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

Award Number: R21NS125350

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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