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

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,302

## Abstract

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.

## Key facts

- **NIH application ID:** 10764280
- **Project number:** 5R21NS125350-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Pan Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,302
- **Award type:** 5
- **Project period:** 2023-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764280

## Citation

> US National Institutes of Health, RePORTER application 10764280, Brain-targeted delivery of therapeutic molecules by exosomes derived from engineered human iPS cells: a potential therapeutic approach for Huntington's disease (5R21NS125350-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10764280. Licensed CC0.

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