# Development of marmoset models of neurodegenerative disease using embryonic stem cell-based gene-editing approaches

> **NIH NIH R24** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $733,301

## Abstract

PROJECT SUMMARY
The long-term goal of this project is to model human neurodegenerative diseases in marmosets via gene-
editing in embryonic stem cells (ESCs). The mouse system is a powerful tool for medical research due to the
ability to manipulate the mouse genome. However, considerable anatomical, physiological, cognitive, and
behavioral differences between mice and humans limit the degree to which insights from mouse models shed
light on human diseases. This is reflected in the high number of failed clinical trails for drugs that were effective
in treating mouse models of human disease. Several lines of evidence suggest that the marmoset represents
an improved animal system for studying a range of human diseases, including stroke and age-associated
neurodegenerative diseases such as Alzheimer's disease (AD). Marmosets are the shortest-lived of the
anthropoid primates (average lifespan of 5–7 years compared with 25 years for the rhesus macaque) and
exhibit age-related changes that are similar to those seen in humans, including β-amyloid deposition in the
cerebral cortex, loss of cholinergic innervation, and reduced neurogenesis, as observed in AD. In addition,
marmosets are highly social and communicative and have demonstrated the capacity to learn sophisticated
cognitive behaviors. Therefore, marmosets represent an ideal genetic platform for generating models of
neurodegenerative diseases that more accurately reflect the human condition and enable the testing of
potential autologous (the-same-species) stem cell-based regenerative therapies. Initial efforts will focus on
generating a marmoset model of AD. The recent emergence of gene-editing and stem-cell technologies in
primates pave the way toward generating marmoset disease models, but improvements in both areas are
necessary to make this approach viable. Here, both conventional homologous recombination and
CRISPR/Cas9 genome-editing technologies will be employed to modify marmoset ESCs. As genetic evidence
demonstrates that mutations in the amyloid precursor protein (APP) gene result in increased β-amyloid
production, the formation of plaques, and cognitive impairment, the marmoset APP will be edited to carry
human point mutations. Genetic tools for studying neuronal cell type-specific circuits underlying cognitive
impairment and neuropathology in AD will also be generated by inserting a Cre recombinase cassette into 3'
end non-translated regions of the parvalbumin and choline acetyltransferase genes. These Cre driver lines will
enable the visualization and functional manipulation of these cell types. Successful completion of the proposed
Aims will generate a greatly improved animal model of AD, enable testing of stem cell-based regenerative
methods for treating AD, and pave the way toward applying these genetic tools for analyzing neuronal circuitry
of healthy brains. Establishing gene-editing in marmoset ESCs will also enable the development of additional
primate models of human diseases,...

## Key facts

- **NIH application ID:** 9867766
- **Project number:** 5R24OD023076-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** KUO-FEN LEE
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $733,301
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867766

## Citation

> US National Institutes of Health, RePORTER application 9867766, Development of marmoset models of neurodegenerative disease using embryonic stem cell-based gene-editing approaches (5R24OD023076-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867766. Licensed CC0.

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