# Functional Validation of TDP-43 splicing repression for frontotemporal degeneration

> **NIH NIH UH3** · JOHNS HOPKINS UNIVERSITY · 2022 · $1,092,581

## Abstract

Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders
with mid to late life onset such as FTLD-TDP or mixed etiology dementias (MED) including Alzheimer's disease
(AD) with TDP-43 pathology. Human studies support the idea that loss of TDP-43 splicing repression underlies
neuron loss in these disorders. We recently established that splicing repression is a major function of TDP-43
and validated TDP-43 repression as a promising therapeutic target for FTLD-TDP. By employing a
comprehensive set of molecular, pathological, neuronal circuit and behavioral/cognitive approaches, we will
functionally validate this type of AAV gene therapeutic strategy to complement TDP-43 repression using both in
vivo mouse models and in vitro human iPSC derived neurons in the UG3 phase of the application. Upon meeting
the Milestones for transition from UG3 to UH3 phase, we will determine: 1) the optimal dose of AAV gene
expression the TDP-43 related repressor required to attenuate neuron loss while limiting any untoward side
effects associated with long term exposure of this gene product; 2) the benefit of this AAV gene therapeutic
strategy using our mouse model lacking TDP-43 in forebrain neurons in terms of attenuation of altered neuronal
circuits, cognitive and behavioural deficits, and neurodegeneration; and 3) ability of AAV gene therapy to restore
TDP-43 repression in cortical neurons derived from human iPSCs. Functional validation of TDP-43 repression
will address a great unmet need for this type of ADRD.

## Key facts

- **NIH application ID:** 10477324
- **Project number:** 5UH3NS115608-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** PHILIP C WONG
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,092,581
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477324

## Citation

> US National Institutes of Health, RePORTER application 10477324, Functional Validation of TDP-43 splicing repression for frontotemporal degeneration (5UH3NS115608-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10477324. Licensed CC0.

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