# Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

Abstract
In Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of
dementia. However, interventions for AD and AD related dementias (ADRDs) are limited to treatment
of symptoms that do not directly alter tau pathology or the resultant neurodegeneration. This
underscores the need for tau-targeted disease-modifying therapeutics. Our work has demonstrated
that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of
MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as
deletion of the CCCH domain suppresses neurodegeneration in mouse models of tauopathy. The
identification of single chain antibody or nanobody leads that inhibit MSUT2 from binding to poly(A)
RNA will provide a biologic means of intervening against tauopathy. We hypothesize that biologic
antagonism of MSUT2/poly(A) RNA-binding after onset of pathological tau deposition will
reverse the toxic consequences of pathological tau. The specific aims of this proposal will develop
potent and specific brain-penetrant biologic based approaches to target MSUT2 and use them to
dissect the temporal and mechanistic relationship between MSUT2 activity and tauopathy. Completion
of the project as proposed will also further demonstrate the importance of MSUT2 in tauopathy. This
knowledge will set the stage for future translational studies by both generating MSUT2 specific lead
biologic agents and further validating a novel candidate therapeutic target for intervention in tauopathy
disorders.

## Key facts

- **NIH application ID:** 10768543
- **Project number:** 5I01BX005742-03
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Brian C. Kraemer
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768543

## Citation

> US National Institutes of Health, RePORTER application 10768543, Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease (5I01BX005742-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768543. Licensed CC0.

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