# Decoding cerebrospinal fluid huntingtin biomarkers

> **NIH NIH R01** · UNIVERSITY OF CENTRAL FLORIDA · 2021 · $414,920

## Abstract

PROJECT SUMMARY
The goal of this project is to functionalize quantitation of cerebrospinal fluid (CSF) huntingtin (HTT) protein as a
Huntington disease (HD) biomarker. The first Phase I/IIa HTT lowering clinical trial for the treatment of HD
recently concluded demonstrating dose-dependent reduction of mutant HTT (mtHTT) protein in the CSF of
treated patients. The use of this measure was based on our previous work using a novel ultrasensitive mtHTT
detection assay to demonstrate that suppression of HTT in the entire mouse CNS results in correlative reduction
of CSF mtHTT, but further studies are required for meaningful use of this measure in the clinic. The therapeutic
under trial is expected to mostly be active in superficial brain regions, while other strategies in development are
expected to mostly be active in deeper brain regions or specific cell types. For this reason, it is necessary to
know the regional and cell type contributions to CSF mtHTT in order to predict what a treatment-induced change
means for the targeted tissue(s). Comparison of brain and CSF mtHTT in mice that express mtHTT everywhere
except the brain region or cell type at study to those with ubiquitous mtHTT expression will be used to discern
the proportional contributions to CSF mtHTT and provide a way to infer magnitude of treatment-induced changes
in the brain by those in CSF. It will also be necessary to know how mtHTT enters CSF. Comparison of brain and
CSF HTT in systems with and without neurodegeneration will be used to distinguish passive release of HTT as
cells die and break open from active transport of HTT to CSF. Furthermore, the kinetics of brain clearance of
mtHTT will be delineated by ectopic delivery of intra- or extracellular mtHTT protein directly to the brains of mice
and subsequent measurement of brain, CSF, and plasma mtHTT at multiple post-delivery time points.
Perturbation of HTT secretion and the glymphatic system will be used to investigate how mtHTT moves from
inside cells of the brain to the CSF and eventually the blood. Concurrently, mtHTT will be quantified in longitudinal
CSF and plasma samples from HD patients and controls and compared to phenotypic data to determine how
biofluid mtHTT changes over typical clinical trial intervals and with progression in individuals, thus separating
time- and treatment-dependent changes. This will also determine if CSF mtHTT concentration can be used to
more accurately predict disease conversion and progression. We will also attempt to quantify wtHTT protein in
CSF to investigate potential extracellular functions of HTT as well as enable allelic discrimination for trials of
selective agents. The results of these studies will provide the necessary basis to interpret clinical quantitation of
CSF HTT, determine which types of therapeutics could be effectively evaluated by this measure, and ascertain
the predictive value of longitudinal CSF HTT quantitation in monitoring HD progression and selecting clinical trial...

## Key facts

- **NIH application ID:** 10145100
- **Project number:** 5R01NS116099-02
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** Amber L Southwell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,920
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145100

## Citation

> US National Institutes of Health, RePORTER application 10145100, Decoding cerebrospinal fluid huntingtin biomarkers (5R01NS116099-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145100. Licensed CC0.

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