# Development of Translatable Neurophysiological Biomarkers to Accelerate Therapeutic Development in Rett Syndrome

> **NIH NIH R61** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $821,000

## Abstract

Rett syndrome (RTT), is a severe neurodevelopmental disorder caused by loss-of function mutations in the X-
linked gene Methyl-CpG-binding Protein 2 (MECP2) and characterized by loss of speech and hand skills,
problems walking, and repetitive hand movements. Genetic restoration of MECP2 in symptomatic mice can
reverse symptoms providing hope that disease-modifying therapies can be created. Impeding the development
of transformative therapies are a lack of biomarkers of treatment-response. Ideally, a biomarker can be applied
in mice and humans to enhance effective translation of preclinical treatment studies and improve human trial
design and execution. Neurophysiological assessments have potential as biomarkers as they are non-invasive,
measure neurological changes, and are translatable between humans and animal models. Recent work in RTT,
from our group, has found differences in neurophysiological measures in both affected humans and mouse
models that correlate with disease severity, but an urgent need exists to identify well-validated and translatable
treatment-response biomarkers in RTT.
 To address this need, we propose here to develop neurophysiological biomarkers that can fulfil a specific
primary Context of Use (COU), an early treatment response biomarker, to facilitate and speed both preclinical
and clinical trials of novel therapies in RTT. The primary goal of the R61 phase of the proposal is to identify
candidate neurophysiological biomarkers of disease improvement in a mouse model of RTT and establish human
multi-site standard operating procedures and normative data. These parallel projects will be foundational to
identify a true treatment responsive biomarker in RTT. To do this we will first determine if potential biomarkers,
quantitative EEG and evoked potentials will change predictively in a mouse model of RTT that allows for genetic
rescue of the RTT phenotype. Simultaneously, we will develop and optimize standard operating procedures to
enable multi-site evaluation of candidate human neurophysiological biomarkers. Additionally, we will evaluate
test-retest reliability of the biomarkers we are developing. Finally, we will determine if the putative
neurophysiological biomarkers change during active clinical change in RTT. For the R33 phase, we will
demonstrate that our human proof-of-concept of candidate neurophysiological biomarkers are stable over the
time frame relevant to clinical trials in RTT and that these biomarkers correlate with RTT clinical severity.
 Overall, this proposal takes advantage of the ability to use mouse models to identify and validate robust
human neurophysiological features as putative biomarkers. These neurophysiological measures will allow for
accelerated therapy development via the replacement of subjective clinical findings with quantitative measures
of early treatment-response. Together, this work will facilitate biomarker development to be employed in
interventional therapy development.

## Key facts

- **NIH application ID:** 10817921
- **Project number:** 5R61NS130216-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** ERIC D MARSH
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $821,000
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817921

## Citation

> US National Institutes of Health, RePORTER application 10817921, Development of Translatable Neurophysiological Biomarkers to Accelerate Therapeutic Development in Rett Syndrome (5R61NS130216-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10817921. Licensed CC0.

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