# Clinical trial readiness biomarkers for gene dosage-dependent disorders

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2022 · $200,625

## Abstract

DNA-based therapy has made tremendous advances recently, as evident by the increase in emerging potential
therapies such as gene replacement and antisense oligonucleotides to alter splicing or downregulate an extra
allele. These therapies hold the promise to treat many IDDs; however, major challenges must be addressed to
achieve successful clinical trials. Safety of such therapies is of the utmost importance since many of the genes
are dosage sensitive. It is therefore critical to identify outcome measures sensitive to target engagement and
able to detect overtreatment and unintended conversion of gain-of-function phenotypes into a loss-of-function
phenotypes, and vice versa. Here, we focus on MECP2- (Rett vs. MECP2 Duplication), RAI1- (Smith-Magenis
vs. Potocki-Lupski syndrome) and SHANK3- (Phelan-McDermid vs. SHANK3 Duplication) associated disorders
as test cases of IDDs that are caused by alterations of these dosage-dependent genes. We propose to identify
molecular and neurocircuitry mediators/effectors of dosage alterations of these genes, both peripherally and
centrally, to develop composite biomarkers that are responsive to gene dosage in each individual at their
particular disease stage. Toward this goal, we capitalize on the established patient cohorts at Baylor College of
Medicine, which
has an extensive history in studying these disorders and their genetics. In Aim 1, we will
establish patient-specific molecular signatures of human induced neurons (iNs), derived from both fibroblasts
and inducible pluripotent stem cells, and blood, using metabolomics and transcriptomics. In Aim 2, we will
establish patient-specific autonomic and sensory neurocircuitry signatures of the momentary disease stage
and severity using novel pre-pulse inhibition paradigm, pupillometry, and evoked potentials. These signatures
will be obtained twice from the same subject, 8-12 months apart, to assess stability. We will then integrate
these dense multimodal datasets from each subject to generate a composite biomarker that accurately
represents personalized response to the gene dosage level at that particular time. In contrast to conventional
population studies – and in the spirit of precision medicine – this analysis framework relies on complete and
diverse datasets from each participant because safety at the individual level is paramount to avoid causing
unintended phenotypes. This project is possible because of the ability to access the innovative services from
all the cores. The strategies we develop will provide a template to advance the use of DNA-based therapy for
treatment of many monogenic disorders and could help inform many disorders that are gene dosage-
dependent. The patient-specific cell lines, molecular, and circuit data will be available for the scientific
community in perpetuity, will complement natural history studies, and will inform future clinical trials. Lastly, the
new methodologies for examining neurocircuitry and the integrative data analy...

## Key facts

- **NIH application ID:** 10427281
- **Project number:** 5P50HD103555-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MIRJANA MALETIC-SAVATIC
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $200,625
- **Award type:** 5
- **Project period:** 2020-07-22 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427281

## Citation

> US National Institutes of Health, RePORTER application 10427281, Clinical trial readiness biomarkers for gene dosage-dependent disorders (5P50HD103555-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10427281. Licensed CC0.

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