# Strategies for treatment of Down syndrome: Identifying age- and sex-specific developmental windows using inducible genetic reduction of Dyrk1a

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $1,919,804

## Abstract

PROJECT SUMMARY/ABSTRACT
 Treatment of cognitive deficits associated with Down syndrome (DS) has become a realistic goal, yet most
potential therapies have not overcome translational barriers from preclinical animal models to clinical trials in
humans with Trisomy 21 (Ts21). Numerous preclinical treatments in mouse models—usually targeting
neurobehavioral disorders—have attempted to treat DS phenotypes with approaches that: a) assume
expression of a single gene at trisomic levels throughout the lifespan causes the trait; b) consider trisomy as
causing changes to developmental mechanisms that lead to a particular phenotype; or c) treat existing DS
phenotypes symptomatically. These methods, commonly studied in just one sex in mouse models, have often
reported at least transient improvement in neurobehavioral phenotypes. Translation of these one-dimensional
preclinical therapies to humans with Ts21 has been largely unsuccessful, potentially because treatments
implemented did not explicitly target mechanisms active during the origins of the abnormal developmental
trisomic trajectories nor consider sex-specific processes in the DS mouse models. One conventional view is
that trisomic gene expression is generally upregulated 1.5-fold that of normal regardless of developmental
stage, and that reducing this gene expression or activity to normal levels at any period can improve a trait. Our
long-term goal challenges this view with an innovative alternative strategy for identifying windows of
opportunity for effective therapeutics by targeting trisomic gene mediated developmental origins of aberrant
cognitive and skeletal phenotypes in individuals with Ts21. This fundamentally new approach to treatment of
DS phenotypes is driven by novel data that DYRK1A protein overexpression in trisomic mice is temporally
regulated and is amplified in the brain specifically during early postnatal development. This paradigm shift to a
combined developmental-genotype-phenotype approach that also addresses sex differences transcends
current treatment approaches. The aims of this proposal use a novel trisomic model that manipulates the
timing of inducible functional reduction of Dyrk1a during specific windows of development. It tests the
hypotheses that amplified (dysregulated) expression of Dyrk1a during temporally-defined windows of
development—evident both in brain and in bone—mark the origins of sex-dependent aberrant trajectories of
DS phenotypes, and provide windows of opportunity for genetic normalization to improve DS phenotypes.
Completion of this transformational project is expected to provide the strongest available evidence for pursuing
sex-specific pharmacogenetic treatments that target DYRK1A during critical temporal windows of early
development in humans with DS to improve neurocognitive and comorbid skeletal outcomes. If successful, the
strategic approach will transform how treatments are devised, tested, and effectively translated into humans
with DS, by firs...

## Key facts

- **NIH application ID:** 10107377
- **Project number:** 1R01AR078663-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** CHARLES R. GOODLETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,919,804
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107377

## Citation

> US National Institutes of Health, RePORTER application 10107377, Strategies for treatment of Down syndrome: Identifying age- and sex-specific developmental windows using inducible genetic reduction of Dyrk1a (1R01AR078663-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10107377. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*