# Commercialization of Selective Dyrk1a Inhibitors for Down Syndrome

> **NIH NIH R44** · ILUMINOS THERAPEUTICS, LLC · 2024 · $1,496,403

## Abstract

Project Summary
Down syndrome (DS) is caused by human chromosome 21 trisomy (hsa21) and is the most
common genetic form of intellectual and cognitive disability, occurring in ~1 in 700 live births. DS
patients also exhibit age-related progressive cognitive decline, neurodegeneration, and the
development of Alzheimer's disease (AD)-like pathology by 40-50 years of age. There are
currently no drugs that are approved specifically for DS to prevent cognitive decline, representing
a clear and urgent unmet medical need. The progressive cognitive decline and neurodegeneration
in DS is strongly linked to the overexpression of Dyrk1a (dual-specificity tyrosine-(Y)-
phosphorylation regulated kinase 1A), which is overexpressed on hsa21 in all DS patients. Mouse
models of DS that include Dyrk1a overexpression exhibit profound cognitive deficits in
hippocampal-dependent spatial learning and motor function associated with AD-like
neuropathology. Notably, normalizing the gene dosage of DYRK1A through a genetic method in
the Ts65Dn model of DS was sufficient to reverse several neuroanatomical AD phenotypes, and
a nonselective small molecule inhibitor of Dyrk1a (CX-4945) was able to reverse
neurodegenerative phenotypes in Dyrk1a-overexpressing mice. These data indicate that Dyrk1a
overexpression is a key factor in the progressive cognitive decline exhibited by DS patients and
is an attractive therapeutic target.
Iluminos Therapeutics, LLC, (Iluminos) co-founders Dr. Travis Dunckley and Dr. Christopher
Hulme have carried out a sustained medicinal chemistry effort (Hulme) and validation strategy
(Dunckley) to develop and validate selective and efficacious Dyrk1a inhibitors. Herein we propose
in Phase I to confirm the efficacy of our lead molecule, Dyr533, in a mouse model of DS. In Phase
II we propose IND enabling studies to advance the commercialization efforts of this therapeutic
approach. Successful completion of these Phases of the proposed STTR will significantly
advance the commercial prospects for Iluminos’ Dyrk1a strategy and may ultimately lead to the
availability of a much needed therapeutic option for DS patients following clinical trials in
subsequent years.

## Key facts

- **NIH application ID:** 10709750
- **Project number:** 4R44NS129400-02
- **Recipient organization:** ILUMINOS THERAPEUTICS, LLC
- **Principal Investigator:** Travis Dunckley
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,496,403
- **Award type:** 4N
- **Project period:** 2022-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709750

## Citation

> US National Institutes of Health, RePORTER application 10709750, Commercialization of Selective Dyrk1a Inhibitors for Down Syndrome (4R44NS129400-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10709750. Licensed CC0.

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