Commercialization of Selective Dyrk1a Inhibitors for Down Syndrome
Award last edited on: 3/14/2023

Sponsored Program
Awarding Agency
Total Award Amount
Award Phase
Solicitation Topic Code
Principal Investigator
Travis Dunckley

Company Information

Iluminos Therapeutics LLC

12063 N Red Mountain Drive
Tucson, AZ 85755
   (480) 650-4423

Research Institution

Arizona State University

Phase I

Contract Number: 1R42NS129400-01
Start Date: 9/15/2022    Completed: 8/31/2023
Phase I year
Phase I Amount
Down syndrome (DS) is caused by human chromosome 21 trisomy (hsa21) and is the mostcommon 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 over expression of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which is over expressed on hsa21 in all DS patients. Mousemodels of DS that include Dyrk1a over expression 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 Dyrk1aoverexpression 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.

Public Health Relevance Statement:

Project narrative:
Down syndrome (DS) is the most common genetic form of intellectual and cognitive disability, occurring in ~1 in 700 live births. DS patients also experience age-related progressive cognitive decline, neurodegeneration, and the development of Alzheimer's disease (AD)-like pathology, for which there are no therapeutic options. The chromosome 21 gene, Dyrk1a, is associated with this progressive cognitive decline and AD-like neuropathology and Iluminos Therapeutics' unique small molecule inhibitor, which we propose to test in vivo DS mice and to progress through IND-enabling studies herein, holds significant promise as a first-in-class treatment approach in Down syndrome.

Project Terms:
Alzheimer's Disease, AD dementia, Alzheimer, Alzheimer Type Dementia, Alzheimer disease, Alzheimer sclerosis, Alzheimer syndrome, Alzheimer's, Alzheimer's disease dementia, Alzheimers Dementia, Alzheimers disease, Primary Senile Degenerative Dementia, dementia of the Alzheimer type, primary degenerative dementia, senile dementia of the Alzheimer type, inhibitor, Behavior, Biological Assay, Assay, Bioassay, Biologic Assays, Western Blotting, Immunoblotting, Western Immunoblotting, protein blotting, Brain, Brain Nervous System, Encephalon, Pharmaceutical Chemistry, Medicinal Chemistry, Pharmaceutic Chemistry, Human Chromosomes, Chromosome 21, Clinical Trials, Cognition, Canis familiaris, Canine Species, Dogs, Dogs Mammals, canine, domestic dog, Down Syndrome, Down's Syndrome, Downs Syndrome, Langdon Down syndrome, Mongolism, Trisomy 21, chromosome 21 trisomy syndrome, congenital acromicria syndrome, morbus Down, pseudohypertrophic progressive muscular dystrophy, trisomy 21 syndrome, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Enzyme-Linked Immunosorbent Assay, ELISA, enzyme linked immunoassay, Exhibits, Genes, Hippocampus (Brain), Ammon Horn, Cornu Ammonis, Hippocampus, hippocampal, Immunohistochemistry, Immunohistochemistry Cell/Tissue, Immunohistochemistry Staining Method, In Vitro, Laboratories, Lead, Pb element, heavy metal Pb, heavy metal lead, Learning, Methods, micronucleus, Mus, Mice, Mice Mammals, Murine, Neuron Degeneration, neural degeneration, neurodegeneration, neurodegenerative, neurological degeneration, neuronal degeneration, Nerve Degeneration, Patients, Pharmacology, Protein Phosphorylation, Phosphorylation, Kinases, Phosphotransferase Gene, Transphosphorylases, Phosphotransferases, Blood Plasma, Plasma Serum, Reticuloendothelial System, Serum, Plasma, Plasma, Common Rat Strains, Rat, Rats Mammals, Rattus, Safety, Science, Specificity, Testing, Toxicology, Translating, Tyrosine, Roentgen Rays, X-Radiation, X-Ray Radiation, X-ray, Xray, base, Gene Dosage, Gene Copy Number, improved, Acute, Chronic, Phase, Medical, Link, Therapeutic, Metabolic, Genetic, tool, Rivers, Cognitive Disturbance, Cognitive Impairment, Cognitive decline, Cognitive function abnormal, Disturbance in cognition, cognitive dysfunction, cognitive loss, Impaired cognition, Intellectual disability, Intellectual limitation, intellectual and developmental disability, Intellectual functioning disability, Live Birth, Services, experience, Toxicities, Toxic effect, Structure, cognitive defects, Cognitive deficits, Modeling, neurobehavior, neuropathology, Genetic Toxicology, Toxicology Genetics, Toxicogenetics, preventing, prevent, Age-Years, Data, Motor, in vivo, Cognitive, Small Business Technology Transfer Research, STTR, Validation, Pathologic, Preparation, Development, developmental, disease phenotype, age related, age dependent, tau phosphorylation, post-translational modification of tau, posttranslational modification of tau, tau posttranslational modification, τ phosphorylation, design, designing, mouse Ts65Dn, Ts65Dn, Alzheimer like pathology, Alzheimer's disease like pathology, amyloid pathology, mouse model, murine model, Alzheimer's disease model, AD model, alzheimer model, therapeutic target, neurodegenerative phenotype, 3xTg-AD mouse, 3xTg, 3xTg-AD mice, commercialization, overexpression, overexpress, cognitive disability, small molecule inhibitor, lead optimization

Phase II

Contract Number: ----------
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
Phase II Amount