RXR Nuclear Receptor Agonists Promote Clearance of Alpha-Synuclein in Cellular Models

Article content

Investigators Present Data Supporting Disease-Modifying Potential of the Io Therapeutics RXR Agonist Compound IRX4204 in Parkinson’s Disease

Article content

SPRING, Texas, Aug. 05, 2026 (GLOBE NEWSWIRE) — Io Therapeutics, Inc., a privately held pharmaceutical company headquartered in Spring, Texas, announced today the presentation of new research demonstrating that IRX4204, the company’s phase II clinical stage highly selective RXR nuclear receptor agonist, promotes degradation of alpha-synuclein protein in human neural cells.

Article content

Article content

Article content

The findings were presented in an oral session titled “Targeting RXR Nuclear Receptor Signaling for Lysosomal Clearance of Alpha-Synuclein: Translational Perspectives and Emerging Pharmacological Applications in Parkinson’s Disease” at the International Retinoids Conference VIII in Niagara Falls, New York. The work was conducted by scientists at the Ann Romney Center for Neurologic Diseases at the Brigham and Women’s Hospital, Mass General Brigham. The presentation was delivered by Arati Tripathi, Ph.D., who led the research efforts with Ulf Dettmer, Ph.D.

Article content

Article content

Parkinson’s disease (PD) is driven by abnormal aggregation, over-accumulation, and toxic effects of alpha-synuclein protein in dopaminergic neurons. Toxicity from accumulated alpha-synuclein leads to neuronal cell death and the progressive clinical manifestations of PD, including tremor, loss of motor and cognitive functions, and ultimately death.

Article content

Dr. Tripathi stated: “Alpha-synuclein is genetically tied to PD and accumulation of αSyn as intraneuronal aggregates in Lewy bodies and neurites is the neuropathological hallmark in PD patients. Strategies aimed at chronically reducing αSyn levels thus represent a rational approach to PD treatment and ultimately prevention. Our work demonstrated that pharmacological modulation of RXR targets alpha-synuclein clearance and counters proteotoxicity. In human cell models and human PD patient-derived induced pluripotent stem cell (iPSC) neurons, RXR agonism actively stimulates the autophagy-lysosome pathway to drive clearance of accumulated alpha-synuclein. This protective response was observed with multiple small-molecule RXR agonists, including bexarotene, an FDA-approved drug for T-cell lymphoma. For further validation, we utilized the experimental clinical-stage RXR agonist IRX4204. Our data show that IRX4204 markedly reduced alpha-synuclein levels in a human cellular model of PD, more potently than bexarotene. We look forward to building upon this promising preliminary observation.”

Article content

Article content

Dr. Dettmer stated: “There are currently no approved drugs proven to slow or reverse progression of PD. Our studies on RXR-mediated alpha-synuclein degradation have important clinical implications. The data demonstrate a druggable pathway for inducing alpha-synuclein clearance from diseased neurons, and provide a mechanistic rationale for continued evaluation of selective RXR agonists such as IRX4204 for treatment of alpha-synuclein-associated pathologies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy.”

Article content

Martin E. Sanders, M.D., Chief Executive Officer of Io Therapeutics, stated: “IRX4204 is a phase II clinical-stage compound invented by Vidyasagar Vuligonda, Ph.D., Chief Science Officer of Io Therapeutics, and Roshantha Chandraratna, Ph.D., co-founder of the company.  IRX4204 is approximately 100-fold more potent as an RXR agonist and far more selectively activates RXR than the earlier-generation RXR agonist bexarotene, which is associated with clinical adverse events linked to its off-target activation of multiple non-RXR nuclear receptors.