Assessment of everolimus as a therapy for vici syndrome in a preclinical model

The National Center for Advancing Translational Sciences awarded Children's Mercy Hospital $899,904 on May 1, 2026, under CFDA 93.350 (National Center for Advancing Translational Sciences) to conduct preclinical assessment of everolimus as a therapy for VICI syndrome.

The award funds evaluation of everolimus, an FDA-approved rapalog compound, as a potential treatment for VICI syndrome, a rare pediatric genetic disorder caused by pathogenic variants in the EPG5 gene. VICI syndrome is characterized by profound developmental delay, seizures, immunodeficiency, cardiomyopathy, and progressive motor decline, with median survival of 42 months. The research leverages patient-derived induced pluripotent stem cells and genetically engineered EPG5 mutant mouse models that recapitulate neurological phenotypes including autophagy deficits, progressive motor dysfunction, and neuroinflammatory signatures. The project will define everolimus pharmacokinetics and pharmacodynamics in the VS mouse models through in vivo preclinical proof-of-principle studies.

Performance occurs at Children's Mercy Hospital in Kansas City, Missouri, with a period of performance from May 1, 2026, through April 30, 2028. The project is part of NCATS' mission to accelerate translational science and reduce bottlenecks in delivering new treatments to patients. Children's Mercy operates as a pediatric medical research center with substantial NIH portfolio participation across multiple institutes and centers.

Abstract

Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immunodeficiency, cardiomyopathy, and progressive motor decline, with a median survival of just 42 months, this devastating disorder is caused by pathogenic variants in the EPG5 gene, which encodes a critical regulator in autophagy. Loss of EPG5 function results in the accumulation of toxic intracellular material and progressive cellular dysfunction. VS is a member of a broader class of diseases known as 'congenital disorders of autophagy' (CDAS), in which core components of autophagy are defective. There are essentially no treatment options for children with VS or other CDAS. We hypothesize that agents that induce pharmacological enhancement of autophagy in VS and other CDAS represent a viable therapeutic strategy. In collaboration with VS families, we have developed and characterized critical preclinical models for VS for therapeutic discovery and validation, including patient-derived induced pluripotent stem (IPS) cells and novel genetically engineered mouse models. These EPG5 mutant mice recapitulate a range of neurological phenotypes seen in VS including biochemical deficits in autophagy, progressive motor dysfunction, and a strong molecular and cellular signature indicative of neuroinflammation. In parallel, we have established a novel engineered IPS cell-based platform for high throughput cell-based screens, which has identified rapamycin-related class of compounds (RAPALOGS) as enhancers of autophagy in the VS cells. This project will evaluate the therapeutic potential of the rapalog everolimus, an FDA-approved drug with over 14 years of safety data, including well-described use in pediatric populations, leveraging the VS mouse models for in vivo preclinical proof-of-principle studies. In aim 1, we will define the pharmacokinetics (PK) and pharmacodynamics (PD) of everolimus in the VS mouse model, optimizing dosing regimens to sustain autophagy induction in vivo after extended use. In aim 2, we will assess the ability of everolimus to slow or halt disease progression in vivo using the VS mouse model. Neurological function and inflammatory response in the VS animal model will be monitored during longitudinal treatment with everolimus. Phenotypic monitoring will include whole animal behavioral assays of motor function and molecular and histological biomarkers of neuroinflammation in various CNS tissues. Successful completion of this project will provide critical preclinical data supporting the repurposing of everolimus for clinical proof of concept in VS patients. Our multidisciplinary team, combining expertise in drug discovery, preclinical disease modeling and analysis in mice, clinical treatment of VS patients, and rare disease research, is well-positioned to advance this therapeutic strategy toward clinical translation in partnership with highly engaged VS families.