TUCSON, Ariz., April 28, 2026 — The Critical Path Institute® (C-Path), a globally recognized nonprofit organization championing accelerated drug development, has awarded a pivotal grant totaling $456,000 to Dr. James Shayman at the University of Michigan. This significant funding is dedicated to advancing therapeutic research aimed at developing a brain-penetrant inhibitor targeting glycosphingolipid storage disorders, a category of devastating lysosomal storage diseases. The grant is part of C-Path’s Bridging Research and Innovation in Drug Development Grants (BRIDGe) program, which seeks to propel promising translational science from bench to bedside.
The funded initiative, formally titled “CNS penetrant inhibition of glucosylceramide synthase for the treatment of Gaucher disease and GM1 gangliosidosis,” zeroes in on addressing the neurological manifestations that remain intractable under current treatment modalities. Despite progress in therapies for peripheral symptoms, neuronopathic lysosomal storage disorders such as Gaucher disease type 3, GM1 gangliosidosis, Tay-Sachs, and Sandhoff disease largely elude treatment due to the impermeability of the blood-brain barrier (BBB) to existing drugs. This therapeutic development aspires to breach that barrier and deliver effective intervention within the central nervous system (CNS).
Dr. Shayman is renowned for inventing eliglustat tartrate, the first orally administered glucosylceramide synthase inhibitor approved worldwide for treating Gaucher disease type 1. Eliglustat functions by mitigating the pathological accumulation of glucosylceramide, a glycosphingolipid whose buildup initiates multi-organ damage in affected patients. However, the compound’s failure to cross the BBB renders it ineffective for neuronopathic forms of the disease, which affect the CNS and cause severe neurological decline.
Building upon decades of fundamental research in glycosphingolipid metabolism, Dr. Shayman teamed up with medicinal chemist Dr. Scott Larsen, also of the University of Michigan, to engineer a new generation of glucosylceramide synthase inhibitors capable of crossing the BBB. This collaboration yielded BPN-25271, a promising CNS-penetrant candidate compound that retains the pharmacodynamic attributes of eliglustat while adding brain accessibility. Early preclinical results have provided encouraging signals of therapeutic potential for this small molecule.
The C-Path BRIDGe grant will facilitate comprehensive preclinical evaluation of BPN-25271. Critical activities will include toxicology, pharmacokinetics, dose-ranging studies, and manufacturing optimization. These studies are prerequisites to submitting an Investigational New Drug (IND) application that would enable first-in-human clinical trials. The ultimate goal is to produce an effective disease-modifying therapy that halts or reverses neurological deterioration in patients afflicted with neuronopathic lysosomal storage disorders.
Dr. Shayman expressed the transformative potential of this research endeavor, emphasizing that “this funding enables us to take fundamental strides toward a therapy capable of addressing the unmet clinical needs of the CNS involvement in lysosomal storage diseases, conditions where currently clinicians can offer little beyond symptomatic care.” He highlighted that BPN-25271 represents an evolution built on the solid scientific framework established by prior discoveries in glucosylceramide biology.
The grant underscores the vital role of interdisciplinary collaboration and innovation in confronting rare, complex neurodegenerative diseases. Through initiatives like the BRIDGe program, C-Path advances translational research by strategically supporting early-stage projects with high potential to move rapidly toward clinical viability. Maaike Everts, Ph.D., Executive Director of C-Path’s Translational Therapeutics Accelerator, remarked that “this project embodies the exact kind of scientific rigor and translational promise that we aim to foster — combining molecular insights with medicinal chemistry to create novel therapeutic strategies capable of making a real difference for patients.”
Lysosomal storage disorders, particularly those with CNS involvement, represent a profound therapeutic challenge in rare disease medicine. These diseases result from enzyme deficiencies leading to substrate accumulation within lysosomes, disrupting cellular function especially in neural tissue. As traditional enzyme replacement therapies and substrate reduction therapies often do not reach the brain, novel approaches like brain-penetrant small molecule inhibitors are highly sought after.
This research initiative leverages contemporary advances in medicinal chemistry to optimize molecular features for enhanced blood-brain barrier permeability while preserving selectivity and potency against glucosylceramide synthase. Achieving this delicate balance is essential to maximizing CNS bioavailability without compromising safety or efficacy. Early-stage pharmacology data for BPN-25271 indicate promising pharmacokinetics and bio-distribution profiles supportive of this approach.
The support from C-Path not only accelerates drug development but also strengthens the global scientific network focused on rare neurodegenerative diseases. By connecting academic researchers, regulatory experts, and patient advocates, the institute creates a robust ecosystem that converts foundational science into tangible therapeutic options. This grant thus represents both a financial investment and a vote of confidence in the translational potential of BPN-25271.
If successful, this therapy would mark a watershed moment in treating neuronopathic forms of Gaucher disease and GM1 gangliosidosis, offering patients a much-needed option to slow or halt the progression of neurological symptoms. It may also set a precedent for treating other neurodegenerative lysosomal storage disorders characterized by glycolipid accumulation, thereby broadening the impact of this breakthrough approach.
In summary, the Critical Path Institute’s $456,000 grant to Dr. Shayman and colleagues is catalyzing the development of a next-generation CNS-penetrant glucosylceramide synthase inhibitor. This targeted approach seeks to overcome the formidable blood-brain barrier and tackle neurological disease manifestations that have, until now, been largely untreatable. The upcoming preclinical studies supported by this funding mark an important juncture on the path toward clinical translation and therapeutic innovation for patients suffering from devastating neuronopathic lysosomal storage disorders worldwide.
Subject of Research: Development of CNS-penetrant glucosylceramide synthase inhibitors for neuronopathic lysosomal storage disorders.
Article Title: Breakthrough Grant Spurs Development of Brain-Penetrant Therapy for Neuronopathic Lysosomal Storage Diseases
News Publication Date: April 28, 2026
Web References: https://c-path.org
Keywords: Lysosomal storage disorders, Gaucher disease type 3, GM1 gangliosidosis, glucosylceramide synthase, blood-brain barrier, CNS penetrant therapy, small molecule inhibitors, medicinal chemistry, rare neurodegenerative diseases, Critical Path Institute, enzyme inhibition, translational therapeutics
Tags: blood-brain barrier drug deliverybrain-penetrant inhibitor developmentBridging Research and Innovation in Drug Development GrantsCNS-targeted rare disease therapiesCritical Path Institute granteliglustat tartrate innovationglucosylceramide synthase inhibitionglycosphingolipid storage disorders therapyGM1 gangliosidosis drug developmentlysosomal storage diseases researchneuronopathic Gaucher disease treatmenttranslational science in drug development
