Pathogenesis Informs Therapy for Glycosphingolipid and Glycoprotein Disorders

National Human Genome Research Institute

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Abstract

The mission of the Glycosphingolipid and Glycoprotein Disorders Unit is to understand the disease progression and molecular pathogenesis of rare disorders in glycosphingolipid and glycoprotein degradation. Understanding these ultra-rare, autosomal recessive, uniformly fatal disorders we believe will provide a window to understanding more common neurodegenerative disorders. The laboratory and clinical programs of the unit are tightly coupled and allow for the generation and testing of new hypotheses and treatments. Postdoctoral fellow, Ted Han and postbaccalaureate fellow Ashley Hirt interrogated gene expression changes in fetal brain development from a family whose child had juvenile onset Tay-Sachs disease. They identified dramatic changes suggesting a more immature brain and perturbation of normal development including a shift in the expression of the sphingolipid pathway away from production of the HEXA substrate, GM2 ganglioside, to compensate for enzyme dysfunction. In addition, as previously reported, there was storage of GM2 ganglioside in tissues as early as 17 week’s gestation highlighting the need to set realistic expectations for patients receiving early therapeutic intervention. In collaboration with the Proia laboratory (GBB/NIDDK), we used ABE base-editing to successfully correct the most common mutation in late-onset Tay-Sachs (LOTS) disease patient fibroblasts and a “humanized” mouse model containing the LOTS mutation. Successful editing in the mouse improved the phenotype and extended the life-span of the mouse from 17 weeks to greater than 1 year paving the way for gene-editing as a therapeutic for LOTS. Similarly, postbaccalaureate fellow Madison Hernandez and staff scientist Hongling Zhu are utilizing base-editing to correct the most common non-Askhenazi mutation in infantile Tay-Sachs disease patients. Our overarching natural history study has enrolled over 100 patients with GM1 and GM2 gangliosidosis (Tay-Sachs (TSD) and Sandhoff diseases (SD)), sialidosis, and galactosialidosis. We maintain and make available to collaborators a large biorepository of blood, urine, cerebrospinal fluid, and primary fibroblasts and, when possible, tissues on deceased patients. NCT03952637 is a first-in-human intravenous AAV9-GLB1 gene therapy for children with Type I and II GM1 gangliosidosis. The study was the culmination of a 10-year collaboration with colleagues Dr. Miguel Sena-Esteves and Dr. Heather Gray-Edwards at U. Massachusetts Medical School, and Dr. Doug Martin at Auburn University. Under the guidance of primary clinician Dr. Precilla D’Souza and research nurse Jean Johnston with postbaccalaureate trainee Anna Crowell fifteen patients have safely received the gene transfer vector. Our major contribution this year was submission of a manuscript now under review describing treatment and 3-year follow-up of 9 Type II GM1 patients. Plans for a Phase II/III study are under discussion with FDA that should begin in 2026. A promising new outcome measure, differential tractography (DT), has been developed by postbaccalaureate fellow Connor Lewis and staff clinician and neurologist Dr. Maria Acosta. Using this technique they have demonstrated gain of white matter tracts in the brains of treated patients and compared them to untreated natural history patients who only show loss of white matter tracts as their disease progresses. DT has also shown positive correlations with clinical outcome metrics in the trial including the Clinical Global Impression Scale and the Vineland-3 Adaptive Behavior Scale. This technique has been extended to study cerebellar dysfunction in patients with late-onset Tay-Sachs and Sandhoff diseases and sialidosis type 1. NCT04221451, the AMETHIST Study, sponsored by Sanofi Genzyme utilizes a proprietary substrate reduction molecule that crosses the blood brain barrier and blocks the first committed step in ganglioside synthesis. Our Unit has been lead site for the trial and furnished the patient data for trial design and outcome measures under cooperative research and data sharing agreements. Research nurse John Yang, primary clinician Catherine Groden, neurologist Dr. Camilo Toro with the help of postbaccalaureate trainee Mark Moran have treated the largest cohort of GM2 patients in this multi-national study that has now been terminated. The manuscript has been accepted for publication and is expected to be released in late 2025.