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 Dr. Ted Han has conducted a genome-wide screen for consequences in gain and loss-of-function of transcription factor EB (TFEB) a master regulator of lysosomal biogenesis and function. Pathways which modulate TFEB activity may represent sites for pharmacologic intervention in multiple lysosomal disorders. By using CRISPR/Cas9 technologies, research fellow Dr. Raluca Nicolai has created a mouse model of GM1 gangliosidosis and with extensive phenotyping has demonstrated that it most closely resembles our Type II GM1 patients. With collaborators from the NIH Mouse Imaging Facility (MIF), she has performed magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and functional MRI on live mice at key timepoints in disease progression; a first for the NIH MIF. 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. In a collaborative project, Drs. Han and Nicoli have performed transcriptome analysis on 4 brain regions from two 17-week gestation fetuses with TSD and age-matched control tissues and found that TSD brains are deficient in many transcripts notably neuronal synapse formation. This aligns with our previous work showing lack of neuronal differentiation in human cerebral organoids derived from iPS cells from a patient with infantile Sandhoff disease. Significant differences in early brain development of GM2 infants will have obvious implications for type and timing of therapy for these patients and may extend to other lysosomal storage disorders involving the brain. Data collected from the natural history study has provided new understanding of disease progression in GM1 and GM2 disease and we have published reviews on both disorders. The natural history study has also elucidated robust outcome measures for two interventional trials currently in progress. 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, Dr. Doug Martin at Auburn University. Under the guidance of primary clinician Dr. Precilla DSouza and research nurse Jean Johnston, twelve patients have safely received the gene transfer. Outcome measures now extend to three years post gene therapy. Additional vector is being prepared and a phase 2/3 pivotal trial is in the planning stages. 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 is the 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 Andrea Ashton, primary clinician Catherine Groden, and neurologist Dr. Camilo Toro oversee the largest cohort of GM2 patients in this multi-national study.