A pentasaccharide for monitoring pharmacodynamic response to gene therapy in GM1 gangliosidosisResearch in context
Pamela Kell,
Rohini Sidhu,
Mingxing Qian,
Sonali Mishra,
Elena-Raluca Nicoli,
Precilla D'Souza,
Cynthia J. Tifft,
Amanda L. Gross,
Heather L. Gray-Edwards,
Douglas R. Martin,
Miguel Sena- Esteves,
Dennis J. Dietzen,
Manmilan Singh,
Jingqin Luo,
Jean E. Schaffer,
Daniel S. Ory,
Xuntian Jiang
Affiliations
Pamela Kell
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
Rohini Sidhu
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
Mingxing Qian
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
Sonali Mishra
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
Elena-Raluca Nicoli
Medical Genetics Branch and Office of the Clinical Director, NHGRI, NIH, Bethesda, MD 20892, USA
Precilla D'Souza
Medical Genetics Branch and Office of the Clinical Director, NHGRI, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, 20892, USA
Cynthia J. Tifft
Medical Genetics Branch and Office of the Clinical Director, NHGRI, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, 20892, USA
Amanda L. Gross
Scott-Ritchey Research Center, Auburn University College of Veterinary Medicine, Auburn, AL, 36849, USA
Heather L. Gray-Edwards
Scott-Ritchey Research Center, Auburn University College of Veterinary Medicine, Auburn, AL, 36849, USA
Douglas R. Martin
Scott-Ritchey Research Center, Auburn University College of Veterinary Medicine, Auburn, AL, 36849, USA
Miguel Sena- Esteves
Department of Neurology, Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, 01605, USA
Dennis J. Dietzen
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
Manmilan Singh
Department of Chemistry, Washington University, St. Louis, MO, 63130, USA
Jingqin Luo
Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA
Jean E. Schaffer
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
Daniel S. Ory
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
Xuntian Jiang
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA; Corresponding author.
Summary: Background: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in β-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. Methods: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. Findings: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with β-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. Interpretations: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. Funding: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.
