Purpose: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. Methods: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. Results: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. Conclusion: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
Bibliographical noteFunding Information:
J.B.E. received honoraria, consulting fees, and/or research support from ArmaGen, Gene Spotlight, Inc., Sangamo, and Sanofi Genzyme, and has done contract work for Shapiro Neuropsychology Consulting LLC. K.E.K. is a consultant for Shire Plc; has received research support from Shire, Sanofi Genzyme, and Alexion Pharmaceuticals, Inc.; and has done previous contract work for Shapiro Neuropsychology Consulting. M.P. is a consultant for Moderna Tx, Inc. and BioMarin Pharmaceuticals, Inc. and has received travel support from BioMarin Pharmaceuticals, Inc. L.E.P. has received honoraria, consulting fees, and/or research support from Sanofi Genzyme, Shire, and BioMarin. P.I.D. receives research support from Biomarin and Genzyme. W.P.M. is an employee of Sangamo Therapeutics, Inc.. P.J.O. has received honoraria, consulting fees, and/or research support from Sanofi Genzyme, Bluebird Bio, and Horizon. T.C.L. has received speaker fees and research support from Sanofi Genzyme. The other authors declare no conflicts of interest.
We are indebted to the patients who enabled this research. We thank Elsa Shapiro for neuropsychological supervision and consultation. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and the National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Translational research support and statistical consultation and analysis was provided by National Institutes of Health (NIH) UL1TR002494. Clinical trial support and drug was provided by Sanofi Genzyme Corporation, who played no role in data analysis, interpretation, manuscript preparation, or submission. Cytokine testing was supported by the Children's Cancer Research Fund. J.B.E., K.D.R., and K.E.K. were supported in part by NIH U54NS065768. A.M.K. and K.D.R. were supported in part by NIH UL1TR002494.
© 2019, The Author(s).
- enzyme replacement therapy
- intrathecal therapy
- neurocognitive decline