TY - JOUR
T1 - Intrathecal enzyme replacement for Hurler syndrome
T2 - biomarker association with neurocognitive outcomes
AU - Eisengart, Julie B.
AU - Pierpont, Elizabeth I.
AU - Kaizer, Alexander M.
AU - Rudser, Kyle D.
AU - King, Kelly E.
AU - Pasquali, Marzia
AU - Polgreen, Lynda E.
AU - Dickson, Patricia I.
AU - Le, Steven Q.
AU - Miller, Weston P.
AU - Tolar, Jakub
AU - Orchard, Paul J.
AU - Lund, Troy C.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - biomarkers
KW - enzyme replacement therapy
KW - intrathecal therapy
KW - mucopolysaccharidosis
KW - neurocognitive decline
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U2 - 10.1038/s41436-019-0522-1
DO - 10.1038/s41436-019-0522-1
M3 - Article
C2 - 31019279
AN - SCOPUS:85064803728
SN - 1098-3600
VL - 21
SP - 2552
EP - 2560
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -
