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Intrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood‐brain barrier (BBB) which limits treatment effects of intravenously applied α‐L‐iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre‐ and post‐treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient. © 2017 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied a-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre-and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.

INTRODUCTION
Mucopolysaccharidosis I (MPS I) is a rare genetic condition caused by the deficiency of the a-L-iduronidase enzyme, which results in storage of glycosaminoglycans (GAGs) [Muenzer et al., 2009]. While MPS severely affects brain structure, symptoms range from the most severe (Hurler syndrome) to the attenuated (Hurler-Scheie and Scheie) forms [Muenzer et al., 2009]. Untreated Hurler patients exhibit cognitive decline and morphological brain abnormalities, while neuropsychological deficits in attenuated forms are variable . For severe patients, hematopoietic stem cell transplantation (HSCT) is the current standard of care that stabilizes cognitive functions [Peters et al., 1996]. In attenuated forms, enzyme replacement therapy (ERT) utilizing recombinant human a-L-iduronidase (rhIDU), improves somatic symptoms and quality of life [Kakkis et al., 2001]. ERT administered intravenously cannot penetrate the intact blood-brain barrier, thereby limiting the potential benefits on brain structure and function [Kakkis et al., 2001]. However, intrathecal (IT) administration of the enzyme directly into the spinal canal improved lysosomal storage and neuropathology in canine models [Dickson and Chen, 2011;Vite et al., 2013]. The objective of this study was to determine whether IT administration of rhIDU in a Hurler-Scheie patient with progressive cognitive decline could stabilize or reverse the cognitive deficits and impact structural brain defects.

MATERIALS AND METHODS Human Subjects
A 23-year old male Hurler-Scheie patient with mild A327P/G265R; missense/missense mutation, who had a measurable cognitive decline and progressive impairment in ability to perform in school over 18 months was enrolled on an Institutional Review Board (IRB), approved at University of Texas Southwestern Medical Center. He had been treated with intravenous rhIDU for 13 years before IT rhIDU and had not undergone HSCT. The patient was enrolled concurrently in an IRB approved non-interventional longitudinal study of brain structure and function in MPS (NCT01870375) at the University of Minnesota.

Treatment and Clinical Evaluation
The patient was treated with 3 cc of rhIDU (approximately 1.74 mg) diluted with 6 cc of Elliotts B 1 artificial cerebrospinal fluid (CSF) solution, for a total IT injection of 9 cc via a fluoroscopy-guided lumbar puncture on day 0, after baseline assessments and repeated monthly for 3 months and every 3 months, thereafter for a total of 24 months. The brain magnetic resonance imaging (MRI) acquired on 3T Siemens Trio was analyzed for volumetric data using T1-weighted images and for white matter (WM) integrity using diffusion tensor imaging (DTI) [Alexander et al., 2007] (for details see supplement).
Neuropsychological testing and MRIs were performed twice prior to the IT administration (baseline, at 1 year) and at 2nd and 3rd years after initiating IT rhIDU. Neurocognitive deficit was quantified as a score of one standard deviation (SD), below the mean on at least one domain of neuropsychological function. The difference between pre-and post-treatment means was evaluated as a percentage of the change. Neuropsychological battery included tests of intelligence, attention, adaptive skills, and visual and verbal memory. All psychological scores are reported as standard scores, with a mean of 100 and a standard deviation of 15 from published normative data. Details of the tests can be found in Table I. Monitoring of adverse events (AEs), CSF laboratory, and clinical evaluations assessed the safety of IT rhIDU [Felice et al., 2011].

Magnetic Resonance Imaging
Brain MRI revealed an increase in the mean WM and corpus callosum (CC) volumes post-IT rhIDU ( Table I). The mean gray matter (GM) volume and the mean left and right hippocampal volumes decreased after IT treatment. Fractional anisotropy (FA) and axial diffusivity (AD) in whole brain WM increased, whereas mean diffusivity (MD) and radial diffusivity (RD) decreased.

Neurocognitive Tests
At baseline, the patient demonstrated significant visual and verbal encoding memory deficits, and a lower than average score on the measure of adaptive behavior. All other tests were in the average range.
The mean IQ scores improved in all subtests. Attention scores increased in impulsivity and variability, and decreased in vigilance and reaction time post-IT rhIDU.
Visual memory increased in both total and delayed recall scores. Importantly, mean verbal memory scores significantly increased for encoding (total number of words recalled after each of three presentations of a list of words) and for delayed recall score (number of words recalled after a delay of 20 min) post-IT rhIDU. The Logical Memory measure (repetition of verbal material in a context) improved and the mean adaptive scores increased in the domains of Socialization, Communication, and Daily Living Skills as well as on the Composite score. Consequently, the patient has marked improvement in ability to read, remember, and perform tasks in school.

Safety Measures
The patient tolerated IT application with minimal adverse events. Occasional mild headache, moderate lumbar stiffness, and one spinal headache spontaneously resolved without intervention within 24 hr.

DISCUSSION
A 23-year-old male with Hurler-Scheie syndrome, showed stable or improved neurocognitive outcomes after 24 months of IT rhIDU, while experiencing no serious adverse events. The patient showed the greatest improvement in his ability to encode verbal stimuli, moving from significantly impaired to the average level. This was accompanied by a significant improvement in adaptive behavior and an improvement to an above average level, in his ability to remember verbal material in a context. Nonverbal memory, both encoding and recall increased although those scores remained below the average range. A baseline of average IQ and attention performance also somewhat improved.
In line with meta-analysis outcomes, hippocampal volume decreases may parallel the improvement in learning and memory [Van Petten, 2004] and may reflect aging [Tisserand et al., 2000] together with a reduction in GAGs storage. Indeed, canine MPS models proved that IT rhIDU normalizes hippocampal GAGs levels [Dierenfeld et al., 2010]. The increase of CC volume aligns with the effects of IT rhIDU in MPS I dogs [Vite et al., 2013]. IT-ERT treatment may facilitate typical brain volumetric changes in early adulthood [Good et al., 2001] since, it leads to almost 10 times higher effects compared to 0.39% average decrease of hippocampal and GM volume and 0.23% increase in WM volume per year in healthy individuals younger than 34 years [Liu et al., 2003]. Similarly to attenuated MPS II  an improvement of WM and CC volume may be related to improved attention. Lower RD values suggest a more intact myelin sheath, accompanied by improved axonal integrity measured as higher AD [Alexander et al., 2007] post-IT. Lower MD and higher FA mirrored these changes. DTI measures in healthy individuals follow a curvilinear longitudinal pattern during lifespan with a relative plateau in early adulthood, although frontal cognitive connections (e.g., cingulum bundle, uncinate fascicle) are continuously maturating around 25 years of age [Yap et al., 2013]. Hence, DTI outcomes indicate an overall improvement of WM integrity and/or continuation of development in frontal fiber bundles post-IT rhIDU.

CONCLUSION
In this single case study of an attenuated MPS I patient, IT rhIDU was associated with improvements or maintenance in memory, attention, and learning functions. The related changes in brain microstructure suggest that IT rhIDU may have a significant impact on neurocognitive function in patients, who have progressive neurocognitive decline resulting from lack of CNS penetration after intravenous administration.

ACKNOWLEDGMENTS
Funding for this study was provided by The Ryan Foundation (a private MPS I family charitable organization), BioMarin Pharmaceutical, Inc., and the Lysosomal Disease Network. The Lysosomal Disease Network (U54NS065768) is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), the National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was received from National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 and by the project "CEITEC 2020 (LQ1601)" from the Ministry of Education, Youth and Sports of the Czech Republic (to AS).