A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design

https://doi.org/10.1016/j.ymgme.2016.08.002Get rights and content

Highlights

  • Robust outcome measures are needed for clinical trials in the mucopolysaccharidoses types 3A and 3B

  • Leiter nonverbal IQ standard scores significantly decline over 6 month intervals in patients less than 7 years old

  • Vineland-II composite scores decline significantly over 6 month intervals.

  • Cognitive and behavioral testing can distinguish declines in patients with MPS over periods relevant to clinical trials

Abstract

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects > 2 years old at three time points over one year (baseline, 6 and 12 months). Fifteen IIIA (9 male, 6 female; age 5.0 ± 1.9 years) and ten IIIB subjects (8 male, 2 female; age 8.6 ± 3 years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3 year old developmental level, and showed a significant age-related decline over a 6 month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8 years of age, but showed significant mean declines over a 6 month interval in those < 7 years old (p = 0.0029) and in those with NVIQ score  45 (p = 0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6 month intervals (p = 0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p < 0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials.

Introduction

Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) is a group of four devastating autosomal recessive genetic diseases due to pathogenic variants in one of four genes encoding enzymes along the pathway responsible for metabolizing the glycosaminoglycan heparan sulfate [1]. Subtypes A, B, C, and D are largely clinically indistinguishable and there is a range of severity observed in each. In all large populations studied the predominant type is either type A or B, with C and D much rarer, and within Europe the estimated incidence of MPS III overall varies from 0.27 to 1.89 per 100,000 live births [2]. MPS IIIA results from deficiency of N-sulfoglucosamine sulfohydrolase, encoded by the SGSH gene [3]; IIIB from deficiency of N-α-acetylglucosaminidase (encoded by NAGLU) [4]; IIIC from deficiency of heparan acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT) [5]; and IIID from deficiency of N-acetylglucosamine-6-sulfatase (GNS) [6]. Each results in the abnormal accumulation of heparan sulfate in multiple tissues and organs [1]. In MPS III the predominant symptoms occur due to accumulation within the CNS, including the brain and spinal cord [7], resulting in neurocognitive decline and eventual death. Children appear normal at birth, with symptoms progressing thereafter through a stereotyped course that may be broadly described as consisting of three phases [8]. Typically, symptoms in the first phase present between age 1 and 4 years and often consist of developmental delay – particularly speech delay – or common behavioral problems. During the second phase, starting around age 3 to 4 years, cognitive and behavioral regression becomes evident, including hyperactive and disinhibited behavior and erratic sleep. It is during this phase that a diagnosis is frequently made, helped by the observations of hepatosplenomegaly, coarsening of facial features, and hirsutism. By early adolescence, most patients progress to a third and final phase of unrelenting neurodegeneration marked by spasticity, wasting, and bulbar dysfunction that leads to death, often in the teens or early twenties.

There is currently no effective treatment for MPS III, but AAV-mediated gene transfer has emerged as a promising strategy to restore enzyme activity to the CNS and affected somatic tissues in mouse models of both MPS IIIA and IIIB [9], [10], [11], [12], [13], [14], [15]. As noted elsewhere [8], a more precise knowledge of the natural history of MPS III is needed in order to interpret results of interventional trials. Particularly lacking from the literature has been prospectively collected individual longitudinal data from patients with MPS III. The purpose of our observational natural history study was to fill this gap by prospectively quantifying the progression of MPS IIIA and MPS IIIB using multiple measures over one year; to identify outcome measures suitable for clinical gene transfer or enzyme replacement studies; and to establish the degree of disease-related biochemical and radiologic abnormalities that might impact the interpretation of safety assessments in such trials.

Section snippets

Materials and methods

A summary of methods is provided below, with additional details in Supplemental data. The study was approved by the Nationwide Children's Hospital (NCH) Institutional Review Board (IRB). Subjects were ascertained from within the patient population in the NCH medical genetics clinic and by letters sent to North American medical genetics clinics and to patient organizations. All subjects met the following inclusion criteria: (1)  2 years of age; (2) confirmed diagnosis of MPS IIIA or MPS IIIB by

Results

Twenty-five subjects were enrolled over a seven month period, including 15 subjects with MPS IIIA and 10 subjects with MPS IIIB. Demographics and DNA sequence analysis results are summarized in Table 1, and the developmental and disease milestones of enrolled subjects are summarized in Supplemental Table 2. The two groups differed in average age at enrollment, which was 5.0 ± 1.9 years in the MPS IIIA cohort (range, 2.1 to 9.2 years) and 8.6 ± 3.0 years in the MPS IIIB cohort (range, 2.3 to 13.7 

Discussion

Effective treatment of MPS III is a challenge, as replacing the missing enzyme in the brain – whether by recombinant enzyme replacement or viral gene transfer – requires delivery to or expression within the brain, which is protected by the blood-brain barrier (BBB) [36], [37]. The laboratories of two of the present authors, however, have developed gene transfer vectors using the adeno-associated virus serotype 9 (AAV9) for delivery of either the SGSH or NAGLU gene, which can efficiently cross

Acknowledgements

The performance of this study was supported by grants from A Cure For Kirby (The Children's Medical Research Foundation), Ben's Dream (The Sanfilippo Research Foundation), A Life For Elisa (The Sanfilippo Children's Research Foundation).This work received support from Ohio State University/NCH Center for Clinical and Translational Science under an NIH Clinical and Translational Science Award (CTSA grant UL1TR001070). KVT received fellowship support from the Cure Sanfilippo Foundation. The

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