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