BACKGROUND: Children with Hunter syndrome have a high prevalence of nerve compression syndromes given the buildup of glycosaminoglycans in the tendon sheaths and soft tissue structures. These are often comorbid with orthopedic conditions given joint and tendon contractures due to the same pathology. While carpal tunnel syndrome and surgical treatment has been well-reported in this population, the literature on lower extremity nerve compression syndromes and their treatment in Hunter syndrome is sparse.
METHODS: We report the case of a 13-year-old male with a history of Hunter syndrome who presented with toe-walking and tenderness over the peroneal and tarsal tunnel areas. He underwent bilateral common peroneal nerve and tarsal tunnel releases, with findings of severe nerve compression and hypertrophied soft tissue structures demonstrating fibromuscular scarring on pathology. Post-operatively, the patient\'s family reported subjective improvement in lower extremity mobility and plantar flexion.
CONCLUSIONS: In this case, peroneal and tarsal nerve compression were diagnosed clinically and treated effectively with surgical release and postoperative ankle casting. Given the wide differential of common comorbid orthopedic conditions in Hunter syndrome and the lack of validated electrodiagnostic normative values in this population, the history and physical examination and consideration of nerve compression syndromes are tantamount for successful workup and treatment of gait abnormalities in the child with Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.

Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disease caused by pathogenic variants of the iduronate-2-sulfatase gene (IDS) and is characterized by a highly variable disease spectrum. MPS II severity is difficult to predict based on IDS variants alone; while some genotypes are associated with specific phenotypes, the disease course of most genotypes remains unknown. This study aims to refine the genotype-phenotype categorization by combining information from the scientific literature with data from two clinical studies in MPS II.
Genotype, cognitive, and behavioral data from 88 patients in two clinical studies (NCT01822184, NCT02055118) in MPS II were analyzed post hoc in combination with published information on IDS variants from the biomedical literature through a semi-automated multi-stage review process. The Differential Ability Scales, second edition (DAS-II) and the Vineland Adaptive Behavior Scales™, second edition (VABS-II) were used to measure cognitive function and adaptive behavior.
The most common category of IDS variant was missense (47/88, 53.4% of total variants). The mean (standard deviation [SD]) baseline DAS-II General Conceptual Ability (GCA) and VABS-II Adaptive Behavior Composite (ABC) scores were 74.0 (16.4) and 82.6 (14.7), respectively. All identified IDS complete deletions/large rearrangements (n = 7) and large deletions (n = 1) were associated with a published \'severe\' or \'predicted severe\' progressive neuronopathic phenotype, characterized by central nervous system involvement. In categories comprising more than one participant, mean baseline DAS-II GCA scores (SD) were lowest among individuals with complete deletions/large rearrangements 64.0 (9.1, n = 4) and highest among those with splice site variants 83.8 (14.2, n = 4). Mean baseline VABS-II ABC scores (SD) were lowest among patients with unclassifiable variants 79.3 (4.9, n = 3) and highest among those with a splice site variant 87.2 (16.1, n = 5), in variant categories with more than one participant.
Most patients in the studies had an MPS II phenotype categorized as \'severe\' or \'predicted severe\' according to classifications, as reported in the literature. Patients with IDS complete deletion/large rearrangement variants had lower mean DAS-II GCA scores than those with other variants, as well as low VABS-II ABC, confirming an association with the early progressive \'severe\' (neuronopathic) disease. These data provide a starting point to improve the classification of MPS II phenotypes and the characterization of the genotype-phenotype relationship.

Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout (Ids KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDSco) encoding human I2S (hI2S) could cross-correct I2S deficiency in Ids KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S. Brain GAG levels in Ids KO mice were lowered but not normalized; higher doses were required to see improvements in brain histology and neurobehavioral testing. rAAV8-LSP-hIDSco administration in NHPs resulted in sustained hepatic hI2S production and therapeutic hI2S levels in cross-corrected somatic tissues but no hI2S exposure in the central nervous system, perhaps owing to lower levels of liver transduction in NHPs than in mice. Overall, we demonstrate the ability of rAAV8-LSP-hIDSco to cross-correct I2S deficiency in mouse somatic tissues and highlight the importance of showing translatability of gene therapy data from rodents to NHPs, which is critical for supporting translation to clinical development.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously delivered IDS is unable to cross the blood-brain barrier (BBB). Hematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (rabies virus glycoprotein [RVG] and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via hematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared with LV.IDS.ApoEII and LV.IDS in MPS II mice at 6 months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG- and LV.IDS.gh625-treated mice than in LV.IDS.ApoEII- and LV.IDS-treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis, and lysosomal swelling were partially normalized in MPS II mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalized by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared with control tissue from LV.IDS- and LV.IDS.ApoEII-transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPS II and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPS II disease than IDS alone.

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 1012 vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.

The mucopolysaccharidoses (MPS) are a group of recessively inherited conditions caused by deficiency of lysosomal enzymes essential to the catabolism of glycosaminoglycans (GAG). MPS I is caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA), while MPS II is caused by a lack of iduronate-2-sulfatase (IDS). Lack of these enzymes leads to early mortality and morbidity, often including neurological deficits. Enzyme replacement therapy has markedly improved the quality of life for MPS I and MPS II affected individuals but is not effective in addressing neurologic manifestations. For MPS I, hematopoietic stem cell transplant has shown effectiveness in mitigating the progression of neurologic disease when carried out in early in life, but neurologic function is not restored in patients transplanted later in life. For both MPS I and II, gene therapy has been shown to prevent neurologic deficits in affected mice when administered early, but the effectiveness of treatment after the onset of neurologic disease manifestations has not been characterized. To test if neurocognitive function can be recovered in older animals, human IDUA or IDS-encoding AAV9 vector was administered by intracerebroventricular injection into MPS I and MPS II mice, respectively, after the development of neurologic deficit. Vector sequences were distributed throughout the brains of treated animals, associated with high levels of enzyme activity and normalized GAG storage. Two months after vector infusion, treated mice exhibited spatial navigation and learning skills that were normalized, that is, indistinguishable from those of normal unaffected mice, and significantly improved compared to untreated, affected animals. We conclude that cognitive function was restored by AAV9-mediated, central nervous system (CNS)-directed gene transfer in the murine models of MPS I and MPS II, suggesting that gene transfer may result in neurodevelopment improvements in severe MPS I and MPS II when carried out after the onset of cognitive decline.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Accumulation of glycosaminoglycans results in multisystemic disease manifestations, which may include central nervous system involvement and cognitive impairment (CI). Patients with MPS II experience a high disease burden, leading to extensive healthcare resource utilization (HRU) and reduced quality of life. Objectives: This study aimed to assess the impact of timing of enzyme replacement therapy (ERT) initiation and CI status on the clinical characteristics and HRU of patients with MPS II. Methods: A retrospective medical chart review of 140 male patients who received a diagnosis of MPS II between 1997 and 2017 was performed at 19 US sites; data on disease manifestations and HRU stratified by age at ERT initiation or CI status were analyzed for the full study population and a subgroup of patients who received a diagnosis of MPS II before the age of 6 years. Results: In patients initiating ERT before 3 years of age, there was a trend toward lower symptom burden and HRU compared with patients who initiated ERT at an older age. Evaluation of developmental and behavioral signs and symptoms in the full study population showed that communication delay (70.0% of patients), cognitive delay (62.1%), behavioral problems (52.9%), and toileting delay (50.0%) were particularly common; earliest documented signs and symptoms were motor delay (median [range] age at first documentation: 4.2 [0.9-18.7] years) and behavioral problems (4.4 [0.6-13.7] years). Patients with CI generally experienced greater symptom burden and higher HRU than those without CI, with the most notable differences documented for communication and toileting delays. Formal cognitive testing was documented in <30% of cognitively impaired patients diagnosed with MPS II before the age of 6 years. Conclusions: Our findings reinforce previous recommendations for ERT to be initiated early to maximally benefit patients with MPS II, especially those younger than 3 years old. Cognitively impaired patients experience a particularly high disease burden and HRU. Patient care could be improved with early cognitive assessments and the development of treatments that address cognitive decline.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.