A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II

Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med advance online publication 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.36

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study.

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile

The role of enzyme replacement therapy in severe Hunter syndrome—an expert panel consensus

Intravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been demonstrated to and is not predicted to cross the blood–brain barrier. Nearly all published experience with ERT with idursulfase has therefore been in patients without cognitive impairment (attenuated phenotype). Little formal guidance is available on the issues surrounding ERT in cognitively impaired patients with the severe phenotype. An expert panel was therefore convened to provide guidance on these issues. The clinical experience of the panel with 66 patients suggests that somatic improvements (e.g., reduction in liver volume, increased mobility, and reduction in frequency of respiratory infections) may occur in most severe patients. Cognitive benefits have not been seen. It was agreed that, in general, severe patients are candidates for at least a 6–12-month trial of ERT, excluding patients who are severely neurologically impaired, those in a vegetative state, or those who have a condition that may lead to near-term death. It is imperative that the treating physician discuss the goals of treatment, methods of assessment of response, and criteria for discontinuation of treatment with the family before ERT is initiated. Conclusion: The decision to initiate ERT in severe Hunter syndrome should be made by the physician and parents and must be based on realistic expectations of benefits and risks, with the understanding that ERT may be withdrawn in the absence of demonstrable benefits

Application of LANDSAT data and digital image processing

There are no author-identified significant results in this report

Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice

The presence of the blood-brain barrier (BBB) presents the most critical challenge in therapeutic development for mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological manifestation, because of alpha-N-acetylglucosaminidase (NaGlu) deficiency. Earlier, we showed a global central nervous system (CNS) transduction in mice by mannitol-facilitated entry of intravenous (IV)-delivered recombinant adeno-associated viral serotype 2 (rAAV2) vector. In this study, we optimized the approach and showed that the maximal transduction in the CNS occurred when the rAAV2 vector was IV injected at 8 min after mannitol administration, and was approximately 10-fold more efficient than IV delivery of the vector at 5 or 10 min after mannitol infusion. Using this optimal (8 min) regimen, a single IV infusion of rAAV2-CMV-hNaGlu vector is therapeutically beneficial for treating the CNS disease of MPS IIIB in adult mice, with significantly extended survival, improved behavioral performance, and reduction of brain lysosomal storage pathology. The therapeutic benefit correlated with maximal delivery to the CNS, but not peripheral tissues. This milestone data shows the first effective gene delivery across the BBB to treat CNS disease. The critical timing of vector delivery and mannitol infusion highlights the important contribution of this pretreatment to successful intervention, and the long history of safe use of mannitol in patients bodes well for its application in CNS gene therapy

Plasmatic and urinary glycosaminoglycans characterization in mucopolysaccharidosis II Patient treated with enzyme-replacement therapy with Idursulfase

We report the structural characterization of plasmatic and urinary GAGs in a Patient affected by MPS II (Hunter syndrome) before and during the first ten months of enzyme-replacement therapy (ERT). Plasmatic GAGs before ERT were rich in pathological DS consisting of iduronic acid (IdoA) and composed of ~90% \uf044Di4s and trace amounts of disulfated disaccharides. DS was also characterized as the main (~90%) urinary GAG mainly composed of ~90% \uf044Di4s with minor percentages of monosulfated and disulfated disaccharides, in particular \u394Di2,4dis. After 300 days of ERT, plasmatic DS strongly decreased but ~14% of IdoA-rich \uf044Di4s was still detected. Similarly, urinary galactosaminoglycans were mainly composed of 78% \uf044Di4s, ~11% \uf044Di6s and ~4% \uf044Di0s with the persistence of \u394Di2,4dis (~4%). About 40% of IdoA-formed \uf044Di4s were also calculated thus confirming that pathological DS is still present in excreted urinary GAGs during ERT. By considering the % of IdoA, we observed rather similar kinetics of excretion in fluids from the beginning of the treatment. Immediately after the first enzyme infusion, a large amount of abnormal DS is removed from tissues reaching the blood compartment and eliminated via the urine, and this process lasts for about two weeks. After this, the percentage of IdoA-rich material present in biological fluids remains fairly constant over the following nine months of treatment. To date, these are the first data regarding plasmatic and urinary kinetics directly measured on products released by the activity of the recombinant enzyme Idursulfase, iduronate-2-sulfatase, evaluated using specific and sensitive analytical procedures