Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I.

Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.

Research challenges in central nervous system manifestations of inborn errors of metabolism.

The Research Challenges in CNS Manifestations of Inborn Errors of Metabolism workshop was designed to address challenges in translating potential therapies for these rare disorders, and to highlight novel therapeutic strategies and innovative approaches to CNS delivery, assessment of effects and directions for the future in the treatment of these diseases. Therapies for the brain in inborn errors represent some of the greatest challenges to translational research due to the special properties of the brain, and of inborn errors themselves. This review covers the proceedings of this workshop as submitted by participants. Scientific, ethical and regulatory issues are discussed, along with ways to measure outcomes and the conduct of clinical trials. Participants included regulatory and funding agencies, clinicians, scientists, industry and advocacy groups.

Novel treatments and future perspectives: outcomes of intrathecal drug delivery.

Intrathecal enzyme replacement therapy (ERT) holds promise as a treatment for the central nervous system manifestations of lysosomal storage diseases. Treatment via the cerebrospinal fluid represents a potential method of delivering recombinant enzyme across the blood-brain barrier. Experiments in animal models of mucopolysaccharidosis (MPS) Type I, MPS II and MPS IIIA have shown that ERT delivered via the intrathecal route distributes throughout the central nervous system and penetrates brain tissue, where it promotes clearance of lysosomal storage material. Studies are underway to investigate the safety and efficacy of intrathecal ERT in patients with MPS I.

Continuous infusion of enzyme replacement therapy is inferior to weekly infusions in MPS I dogs.

Intravenous enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) is used weekly to treat mucopolysaccharidosis (MPS) I. We tested continuous administration of rhIDU at two dosing levels (0.58 mg/kg per week and 2 mg/kg per week) in MPS I dogs, and compared the efficacy of continuous infusion with the clinically used 0.58 mg/kg weekly three-hour infusion. Peak plasma concentrations of rhIDU were much higher in weekly-treated dogs (mean 256 units/ml) than steady-state concentrations in dogs treated with continuous infusion (mean 1.97 units/ml at 0.58 mg/kg per week; 8.44 units/ml at 2 mg/kg per week). Dogs receiving continuous IV rhIDU, even at a higher (2 mg/kg per week) dose, had consistently lower iduronidase levels in tissues than dogs receiving a weekly (0.58 mg/kg per week) dose. GAG storage was also less improved by continuous intravenous infusion. Adverse events were similar in all dosing groups. We found that continuous administration of 2 mg/kg per week rhIDU to MPS I dogs was insufficient to achieve GAG storage reduction comparable to 0.58 mg/kg weekly dosing.

Penetration, diffusion, and uptake of recombinant human alpha-L-iduronidase after intraventricular injection into the rat brain.

Central nervous system disease can have devastating consequences in the severe or Hurler form of mucopolysaccharisosis I (MPS I). Intravenously administered recombinant human alpha-L-iduronidase (rhIDU) is not expected to reach and treat the brain disease due to the blood-brain barrier. To determine whether administration of rhIDU into the cerebrospinal fluid could successfully treat the brain, we studied intraventricular administration of rhIDU in rats. RhIDU was stereotactically administered directly to the lateral ventricle of the intact rat brain and the brain tissues assessed by enzyme assays, immunofluorescence and confocal microscopy 30 min, 24 h, or 7 days later. Quantitation of activity revealed that rhIDU was widely distributed throughout the brain following injection into the lateral ventricle, with activities increased by a factor of 3.3 higher than control in most samples 30 min-24 h after injection and highest levels on the side of injection. The enzyme crossed the ependymal lining of the ventricle and entered neurons into lysosomal-like vesicles. The enzyme was able to diffuse through brain tissue as demonstrated by a decreasing signal gradient from 0.2 to 4.8 mm from the ventricle surface. The largest amount of rhIDU, as detected by immunostaining, was observed 24 h after injection and decreased approximately 50% during the first 7 days. Although the immunostaining decreased with time, specific vesicular staining was still detectable 28 days after injection. The data suggest that rhIDU given into the ventricle can diffuse, penetrate at least several millimeters of brain tissue and be taken up into neurons and glial cells.