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Clinical Trial
. 2015 Sep-Oct;116(1-2):69-74.
doi: 10.1016/j.ymgme.2015.07.005. Epub 2015 Jul 26.

Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I

Patricia I Dickson  1 , Ilkka Kaitila  2 , Paul Harmatz  3 , Anton Mlikotic  4 , Agnes H Chen  5 , Alla Victoroff  6 , Merry B Passage  6 , Jacqueline Madden  3 , Steven Q Le  6 , David E Naylor  7 ; Mucopolysaccharidosis I Intrathecal Research Collaborative
Affiliations
Clinical Trial

Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I

Patricia I Dickson et al. Mol Genet Metab. 2015 Sep-Oct.

Abstract

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.

Keywords: Alpha-l-iduronidase; Enzyme replacement therapy; Hurler; Intrathecal; Lysosomal storage disease; Scheie.

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Figures

Fig. 1
Fig. 1
Efficacy outcomes in study subjects. (A) JOA score for the lower extremity. Intrasubject change (mean ± SD) during the 4-month pilot study was 0.83 ± 1.04, 95% CI (−1.75; 3.42), n = 3. (B) Functional independence measure in the subjects, which is a patient-reported measure of ability to perform activities of daily living. Intrasubject change (mean ± SD) during the 4-month pilot study was 1.33 ± 3.22, 95% CI (−6.65; 9.32), n = 3. (C) Six-minute walk test results. Subject 1 was nonambulatory and did not perform a six-minute walk test. Intrasubject change (mean ± SD) during the 4-month pilot study was 26.4 ± 56.0, 95% CI (−477; 530), n = 2. (D) CSF GAG measurements, which were taken immediately pre-dose at each dosing visit. Intrasubject change (mean ± SD) during the 4-month pilot study was 4.13 ± 3.16, 95% CI (−3.73; 12.0), n = 3. JOA: Japanese Orthopedic Association; CSF: cerebrospinal fluid; GAG: glycosaminoglycans; SD: standard deviation, CI: confidence interval.
Fig. 2
Fig. 2
Spinal cord compression in subject 2 (final imaging study). Sagittal T2-weighted MR image of the cervical and thoracic spine. There is absence of the expected cerebrospinal fluid signal around the cervical cord (arrow) and a hyperintense region (“signal change”) within the cervical cord (arrowhead). T1 weighted axial image illustrating anterior and posterior spinal cord flattening (inset). SC: spinal cord.
See this image and copyright information in PMC

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