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.


a b s t r a c t
Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4month 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. &

Value of the data
There are very few clinical data reports of cervical spinal stenosis due to mucopolysaccharidosis type I, or attempts at treatment.
Quantitative as well as qualitative data are presented. The data may inform future studies of intrathecal enzyme replacement therapy for lysosomal storage disorders.

Subjects
Study subjects are narratively described in data file 1. They were treated with intrathecal laronidase as described in Ref. [1].

Measures of safety
To evaluate possible adverse effects of study treatments, participants had physical and neurologic examination before and after each study treatment. All new physical complaints were evaluated and recorded including their severity and attribution to study treatments. Table 1 lists nonserious adverse events.

Objective measures of efficacy
Response to treatment was assessed using a combination of subjective and objective measures. We evaluated somatosensory evoked potentials in the upper and lower extremity as per [2]. Results are shown in Table 2. MRI of brain and spinal cord were obtained to assess degree of cord compression and measurement of meningeal thickness was taken. MRI were performed using a 1.5-Tesla GE LX9.1. Brain imaging included sagittal T1-weighted, axial FLAIR, axial T2-weighted and axial diffusion-weighted images. Sagittal T1-and T2-weighted images of the whole spine and axial T1-weighted images of the cervical spine were obtained. Axial T1-weighted studies of the cervical spine were used to score spinal cord compression according to the methods of Houten and Cooper [3]. Brain images were evaluated for  a N9-N13B was present at baseline in subject 1 at a latency of 3.30 ms but absent at the Day 120 visit. N13A-N20 was present in subject 5 at the Day 120 visit at a latency of 10.8 ms but absent at baseline. Subject 2 did not have baseline measurements (the subject was not enrolled in the pilot study). Subject 4 did not have day 120 measurements (termination of participation due to subject death). Table 3 MRI cervical spinal cord compression (maximum grade).

4-Month pilot study 12-Month extension study
Subject number Baseline End of study Baseline Six months End of study Grading system: 0, 3601 cushion of CSF around cord; 1, loss of CSF cushion w/o indentation of the cord but may have slight anterior cord flattening; 2, mild spinal cord compression; and 3, severe cord compression. Table 4 Brain MRI abnormal T2 signal intensity.

4-Month pilot study 12-Month extension study
Subject number Baseline End of Study Baseline Six months End of study Grading system: score signal changes on T2-weighted images as 0, absent; 1, patchy and confined to the periventricular area; 2, patchy but in other white matter areas as well as periventricular; and 3, diffuse. Table 5 Brain MRI enlargement of perivascular spaces.

4-Month pilot study 12-Month extension study
Subject number Baseline End of study Baseline Six months End of study Grading system: 0, no enlargement; 1, o3 mm enlargement; 2, between 3 and 8 mm enlargement; and 3, 48 mm enlargement. abnormal signal intensity in T2, enlargement of perivascular spaces, and ventricular size as per Matheus et al. [4]. Results are shown in Tables 3-7. Subjects enrolled in the extension study also underwent pulmonary function testing using spirometry (Fig. 1). Cerebrospinal fluid glycosaminoglycans were measured at Seattle Children's Hospital using a clinically-available test (Fig. 2). The laboratory uses a dimethylene blue dye-binding assay to quantitate total glycosaminoglycans [5]. Functional Independence Measure (FIM) score and Japanese Orthopedic Association (JOA) score measures were used to assess any changes in functional status and myelopathy. Results are shown in Fig. 1 of Ref. [1]. Scoring criteria for JOA and FIM are given in data files 2 and 3. The grading systems that were used to indicate the severity of spinal cord compression and brain imaging findings are given in data file 4. Fig. 2. CSF opening pressure. We measured opening pressure prior to each dose of intrathecal laronidase by manometry at the level of the right atrium. We did not obtain opening pressure measurements at Days 0 and 30 for subject 1 due to technical issues performing the lumbar puncture during those visits. Subjects 2-4 had a history of hydrocephalus and implanted CSF drainage shunts.