Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I.
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SUBMITTER: Dickson PI
PROVIDER: S-EPMC4573094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC4572891 | biostudies-literature
Project description:Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ? 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058-0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. CLINICAL TRIAL REGISTRATION:NCT00741338.
| S-EPMC5238455 | biostudies-literature
Project description:Age-related degeneration of the cervical spinal column is the most common cause of spinal cord lesions. T1 mapping has been shown to indicate the grade and site of spinal cord compression in low grade spinal canal stenosis (SCS). Aim of our study was to further investigate the diagnostic potential of a novel T1 mapping method at 0.75 mm resolution and 4 s acquisition time in 31 patients with various grades of degenerative cervical SCS. T1 mapping was performed in axial sections of the stenosis as well as above and below. Included subjects received standard T2-weighted MRI of the cervical spine (including SCS-grading 0-III), electrophysiological, and clinical examination. We found that patients with cervical SCS showed a significant difference in T1 relaxation times within the stenosis (727 ± 66 ms, mean ± standard deviation) in comparison to non-stenotic segments above (854 ± 104 ms, p < 0.001) and below (893 ± 137 ms, p < 0.001). There was no difference in mean T1 in non-stenotic segments in patients (p = 0.232) or between segments in controls (p = 0.272). Mean difference of the T1 relaxation times was significantly higher in grade III stenosis (234 ± 45) vs. in grade II stenosis (176 ± 45, p = 0.037) vs. in grade I stenosis (90 ± 87 ms, p = 0.010). A higher difference in T1 relaxation time was associated with a central efferent conduction deficit. In conclusion, T1 mapping may be useful as a tool for SCS quantification in all grades of SCS, including high-grade stenosis with myelopathy signal in conventional T2-weighted imaging.
| S-EPMC7662110 | biostudies-literature
Project description:BackgroundIdursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization.ResultsTwo patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication.ConclusionRapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.
| S-EPMC9635105 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy and safety of IV laronidase for MPS I.MethodsA systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs.ResultsThe selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 μg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion.ConclusionsOur findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.
| S-EPMC5578671 | biostudies-literature
Project description:BackgroundDegenerative changes of the cervical spinal column are the most common cause of spinal cord lesions in the elderly. Conventional clinical, electrophysiological and radiological diagnostics of spinal cord compression are often inconsistent.Materials and methodsThe feasibility and diagnostic potential of a novel T1 mapping method at 0.5 mm resolution and 4 s acquisition time was evaluated in 14 patients with degenerative cervical spinal canal stenosis (SCS) and 6 healthy controls. T1 mapping was performed in axial sections of the stenosis as well as above and below. All subjects received standard T2-weighted MRI of the cervical spine (including SCS-grading 0-III), electrophysiological and clinical examinations.ResultsPatients revealed significantly decreased T1 relaxation times of the compressed spinal cord within the SCS (912 ± 53 ms, mean ± standard deviation) in comparison to unaffected segments above (1027 ± 39 ms, p < .001) and below (1056 ± 93 ms, p < .001). There was no difference in mean T1 in unaffected segments in patients (p = .712) or between segments in controls (p = .443). Moreover, T1 values were significantly lower in grade II (881 ± 46 ms, p = .005) than in grade I SCS (954 ± 29 ms). Patients with central conduction deficit tended to have lower T1 values within the SCS than patients without (909 ± 50 ms vs 968 ± 7 ms, p = .069).ConclusionRapid high-resolution T1 mapping is a robust MRI method for quantifying spinal cord compression in patients with cervical SCS. It promises additional diagnostic insights and warrants more extended patient studies.
| S-EPMC6411921 | biostudies-literature
Project description:DesignProspective diagnostic study.ObjectivesAnatomical evaluation and graduation of the severity of spinal stenosis is essential in degenerative cervical spine disease. In clinical practice, this is subjectively categorized on cervical MRI lacking an objective and reliable classification. We implemented a fully-automated quantification of spinal canal compromise through 3D T2-weighted MRI segmentation.SettingMedical Center - University of Freiburg, Germany.MethodsEvaluation of 202 participants receiving 3D T2-weighted MRI of the cervical spine. Segments C2/3 to C6/7 were analyzed for spinal cord and cerebrospinal fluid space volume through a fully-automated segmentation based on a trained deep convolutional neural network. Spinal canal narrowing was characterized by relative values, across sever segments as adapted Maximal Canal Compromise (aMCC), and within the index segment as adapted Spinal Cord Occupation Ratio (aSCOR). Additionally, all segments were subjectively categorized by three observers as "no", "relative" or "absolute" stenosis. Computed scores were applied on the subjective categorization.Results798 (79.0%) segments were subjectively categorized as "no" stenosis, 85 (8.4%) as "relative" stenosis, and 127 (12.6%) as "absolute" stenosis. The calculated scores revealed significant differences between each category (p ≤ 0.001). Youden's Index analysis of ROC curves revealed optimal cut-offs to distinguish between "no" and "relative" stenosis for aMCC = 1.18 and aSCOR = 36.9%, and between "relative" and "absolute" stenosis for aMCC = 1.54 and aSCOR = 49.3%.ConclusionThe presented fully-automated segmentation algorithm provides high diagnostic accuracy and objective classification of cervical spinal stenosis. The calculated cut-offs can be used for convenient radiological quantification of the severity of spinal canal compromise in clinical routine.
| S-EPMC11230899 | biostudies-literature
Project description:Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied α-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre- and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.© 2017 Wiley Periodicals, Inc.
| S-EPMC5367919 | biostudies-literature
Project description:BackgroundFocally increased spinal cord motion at the level of cervical spinal stenosis has been revealed by phase-contrast MRI (PC-MRI).ObjectiveTo investigate spinal cord motion among patients suffering of degenerative cervical myelopathy (DCM) across the entire cervical spine applying automated segmentation and standardized PC-MRI post-processing protocols.MethodsProspective, matched-pair controlled trial on 29 patients with stenosis at C5/C6. MRI-protocol covering all cervical segments: 3D T2-SPACE, prospectively ECG-triggered sagittal PC-MRI. Segmentation by trained 3D hierarchical deep convolutional neural network and data processing were conducted via in-house software pipeline. Parameters per segment: maximum velocity, peak-to-peak (PTP)-amplitude, total displacement, PTP-amplitudeHB (PTP-amplitude per duration of heartbeat), and, for characterization of intraindividual alterations, the PTP-amplitude index between the cervical segments C3/C4-C7/T1 and C2/C3.ResultsSpinal cord motion was increased at C4/C5, C5/C6 and C6/C7 among patients (all parameters, p < 0.001-0.025). The PTP-amplitude index revealed an increase from C3/C4 to C4/C5 (p = 0.002), C4/C5 to C5/C6 (p = 0.037) and a decrease from C5/C6 to C6/C7 and C6/C7 to C7/T1 (p < 0.001, each). This implied an up-building stretch on spinal cord tissue cranial and a mechanical compression caudal of the stenotic level. Furthermore, significant far range effects across the entire cervical spinal cord were observed (e.g. PTP-amplitude C2/C3 vs. C6/C7, p = 0.026) in contrast to controls (p = 1.00).ConclusionThis study revealed the nature and extends of mechanical stress on the entire cervical spinal cord tissue due to focal stenosis. These pathophysiological alterations of spinal cord motion can be expected to be clinically relevant.
| S-EPMC7875814 | biostudies-literature
Project description:Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing α-l-iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4-7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic.
| S-EPMC4429692 | biostudies-literature