Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial.

BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). METHODS: Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). RESULTS: No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. CONCLUSION: Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.

Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.

Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.

Increased concentration of the CSF Tau protein and its phosphorylated form in the late juvenile metachromatic leukodystrophy form: a case report.

Metachromatic leukodystrophy (MLD) is an autosomal recessive, lysosomal storage disease due to deficiency or absence of arylsulfatase A enzyme (ASA) with sulfatide accumulation in the central and peripheral nervous system, kidneys, and gallbladder, leading to many dysfunctions. One of the clinical forms of the disease is a late juvenile MLD. To our best knowledge, this is the first report describing increased Tau/pTau and normal Aß1-42 concentrations in the CSF of the late juvenile MLD patient.

Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters.

We describe the cases of 2 sisters with adult metachromatic leukodystrophy (MLD). Whereas one sister presented with disorganized schizophrenia-like symptoms as the initial manifestation of MLD, the other remained symptom free except for a 4-week period of postpartum depression. In both patients, there was some residual activity of leukocyte arylsulfatase A (1.7% and 5.5% of normal), and a marked increase in urinary sulfatides was present, as measured by tandem mass spectrometry. An arylsulfatase A pseudodeficiency was therefore excluded. The most common mutations of the adult phenotype, Ile-179-Ser and Pro-426-Leu, were not found. In the literature, only 1 case of adult MLD manifesting as disorganized schizophrenia-like symptoms has been described, whereas postpartum depression has been so far unknown as a presenting symptom of MLD.

Detection of donor lymphocytes in the cerebrospinal fluid of a patient with metachromatic leukodystrophy following bone marrow transplantation.

An unrelated donor bone marrow transplant (UD-BMT) was carried out on a 10-year-old patient with metachromatic leukodystrophy (MLD). We collected cerebrospinal fluid (CSF) on day +168 and cultured it with recombinant IL-2 and PHA-P to examine the origin of cells in the CSF. Analysis on variable number of tandem repeat (VNTR) of lymphocytes in the CSF amplified by PCR revealed that lymphocytes in the CSF were of donor origin. These data support that BMT at an early stage may prevent deterioration in MLD. Although the patient developed grade III acute GVHD with rash and diarrhea, we successfully treated acute GVHD using rabbit anti-human thymocyte immunoglobulin (ATG). UD-BMT may be an alternative treatment for patients with MLD in the absence of an HLA matched family donor.

Possible use of CSF glycosphingolipids for the diagnosis and therapeutic monitoring of lysosomal storage diseases.

We used a high-performance liquid chromatography method to measure CSF gangliosides, neutral glycolipids, and sulfatides in patients with lysosomal storage disorders. These measurements could be done on less than 1 milliliter of CSF. In patients with GM1 gangliosidosis, GM1 ganglioside was increased, and in GM2 gangliosidosis patients, GM2 ganglioside was increased in CSF. Sulfatides were variably increased in CSF early in the course of the disease and appeared to be a means of monitoring patients, following bone marrow transplantation. Fabry's disease patients showed an increase in globotriaosylceramide, but Krabbe's disease patients did not demonstrate an increase in galactosylceramide. This study suggests that CSF glycosphingolipid measurements may prove helpful in the diagnosis and monitoring of lysosomal storage diseases.

Metachromatic leukodystrophy: on an atypical case.

We describe an atypical case of juvenile metachromatic leukodystrophy. Motor conduction velocity was still within the normal range 3 years after clinical onset, in contrast to what is commonly found in this disease. Another unusual feature is the normal level of CSF protein. These data are discussed in the light of the sural nerve biopsy findings, which revealed only slight impairment.

Bone-marrow transplantation for metachromatic leucodystrophy.

An 11-month-old boy with late infantile metachromatic leucodystrophy was given a bone-marrow transplant (BMT) from an HLA-identical sister; 6 months later his cerebrospinal fluid leucocytes were exclusively of donor origin. Coupled with the patient's continued developmental progress, as assessed 33 months after the procedure, the findings suggest that BMT may be an effective treatment for some congenital metabolic disorders which affect the central nervous system.

Radioimmunoassay of myelin basic protein in spinal fluid. An index of active demyelination.

With a sensitive radioimmunoassay that can measure as little as 2 ng of basic protein in cerebrospinal fluid we studied 303 patients with a variety of neurologic diseases. Patients with active demyelinating diseases had high levels (17 to 100 ng per milliliter) of basic protein. Moreover, patients with multiple sclerosis in acute exacerbation had these high levels, those with slowly progressive multiple sclerosis had lower levels (6 to 16 ng per milliliter), and those in remission had less than 4 ng per milliliter, comparable to the control population. Thus, the assay appears to be a useful index of active demyelination.