The research laboratory has focused on understanding the disease process and developing treatments for MLD. Cultured fibroblast cell lines from patients with MLD and the mouse model of MLD have been extensively studied. Successes with both the cell lines and the mouse model have informed experiments designed to accumulate further preclinical safety data using larger animals.
In human MLD, mutations in the ARSA gene cause dysfunction of the enzyme arylsulfatase A (ARSA) and the lipid sulfatide accumulates in the central nervous system causing progressive neurodegeneration. The mouse model of MLD also accumulates sulfatide in the brain especially the cerebellum.
The blood brain barrier, present in all of us and the MLD mouse, protects the brain but is a major impediment to treating MLD and other lysosomal storage diseases with a neurological component. We have developed a strategy to treat the MLD mouse using adult mice with a mature blood brain barrier. This mimics the clinical situation where almost all patients with MLD are diagnosed at an age when the blood brain barrier is formed.
The therapy is to surgically access the lateral ventricle of the brain. The lateral ventricle is filled with cerebral spinal fluid (CSF) and contains the choroid plexus that produces the CSF. The measure of success for the treatment is the reduction of the concentration of sulfatide in the cerebellar region of the brain to levels seen in wild type mice.
The treatment is gene therapy using a lentivirus – based gene therapy vector (LV-hARSA) that contains DNA that codes for a functional ARSA. Surgical delivery of LV-hARSA vector into the lateral ventricle of adult MLD mice results in the widespread transduction of ependymal cells
throughout the CNS and stable expression for months. Ependymal cells line the CSF containing compartments in the brain. A single dose of LV-hARSA delivered into the lateral ventricle of adult MLD mice reduces cerebellar sulfatide concentrations by 18% to the same level as seen in
wild type mice. More than 100 mice and rats have been treated and tolerated both the surgical procedure and LV-hARSA without adverse events.
Looking Forward: Ongoing research is defining the minimal effective dosage and identifying the regions in the DNA in the transduced brain cells that contain the introduced ARSA gene.
Further research uses large brained animals that more closely approximate the human brain in size and structure for continued safety and pharmacokinetic studies. With the continued support of the Bethanys Hope Foundation – and favourable results in these studies – the objective is to move towards a clinical trial application to Health Canada.