006 – Neuroinflammation in Metachromatic Leukodystrophy: A missing key factor in treating a lysosomal storage disorder?
Shanice Beerepoot (1, 2) – Stefan Nierkens (2) – Jaap Jan Boelens (2, 3) – Caroline Lindemans (4, 5) – Marianna Bugiani (6) – Nicole I. Wolf (1)
Department of Child Neurology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands (1) – Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands (2) – Department of Pediatrics, Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA (3) – Pediatric Blood and Marrow Transplantation Program, Princess Maxima Center and University Medical Center Utrecht, Utrecht, the Netherlands (4) – Regenerative medicine institute, University Medical Center Utrecht, Utrecht, the Netherlands (5) – Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands (6)
Metachromatic leukodystrophy (MLD) is a fatal demyelinating lysosomal storage disorder caused by arylsulfatase A (ASA) deficiency. Even though multiple treatment strategies have been explored, including enzyme replacement therapy, hematopoietic stem cell transplantation (HCT), and gene therapy (GT), none of them has proven entirely effective in treating MLD patients. Besides, treatment effects differ between the central and peripheral nervous system, with the peripheral demyelination being the most refractory to therapy. The reasons for this are not well understood. One explanation might be that the delivery of ASA to the nervous system is insufficient. Another possible explanation is that demyelination induces neuroinflammation in MLD, and that (accurate) modulation of inflammation on a tissue level, in addition to metabolic correction is necessary to halt the disease. This is supported by the finding that viral vector-mediated hematopoietic stem cell gene therapy (HSC-GT) positively affects MLD symptoms and survival, while just viral vector-mediated (intracerebral) GT does not. Moreover, sulfatide accumulation and demyelination can induce the release of inflammatory cytokines, activate microglia and endoneural macrophages, and recruit lymphocytes from the peripheral circulation into the nervous system. This may even result in systemic inflammation, since several inflammatory cytokines (eg. CCL2, IL-8, and VEGF) are found significantly elevated in both cerebrospinal fluid and plasma of MLD patients when compared to unaffected controls. Although neuroinflammation is known to play a role in progression of other neurodegenerative diseases, its role in MLD physiopathology and response to cellular enzyme replacement treatments such as HCT and GT remain unclear. We present the hypothesis that neuroinflammation in MLD leads to a vicious cycle of demyelination, that may persist to variable extent after HCT and HCS-GT, which explains the differences in disease burden between the central and peripheral nervous system.