Cell replacement therapy in neurological disease

Diseases of the brain and spinal cord represent especially daunting challenges for cell-based strategies of repair, given the multiplicity of cell types within the adult central nervous system, and the precision with which they must interact in both space and time. Nonetheless, a number of diseases are especially appropriate for cell-based therapy, in particular those in which single phenotypes are lost, and in which the re-establishment of vectorially specific connections is not entirely requisite for therapeutic benefit. We review here a set of potential therapeutic indications that meet these criteria as potentially benefiting from the transplantation of neural stem and progenitor cells. These include: (i) transplantation of phenotypically restricted neuronal progenitor cells into diseases of a single neuronal phenotype, such as Parkinson's disease; (ii) implantation of mixed progenitor pools into diseases characterized by the loss of a limited number of discrete phenotypes, such as spinal cord injury and the motor neuronopathies; (iii) transplantation of glial and nominally oligodendrocytic progenitor cells as a means of treating disorders of myelin; and (iv) transplantation of neural stem cells as a means of treating lysosomal storage disorders and other diseases of enzymatic deficiency. Among the diseases potentially approachable by these strategies, the myelin disorders, including the paediatric leucodystrophies as well as adult traumatic and inflammatory demyelinations, may present the most compelling targets for cell-based neurological therapy

Defective Glial Maturation in Vanishing White Matter Disease

Vanishing white matter (VWM) disease is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B. It is a disease of infants, children, and adults who experience a slowly progressive neurologic deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathologic findings include cystic degeneration of the white matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, weinvestigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other white matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot, and quantitative polymerase chain reaction. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM. We also demonstrated a significant increase in numbers of premyelinating oligodendrocyte progenitors in VWM, which may explain the coexistence of oligodendrocytosis and myelin paucity in the patients' white matter. © 2010 by the American Association of Neuropathologists, Inc