Glial progenitor cell-based treatment of the childhood leukodystrophies

Abstract

The childhood leukodystrophies comprise a group of hereditary disorders characterized by the absence, malformation or destruction of myelin. These disorders share common clinical, radiological and pathological features, despite their diverse molecular and genetic etiologies. Oligodendrocytes and astrocytes are the major affected cell populations, and are either structurally impaired or metabolically compromised through cell-intrinsic pathology, or are the victims of mis-accumulated toxic byproducts of metabolic derangement. In either case, glial cell replacement using implanted tissue or pluripotent stem cell-derived human neural or glial progenitor cells may comprise a promising strategy for both structural remyelination and metabolic rescue. A broad variety of pediatric white matter disorders, including the primary hypomyelinating disorders, the lysosomal storage disorders, and the broader group of non-lysosomal metabolic leukodystrophies, may all be appropriate candidates for glial progenitor cell-based treatment. Nonetheless, a variety of specific challenges remain before this therapeutic strategy can be applied to children. These include timely diagnosis, before irreparable neuronal injury has ensued; understanding the natural history of the targeted disease; defining the optimal cell phenotype for each disorder; achieving safe and scalable cellular compositions; designing age-appropriate controlled clinical trials; and for autologous therapy of genetic disorders, achieving the safe genetic editing of pluripotent stem cells. Yet these challenges notwithstanding, the promise of glial progenitor cell-based treatment of the childhood myelin disorders offers hope to the many victims of this otherwise largely untreatable class of disease.

Keywords: Cell therapy; Glial progenitor cells; Leukodystrophies; Multiple sclerosis; Myelin; Oligodendrocyte progenitor cells; Pluripotent stem cells; Remyelination; Stem cells; White matter.

Figure 1. Sources and targets of human glial progenitor cells

This schematic illustrates the principal sources of clinically-scalable and engraftable human glial progenitor cells, and highlights some of the principal opportunities for their use in treating the childhood disorders of central myelin.

Figure 2. CD140a-defined glial progenitor cells migrate broadly when introduced to the adult brain

Human fetal-derived GPCs broadly migrate within the major white matter tracts upon transplantation in the adult rat brain. Adult wild type male rats (8–12 wks old) were transplanted with 100,000 fetal-derived human CD140a+ GPCs and sacrificed 12 weeks later to assess the migration and expansion potential of human cells in both the uninjured brain (top), and in the lysolecithin-lesioned brain, which harbors focally demyelinated lesions (lower panel, pink areas rostral and caudal). Reconstruction of the rat brain performed using 20 μm coronal sections 1 mm apart. Human cells were identified and mapped by immunolabeling fort human nuclear antigen. Cells migrated predominantly within the major white matter tracts and reached a typical maximal radius of 10 mm from the point of administration. The presence of demyelinated lesions distant from the injection site did not evidently affect the migration or expansion patterns of the donor cells.

Figure 3. iPSC-derived hGPCs are as effective as tissue-derived hGPCs in myelinating host brain

Human fetal-derived and pluripotent cell-derived GPCs are capable of whole neuraxis myelination. Dot maps indicating the distribution of human donor cells (red), immunolabeled using an anti-human nuclear antibody in 14 μm sagittal sections, 12 months (A1) and 7 months (B1) after neonatal transplant into the shiverer mouse brain. Human GPC-derived myelination in the shiverer forebrain at these same time-points (A2, B2), as identified by myelin basic protein-immunoreactivity (MBP; green). Both fetal and iPSC-derived human oligodendroglia myelinated host axons (A3, A4 and B3: MBP, green; neurofilament, red; human nuclei, blue), formed myelin with normal ultrastructure (A5, B4), and reconstituted nodes of Ranvier (A6 and B5: βIV spectrin, green; Caspr in red).