Genetics of the corneal endothelial dystrophies: an evidence-based review.

The aim of this review was to provide an evidenced-based review of the genetic basis of the corneal endothelial dystrophies. A review of the English language peer-reviewed literature describing the molecular genetic basis of posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), Fuchs endothelial corneal dystrophy (FECD) and X-linked endothelial corneal dystrophy (XECD) was performed. Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD. However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset). In addition, insufficient evidence exists to consider the autosomal dominant form of CHED (CHED1) as distinct from PPCD. An accurate classification of the corneal endothelial dystrophies requires a critical review of the evidence to support the role of each suggested chromosomal locus, gene and genetic mutation associated with a corneal endothelial dystrophy. Only after the separation of evidence from opinion is performed can a critical examination of the molecular pathways that lead to endothelial dysfunction in each of these disorders be accurately performed.

Intravenous administration of human embryonic stem cell-derived neural precursor cells attenuates cuprizone-induced central nervous system (CNS) demyelination.

AIMS: Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v.) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. METHODS: C57Bl/6 mice were fed cuprizone (0.2%) for 2 weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional 2 weeks of dietary cuprizone treatment, CNS tissues were analysed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). RESULTS: Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, glial fibrillary acidic protein. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice. CONCLUSIONS: These findings indicated that systemically administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells.