Genetics of keratoconus; how realistic is gene therapy?

Abstract

AbstractKeratoconus (KC) is a complex, non‐inflammatory eye condition that impairs the focusing ability of the eye by progressively thinning and distorting the cornea. Its causes remain elusive, as it is a genetically heterogeneous, multifactorial degenerative disorder. KC follows an autosomal (either recessive or dominant) pattern of inheritance and is associated with genes which interact with environmental, genetic and/or other factors.At present, the only fairly reliable treatment that slows down the progression of KC is cornea collagen cross‐linking. In extreme cases a corneal transplant may be required. This fact alone makes gene therapy for KC, a promising therapeutic approach. Such hopes are bolstered by the biophysical properties of the corneal tissues which include the corneal immune privilege, the transparency of the corneal tissue together with its and ex vivo stability, and the uncomplicated operative approach to the eye anterior chamber. In addition, recent advances in vectors, along with the ability to modulate the corneal milieu in order to ensure a relatively long survival of the target gene and allow its successful translation, further bolster the hopes for successfully treating KC via gene therapy.Over the last two decades, however, genome‐wide association studies and studies on SNP and genetic loci identification have identified more than 50 genomic loci that are implicated in both the dysregulation of the corneal collagen matrix formation and maintenance or the cell differentiation pathways that sustain corneal integrity. Among the most prominent genes involved in KC are the VSX1 gene, which is involved, among others, in posterior polymorphous corneal dystrophy; the SOD1 gene which determines the effects of reactive oxygen species; the ZNF469 gene which is also involved in the Brittle Cornea Syndrome; the TGF8 pathway which is involved in the regulation of the extracellular matrix composition; the TGFI gene which plays a role in cell‐collagen interactions. The roles of the MicroRNAs (especially that of the miRNA 184) and of mitochondrial DNA must, also, be stressed. Recently, we bibliographically identified and documented 18 different KC symptoms and clinical signs and cross referenced them to 24 different genes/genetic loci. It turns out that each of these symptoms is associated with from between 3 and 14 identified KC genes. We similarly identified 49 diseases and/or syndromes that involve at least some of the KC‐implicated genes and cross‐referenced them to these 24 genes. Again, it turns out that each one of the 49 diseases/syndromes is associated with from between 1 and 23 KC‐implicated genes.The complex interrelations among the different biophysical and biochemical processes involved in KC, the multitude of related genomic loci, and the large number of comorbidities, collectively, they cast gene therapy in an unfavourable light as a realistic treatment option for KC., On the other hand, the possible identification of a pivotal role for only a handful of genes, may open the path for gene therapy in KC.