On the genetics of retinitis pigmentosa and on mutation-independent approaches to therapeutic intervention

Abstract

Retinitis pigmentosa (RP), the group of hereditary conditions involving death of retinal photoreceptors, represents the most prevalent cause of visual handicap among working populations in developed countries. Here we provide an overview of the molecular pathologies associated with such disorders, from which it becomes clearly apparent that RP is one of the most genetically heterogeneous of hereditary conditions for which molecular pathologies have so far been elucidated. While heterogeneity of such magnitude would appear to represent a major impediment to the development of therapeutics, mutation-independent approaches to therapy are being developed to effectively by-pass such diversity in genetic aetiology. The implications of such technologies in terms of therapeutic intervention in RP, and indeed other genetically heterogeneous conditions, will be addressed.

Fig. 1. Retinal histology from a wild-type mouse retina. The various layers of the retina are identified: retinal pigment epithelium (RE), rod outer segments (ROS), inner segments (RIS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer and ganglion cell layer (GCL).

Fig. 2. Graphical summary of key components of the visual transduction cascade. Rhodopsin is indicated by RHO, transducin by T and phosphodiesterase by PDE.

Fig. 3. Rod-isolated, combined rod and cone responses to the maximal intensity flash presented in the dark-adapted state and single flash light-adapted cone responses are shown from (A) a normal individual, (B) a patient with moderately advanced RP and (C) a patient with advanced RP.

Fig. 4. Photographs of a normal (left panel) and RP retina (right panel). Features typical of RP, such as marked pigment epithelial thinning, optic disc pallor, retinal vascular attenuation and the classical ‘bone spicule’ intraretinal pigmentary deposits, are clearly evident in the RP retina.

Fig. 5. Graphical representation of the principle of mutation-independent suppression utilizing the degeneracy of the genetic code. A ribozyme is designed to cleave a target transcript at a degenerate site. In parallel, a replacement gene that encodes wild-type protein but has been subtly modified at degenerate sites such that the ribozyme cannot cleave transcripts from the replacement gene is supplied.