Abstract
Inherited retinal diseases are an extremely diverse group of genetically and phenotypically heterogeneous conditions characterized by variable maturation of retinal development, impairment of photoreceptor cell function and gradual loss of photoreceptor cells and vision. Significant progress has been made over the last two decades in identifying the many genes implicated in inherited retinal diseases and developing novel therapies to address the underlying genetic defects. Approximately one-quarter of exonic mutations related to human inherited diseases are likely to induce aberrant splicing products, providing opportunities for the development of novel therapeutics that target splicing processes. The feasibility of antisense oligomer mediated splice intervention to treat inherited diseases has been demonstrated in vitro, in vivo and in clinical trials. In this review, we will discuss therapeutic approaches to treat inherited retinal disease, including strategies to correct splicing and modify exon selection at the level of pre-mRNA. The challenges of clinical translation of this class of emerging therapeutics will also be discussed.
Highlights
Inherited retinal diseases (IRDs) are a diverse group of clinically and genetically heterogeneous disorders
IRDs are characterized by bilateral progressive retinal degeneration which primarily affects the photoreceptor and the retinal pigment epithelium (RPE) cells but it may rarely affect other retinal cell types such as the Muller glia and bipolar cells
Some IRDs, such as Best disease and vitelliform macular dystrophy, can be restricted to the macular region whilst others, such as rod cone dystrophy and choroideremia, affect cells distributed throughout the entire retina
Summary
Inherited retinal diseases (IRDs) are a diverse group of clinically and genetically heterogeneous disorders. These can be broadly divided into two categories, firstly, approaches that focus on neuro-replacement, and secondly, approaches that focus on neuro-preservation The first of these is most appropriate for patients who present with end stage disease where few photoreceptors remain and retinal function is restored through cell replacement therapy or bionic vision via retinal visual prosthesis implant. One mutation-specific therapeutic approach is the use of translational read-through inducing drugs (TRIDs) This class of molecules can restore full-length, functional protein by facilitating the recoding of a premature translational termination codon resulting from in-frame nonsense mutation. Since these types of mutations have been reported in many IRD associated genes, TRID treatments may have the potential to address a more substantial percentage of IRD cases. The limited efficacy of such drugs requires further investigation (see Nagel-Wolfrum et al, for review [20])
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