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.

Background: The role played by microRNAs (miRs) as common regulators in physiologic processes such as development and various disease states was recently highlighted. Retinitis pigmentosa (RP) linked to RHO (which encodes rhodopsin) is the most frequent form of inherited retinal degeneration that leads to blindness, for which there are no current therapies. Little is known about the cellular mechanisms that connect mutations within RHO to eventual photoreceptor cell death by apoptosis. Results: Global miR expression profiling using miR microarray technology and quantitative real-time RT-PCR (qPCR) was performed in mouse retinas. RNA samples from retina of a mouse model of RP carrying a mutant Pro347Ser RHO transgene and from wild-type retina, brain and a whole-body representation (prepared by pooling total RNA from eight different mouse organs) exhibited notably different miR profiles. Expression of retina-specific and recently described retinal miRs was semi-quantitatively demonstrated in wild-type mouse retina. Alterations greater than twofold were found in the expression of nine miRs in Pro347Ser as compared with wild-type retina (P < 0.05). Expression of miR-1 and miR-133 decreased by more than 2.5-fold (P < 0.001), whereas expression of miR-96 and miR-183 increased by more than 3-fold (P < 0.001) in Pro347Ser retinas, as validated by qPCR. Potential retinal targets for these miRs were predicted in silico. Conclusion: This is the first miR microarray study to focus on evaluating altered miR expression in retinal disease. Additionally, novel retinal preference for miR-376a and miR-691 was identified. The results obtained contribute toward elucidating the function of miRs in normal and diseased retina. Modulation of expression of retinal miRs may represent a future therapeutic strategy for retinopathies such as RP.

While individually classed as rare diseases, hereditary retinal degenerations (IRDs) are the major cause of registered visual handicap in the developed world. Given their hereditary nature, some degree of intergenic heterogeneity was expected, with genes segregating in autosomal dominant, recessive, X-linked recessive, and more rarely in digenic or mitochondrial modes. Today, it is recognized that IRDs, as a group, represent one of the most genetically diverse of hereditary conditions - at least 260 genes having been implicated, with 70 genes identified in the most common IRD, retinitis pigmentosa (RP). However, targeted sequencing studies of exons from known IRD genes have resulted in the identification of candidate mutations in only approximately 60% of IRD cases. Given recent advances in the development of gene-based medicines, characterization of IRD patient cohorts for known IRD genes and elucidation of the molecular pathologies of disease in those remaining unresolved cases has become an endeavor of the highest priority. Here, we provide an outline of progress in this area.

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm’s canal (SC). Elevated IOP, which can be caused by increased resistance to AH outflow, is a major risk factor for open-angle glaucoma. Matrix metalloproteinases (MMPs) contribute to conventional aqueous outflow homeostasis in their capacity to remodel extracellular matrices, which has a direct impact on aqueous outflow resistance and IOP. We observed decreased MMP-3 activity in human glaucomatous AH compared to age-matched normotensive control AH. Treatment with glaucomatous AH resulted in significantly increased transendothelial resistance of SC endothelial and TM cell monolayers and reduced monolayer permeability when compared to control AH, or supplemented treatment with exogenous MMP-3. Intracameral inoculation of AAV-2/9 containing a CMV-driven MMP-3 gene (AAV-MMP-3) into wild type mice resulted in efficient transduction of corneal endothelium and an increase in aqueous concentration and activity of MMP-3. Most importantly, AAV-mediated expression of MMP-3 increased outflow facility and decreased IOP, and controlled expression using an inducible promoter activated by topical administration of doxycycline achieved the same effect. Ultrastructural analysis of MMP-3 treated matrices by transmission electron microscopy revealed remodelling and degradation of core extracellular matrix components. These results indicate that periodic induction, via use of an eye drop, of AAV-mediated secretion of MMP-3 into AH could have therapeutic potential for those cases of glaucoma that are sub-optimally responsive to conventional pressure-reducing medications.