Targeting molecular pathways for the treatment of inherited retinal degeneration

Abstract

Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells. Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases. The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients. Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation. One of these targets is the increase of intracellular calcium ions, that has been detected in several murine models of inherited retinal degeneration. Recently, neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration. Here, we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches, such as the neuroprotective activity of the Pigment epithelium-derived factor. The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches. We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.

Keywords: Leber’s congenital amaurosis; achromatopsia; calcium; calpains; calpastatin; congenital stationary night blindness; retinitis pigmentosa; stargardt disease.

Figure 1

Stages of photoreceptor degeneration and applicable therapies. Degeneration is represented in a graph showing the reduction in photoreceptors cells during degeneration. Below we report the time windows of different therapeutic options. Gene therapy is appropriate for early stages of photoreceptor degeneration and neuroprotective strategies can treat ongoing photoreceptor cell degeneration. Both these treatments act on endogenous photoreceptors. Cell replacement, optogenetics and retinal prosthesis are strategies to treat patients at advanced/late stages of degeneration.

Figure 2

Cell death mechanisms. The calcium-calpain pathway plays a major role in photoreceptor demise linked to IRD. Increases of intracellular calcium trigger calpain proteases which, by acting on AIF, lead to cell death through BAX activation. High intracellular Ca²⁺ can be caused by increases of intracellular cGMP, which can also activate PKG, as well as by protein misfolding, such as in photoreceptors bearing mutations in rhodopsin (RHO). High intracellular cGMP can be a consequence of loss of function in the phosphodiesterase 6 enzyme (PDE6), which idolizes cGMP. AIF: Apoptosis inducing factor; BAX: BCL2-associated X protein; cGMP: cyclic guanosine monophosphate; IRD: inherited retinal degeneration; PKG: cGMP-dependent protein kinase.