The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Abstract

Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

Suppression of cGMP-Dependent Photoreceptor Cytotoxicity With Mycophenolate Is Neuroprotective in Murine Models of Retinitis Pigmentosa

“…91 As such, the pathophysiology of PDE6-mediated cGMP dysregulation in the context of retinal degeneration is likely much more complex than our current understanding of cGMP homeostasis in photoreceptors. 16 Taken together with the literature, our data show that the effect of different mutations in Pde6b on whole retinal cGMP dysregulation is difficult to predict and do not correlate with cGMP-dependent photoreceptor cell death. This seeming contradiction in the results of cGMP IHC versus whole retinal cGMP is due to the inherent differences in the two assays as follows: (1) Whole retinal cGMP is quantitative but is an average measurement of all retinal cell types, while cGMP IHC is semiquantitative but is a biomarker specific to the photoreceptors.…”

“… 91 As such, the pathophysiology of PDE6-mediated cGMP dysregulation in the context of retinal degeneration is likely much more complex than our current understanding of cGMP homeostasis in photoreceptors. 16 Taken together with the literature, our data show that the effect of different mutations in Pde6b on whole retinal cGMP dysregulation is difficult to predict and do not correlate with cGMP-dependent photoreceptor cell death.…”

“…4,10,12 Paquet-Durand and colleagues 13 have shown that this anti-cGMP antibody signal is an intracellular biomarker for cGMP-dependent cytotoxicity and an alternative pathway for photoreceptor cell death. 4,[14][15][16][17][18] Interestingly, cGMP immunolabeling on IHC is also seen in other rodent models with mutations in other genes not directly related to cGMP hydrolysis, namely those associated with RP (Prph2, Cngb1, Rho), Leber congenital amaurosis (Aipl1), and achromatopsia (Cnga3). 4,19 This indicates that cGMP-dependent photoreceptor toxicity may be a common phenomenon that occurs independently of mutations affecting cGMP metabolism and whole retinal cGMP levels.…”

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Rod phosphodiesterase 6 consists of a catalytic αβ complex encoded by Pde6a and Pde6b and two inhibitory γ subunits encoded by Pde6g. The control of cGMP levels by this enzyme is expected to affect both PR function and viability, as cGMP has a central role in the phototransduction cascade and PR cell metabolism [177], and elevated cGMP levels have been linked to PR cell loss [178]. Indeed, Pde6a and Pde6b mutants show depressed ERG responses at an early age and rapid PR loss with D 50 values of 11-30 days ( Figure 6, Table S1).…”

Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges

“…Cyclic guanosine-monophosphate (cGMP) is a crucial molecule for photoreceptor signal transduction and has two main cellular effectors—cyclic nucleotide gated ion channels (CNGCs) and cGMP-dependent protein kinase G (PKG) [169]. It has been reported that over-activation of PKG can be enough to cause photoreceptor cell death and that its activation levels are higher in mutant photoreceptors.…”