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Vishal M Shinde, Pravalika Kotla, Marina S Gorbatyuk; Rod Photoreceptor Specific Calpain deficiency in T17M Rho and P23H Rho mice prevents loss of retinal functional and photoreceptor cells death. . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2585.
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© ARVO (1962-2015); The Authors (2016-present)
The Calpain (Calp) family of cysteine proteases is known to play a significant role in the progression of retinal degeneration in several animal models. Few studies have attempted pharmacological inhibition of Calpains as an approach to prevent retinal degeneration. However, these therapies have several drawbacks. In this study we validated a rod cell specific loss of Calp-2 in the degenerating retinas of T17M Rho and P23H Rho mice as a potential therapeutic strategy.
Conditional Calp-2 knockout in photoreceptors was achieved by a loxp-cre system with Calp loxp and Rho-Cre mice. Calp-2 -/- mice were bred with T17M Rho or P23H Rho to provide a comparison of either Calp-2+/- T17M Rho or Calp-2+/- P23H Rho mice with C57BL6 and ADRP mice. In vivo analysis of retinal function was performed using scotopic ERG at postnatal (P) day 30 and 90. Retinal morphology of all therapeutic and control groups was evaluated using spectral domain optical coherence tomography (SD-OCT) at P30 and P90.
ERG responses in both Calp-2-deficient ADRP mouse models were significantly elevated as compared to ADRP controls. In P30 Calp-2 +/- T17M Rho, the a- and b-wave amplitudes were significantly elevated by over 4 and 3 fold, furthermore the b-wave amplitude reached the level of one registered in C57BL6 mice. At P90, both scotopic ERG amplitudes demonstrated a 2- and 1.5-fold increase, respectively. Another Calp-2-deficient ADRP model, the Calp-2+/- P23H Rho mice also revealed a raise in the a and b wave amplitudes that were elevated by 3.8 and 1.9 fold at P30 and by 1.7 and 1.5 fold at P90, correspondingly. Preservation of functional loss of ADRP retina was in agreement with a maintaining of retinal integrity as measured by SD-OCT. The thickness of the outer nuclear layer (ONL) in the superior and inferior retinal regions was significantly increased by 150% and 157% in Calp-2 T17M Rho and by 132% and 140% in Calp-2 P23H Rho at P30, respectively. The preservation of the ONL thickness in both the Calp-2-deficient mice was more prominent at P90 as compared to ADRP controls.
Conditional knockdown of Calp-2 in ADRP retinas significantly retards the onset of retinal degeneration in both mouse models. These data suggest that the Calpain proteases could be viable therapeutic targets for future ADRP gene therapy.
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