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kangwei jiao, Ming Yang, Chunling Wei, zhulin Hu, Francois Paquet-Durand; Combination therapy of Calpain and HDAC inhibition protects photoreceptor cells degeneration in rd1 mutant. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4424.
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© ARVO (1962-2015); The Authors (2016-present)
Interventional studies indicated that monotherapy with Calpain inhibitor and HDAC inhibitor might be an efficacious and safe way for the preservation of photoreceptors for Retinitis Pigmentosa. Our hypothesis is that a combination of drugs targeting on the one hand proteolytic processes, that may either directly against different mechanisms of the photoreceptor cell death signaling, or ideally lead to synergic effects and a profile of reduced toxicity, will be more effective at treating RP than either drug alone.
C3H Pde6brd1/rd1 (rd1, n = 5) and congenic C3H wild-type (wt, n = 3) mice were cultured from post-natal (PN) days 5 to PN11. We performed monotherapy with SAHA 1 µM and CAST 20µM, along with combination therapy with SAHA 1 µM and CAST 20µM in rd1 mutant mice in vitro. We used a variety of degeneration markers (i.e. TUNEL, HDAC activity calpain-2 immunostaining) to study the progression in photoreceptor degeneration of rd1 mutant in vitro. Statistical comparisons were made using one-way ANOVA and Bonferroni’s correction.
In the cultured rd1 retina, at P11, the percentage of cells in the ONL displaying HDAC activity and Calpian-2 activity there was markedly increased when compared to wt. Treatment with SAHA strongly reduced the number of HDAC activity positive cells (0.26% ± 0.06 SD, n = 6, p < 0.001). Remarkably, treatment with CAST also reduced this number (0.16% ± 0.07 SD, n = 6, p < 0.05), However, both of CAST and SAHA monotherapy did not halt retinal degeneration completely in rd1 mutant. While HDAC activity and Calpain-2 activity in rd1 combination therapy with SAHA + CAST were significantly decreased compared with that in rd1 without treatment (0.29% ± 0.09 SD, n=6, p < 0.001).
We showed that Calpain and HDAC were of major importance for the progression of photoreceptor degeneration in RP mutants. However, monotherapy of CAST and SAHA were not halting retinal degeneration completely in rd1 mutant. This study highlight the efficacy of a combination therapy targeting calpain-type proteases and HDAC, with a strong bearing for the future design of neurodegeneration studies in RP via cGMP independent pathway. Furthermore, our study may serve to predict the time-courses of retinal degeneration in human RP patients suffering from Pde6b mutations and could help to define the optimal time-points for clinical interventions.
This is a 2020 ARVO Annual Meeting abstract.
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