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Paul Yang, Rachel Lockard, Hope E. Titus, Kyle K. Weller, Aaron S Coyner, Robert M Duvoisin, Richard G Weleber, Catherine W Morgans, Mark E Pennesi; Early Treatment with Mycophenolate Mofetil Reduces Retinal Degeneration and cGMP Dysregulation in rd10 and rd1 mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2503. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Rd10 and rd1 mice possess missense and nonsense mutations, respectively, in Pde6b, which regulates cGMP levels in the phototransduction cascade. Indeed, cGMP dysregulation is implicated as a mechanism of retinal degeneration in both mouse models. Mycophenolate mofetil (MMF), a commonly-used drug in uveitis, works by depleting precursors to guanine nucleotides such as cGMP. We hypothesize that MMF is neuroprotective in rd10 and rd1 mice.
Rd10 and rd1 mice were treated with MMF (25-100 mg/kg/d, i.p.) from P12-35 and P8-15, respectively. Optical coherence tomography (OCT) was used to quantify outer retinal thickness (REC+). IHC was used to assess retinal morphology, Mueller cell activation, and cGMP positivity. ERG and optokinetic response (OKT) was used to assess retinal function and visuospatial sensitivity, respectively. Mass spectrometry was used to quantify cGMP and mycophenolic acid (MPA) levels from whole retina, as well as MPA levels from plasma. ANOVA and Sidak were used for multiple comparisons.
Treatment with MMF 100 mg/kg initiated at P12 produced robust and significant neuroprotection in rd10 mice by P22, but the effect waned with lower doses (25-50 mg/kg) and delayed treatment initiation at older ages (P13-14). Compared with naïve animals, treated rd10 mice had significantly improved REC+ (50.7±2.4 vs 113±1.4 µm, P<0.0001), outer nuclear row number (4±0.5 vs 11.3±0.5, p<0.0001), and ERG a wave amplitude (101±11 vs 409±29 µV, p<0.0001), as well as intact photoreceptor morphology and no Mueller cell activation. Additionally, photoreceptor cGMP positivity on IHC (14.1±2.5 vs 0.08±0.04 cells/1x104 µm2, p<0.0001) and whole retinal cGMP levels (12.7±1.3 vs 3.8±1.4 pmol/mL, p<0.003) were significantly reduced. Beyond P22, the effect of MMF waned at P27 and P35, which correlated with a decline in whole retinal and plasma MPA levels. At P35, treated rd10 mice had better OKT threshold (0.18±0.02 vs 0.25±0.007 cycles/deg, p<0.001). MMF had modest effects in rd1 mice with respect to REC+ and photoreceptor cGMP positivity, but had no effect on whole retinal cGMP levels.
Early treatment with MMF significantly reduced retinal degeneration and cGMP dysregulation with greater efficacy in rd10 mice than rd1 mice. These results show that MMF may be potentially beneficial in patients with retinitis pigmentosa by slowing the rate of disease progression.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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