The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

Intravitreal triamcinolone acetonide as adjunctive treatment with systemic therapy for uveitic macular edema.

PURPOSE: To report the outcome of a single intravitreal triamcinolone acetonide (IVTA) injection as an adjunctive treatment with systemic medication for refractory uveitic cystoid macular edema (CME). METHODS: This was a retrospective, noncomparative, interventional case series. Medical records of 25 patients (35 eyes) with quiescent uveitic CME who were treated with oral immunosuppressive therapy and underwent 4 mg/0.1 mL IVTA injection were reviewed. Data was collected 6 months post-injection and included details of uveitis, best-corrected visual acuity (BCVA), CME, systemic therapy required, and potential complications of IVTA injection. RESULTS: Thirty eyes (85%) responded with improvement in vision. The mean BCVA improvement was 0.33 (from 0.67 to 0.34 logarithm of the minimum angle of resolution; Snellen equivalent, between 2 and 3 lines) (p<0.001), at a mean time of 6.2 weeks (range 2-16). Resolution of CME was achieved in 31 (88%) of the treated eyes. Following initial response to IVTA, CME relapsed in 8 eyes (26%) after a mean time of 4.2 months (range 2.5-5.5). The dosage of oral corticosteroids and/or second-line immunosuppressive agents was able to be reduced or stopped in 22 patients, 29 of 35 eyes (82.8%). The most common adverse effect was increased intraocular pressure, in 17 (49%) of the treated eyes. Steroid-induced cataract was observed in 6 eyes (17%). CONCLUSIONS: Intravitreal triamcinolone acetonide appears to be an effective supplementary tool in the management of CME refractory to systemic immunosuppressive therapy. Retreatment might be required in some and may be associated with elevated intraocular pressure and cataract.