Purpose

It has been proposed that the peripheral retina, responding to local optical defocus, contributes to myopia and associated altered eye growth in humans. To test this hypothesis, we measured the changes in central (on-axis) and peripheral ocular dimensions in guinea pigs wearing a concentric bifocal spectacle lens design with power restricted to the periphery.

Methods

Five groups of guinea pigs (n = 83) wore either a unifocal (UF) spectacle lens (-4, 0, or +4 Diopters [D]), or a peripheral defocus (PF) spectacle lens that had a plano center (diameter of 5 mm) with either -4 or +4 D in the surround (-4/0 or +4/0 D). The overall optical diameter of all lenses was 12 mm. Lenses were worn over one eye from 8 to 18 days of age for negative and plano lenses, or from 8 to 22 days of age for positive lenses. Refractive error was measured centrally and 30° off-axis in the temporal and nasal retina. The shape of the eye was analyzed from images of sectioned eyes.

Results

Lenses of -4 D UF induced myopia, reflecting enhanced ocular elongation, which was centered on the optic nerve head and included the surrounding peripapillary zone (PPZ, 18° in diameter). Some ocular expansion, including within the PPZ, also was recorded with -4/0 and +4/0 D PF lenses while the +4 D UF lens inhibited rather than enhanced elongation, centrally and peripherally.

Conclusions

Peripheral defocus-induced ocular expansion encompasses the PPZ, irrespective of the sign of the inducing defocus. Understanding the underlying mechanism potentially has important implications for designing multifocal lenses for controlling myopia in humans and also potentially for understanding the link between myopia and glaucoma.

Purpose

Eye growth compensates in opposite directions to single vision (SV) negative and positive lenses. We evaluated the response of the guinea pig eye to Fresnel-type lenses incorporating two different powers.

Methods

A total of 114 guinea pigs (10 groups with 9-14 in each) wore a lens over one eye and interocular differences in refractive error and ocular dimensions were measured in each of three experiments. First, the effects of three Fresnel designs with various diopter (D) combinations (-5D/0D; +5D/0D or -5D/+5D dual power) were compared to three SV lenses (-5D, +5D, or 0D). Second, the ratio of -5D and +5D power in a Fresnel lens was varied (50:50 compared with 60:40). Third, myopia was induced by 4 days of exposure to a SV -5D lens, which was then exchanged for a Fresnel lens (-5D/+5D) or one of two SV lenses (+5D or -5D) and ocular parameters tracked for a further 3 weeks.

Results

Dual power lenses induced an intermediate response between that to the two constituent powers (lenses +5D, +5D/0D, 0D, -5D/+5D, -5D/0D and -5D induced +2.1 D, +0.7 D, +0.1 D, -0.3 D, -1.6 D and -5.1 D in mean intraocular differences in refractive error, respectively), and changing the ratio of powers induced responses equal to their weighted average. In already myopic animals, continued treatment with SV negative lenses increased their myopia (from -3.3 D to -4.2 D), while switching to SV positive lenses or -5D/+5D Fresnel lenses reduced their myopia (by 2.9 D and 2.3 D, respectively).

Conclusions

The mammalian eye integrates competing defocus to guide its refractive development and eye growth. Fresnel lenses, incorporating positive or plano power with negative power, can slow ocular growth, suggesting that such designs may control myopia progression in humans.

Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.