UC Berkeley

Myopia, or nearsightedness, is a common vision disorder characterized by an abnormal increase in eye elongation, leading to a mismatch in the refractive power of the eye and the location of the retina. Myopia has dramatically increased in prevalence over the last 50 years, currently affecting half of college-aged individuals in the United States and almost all young adults in certain Asian populations. This trend is not a temporary aberration; myopia is projected to afflict nearly half of the global population by the year 2050.

Traditionally, myopia is "corrected" using glasses, contact lenses, or refractive surgery. Although these solutions allow for clear vision, they do not rectify the underlying structural changes associated with myopia, including the lengthening of the eye and the thinning of its layers. As a result, there remains an increased risk of vision-threatening complications, such as glaucoma, retinal detachment, myopic maculopathy, and choroidal neovascularization. In the past, these complications were regarded as characteristic of "pathological" myopia. However, it is now known that no amount of myopia is considered safe; the more severe the myopia, the greater the risk, starting from even the smallest measurable amounts.

In addition, not all myopes have access to refractive correction. Uncorrected refractive error accounts for over half of global vision impairment. It has also been estimated that uncorrected myopia is associated with an annual global potential productivity loss of $244 billion.

With these startling figures, there have been renewed efforts to develop and prescribe treatments for myopia. Inspired by the influence of animal models on myopia research thus far, we sought to further one of the most popular mammalian models of myopia, the guinea pig, to allow for mechanistic exploration that is not possible in human clinical trials.

Chapter 1 reviews the process of emmetropization and refractive error development as understood from observations in humans and experiments in animal models. Current clinical recommendations are also summarized.

Chapter 2 presents a qualitative synthesis of the known relevant ocular characteristics of the guinea pig myopia model. Guinea pigs have emerged as a popular mammalian model because of the relative ease of housing and husbandry, larger eyes, and better visual acuity compared to other laboratory rodents. However, guinea pigs aren't perfect subjects for the human condition we are attempting to model. Knowledge of the optical quality of the guinea pig eye isn't firmly established, and experimental models of myopia depend on manipulating the visual experience.

In Chapter 3, we detail the optical aberrations of the guinea pig eye. Using a custom-built Shack-Hartmann wavefront sensor, we fit a Zernike polynomial function to the images collected from adolescent guinea pigs. The optical quality of the eyes was assessed in terms of individual Zernike coefficients, and data were further analyzed to derive root-mean-square wavefront errors, modulation transfer functions, point spread functions, and depth of focus. These data are compared with visually normal young adult human eyes. While visual acuity is much poorer in the guinea pig eye compared to the human eye, high order aberrations do not appear to be major sources of image quality degradation. It is still unknown what optical information the eye is using to generate growth modulatory signals. However, the measurement of the optical aberrations of the guinea pig eye is an important step forward, allowing the nature of the defocus stimuli and their effects on retinal image quality to be better understood in this mammalian model.

Chapter 4 presents the results of a novel method of inducing myopia in the guinea pig model. Historically, spectacle-mounted lenses and diffusers are used to induce myopia in guinea pigs. These lenses are typically mounted on Velcro ring supports, which are then glued to the fur surrounding the guinea pigs' eyes. While shown to be safe and effective, there are significant limitations with this process. The lenses (or diffusers) can be removed by the guinea pigs if they scratch at the velcro site, requiring very frequent monitoring and reapplication. As a result, experiments using spectacle-mounted lenses cannot be conducted over a long period of time. We designed and tested rigid gas permeable contact lenses as an alternative method for inducing myopia in guinea pigs, which will also allow for testing contact lens treatments in this animal model.

Finally, the ability of atropine to prevent the development of myopia is a fairly consistent finding in animal studies. However, important exceptions have been noted. In Chapter 5, we establish that topically applied 1\% atropine is effective in reducing myopia progression in guinea pigs. After two weeks of treatment with either daily or weekly applied atropine, guinea pigs treated with our contact lens-induced myopia model developed significantly less myopia compared to those treated with a placebo drop.

The overarching goal of this research is to further our basic understanding of the guinea pig eye so that we can continue to use this model to test translational clinical treatments.