Abstract
Aniridia is a panocular eye disorder associated with heterozygous mutations in the homeobox gene PAX6. Characterized by a complete or partial loss of the iris, aniridia is also known to cause many deleterious phenotypes of varying severity, including corneal keratopathy, lens hypoplasia, nystagmus, and cataracts. While most previous investigations have focused on the anterior eye segment, aniridia is also known to disrupt normal retinal development, an area we explore in the following chapters.
Our first chapter describes the relationship between glaucoma, aniridia, and the ongoing challenges facing clinicians and researchers. As retinal deficits represent the most critical impairments to vision, it is important to establish how Pax6-deficiencies disrupt normal retinal formation and how these disruptions are exacerbated in post-natal development.
Chapter 2 discusses our own investigations into the long-term effects of a potential aniridia treatment, the MEK-inhibitor PD0325901. Using a Pax6-deficient small-eye mouse model (Pax6Sey-Neu/+) we found a wide-ranging combination of morphological damage and visual impairments in aniridic retinas. Measurements of intraocular pressure (IOP) indicated a glaucomatous phenotype which correlated with a decreased visual acuity in afflicted mice. Ex vivo assessments of Pax6Sey-Neu/+ retinas found increased incidence of localized damage we termed “hotspots,” and disruption of retinal ganglion cell (RGC) axon bundles. All these deficits were at least partially mitigated in Pax6Sey-Neu/+ mice treated with PD0325901, suggesting that Pax6-dosage compensation moderately protected against aniridia phenotypes.
Our subsequent studies in Chapter 3 used Pax6Sey mouse models from the C57Bl/6 and 129S/Svlmj backgrounds to demonstrate how IOP and visual acuity decline in aniridic mice in an age-dependent manner. Further studies of retinal of these mice found highly varying retinal thicknesses and retinal subtype densities in these hotspots. Most interesting, however, was the increased recruitment and activation of microglia and astrocytes in Pax6Sey retinas, which suggests a tissue-wide neuroinflammatory response to aniridia.
In Chapter 4, we further discuss the pathogenesis of aniridia, including the disease’s relationship to PAX6 and how disruption of critical developmental pathways leads to tissue hypoplasia. Likewise, we explore the various murine models used to study Pax6-deficiencies, their benefits and complications, and how these models contribute to translational research. We also review the possible causes of retinal damage, and how this damage is reflected in tissue morphology and functional assessments. Finally, we interrogate the current methods for diagnosing, tracking, and treating aniridia, especially the ongoing work in pharmacological interventions, including the dosage-compensation mechanisms we describe in Chapter 2, and some novel formulations of the mutation suppressant ataluren. Collectively, these findings provide the basis for a viable, case-specific approach for study which will better address the highly varied phenotypes of aniridia patients.
