Ocular phenotypes in a mouse model of Pompe disease

Abstract

Purpose : Pompe disease is an autosomal recessive disorder resulting from a deficiency of acid alpha-glucosidase (GAA), leading to progressive lysosomal glycogen accumulation in tissues due to mutations in the GAA gene. Some patients have ocular phenotypes such as bilateral ptosis, strabismus, myopia, and astigmatism. There are multiple mouse models, however no ocular phenotypes have ever been reported. In-house RNAseq data showed iris is the second highest tissue expressing GAA in mouse. This study aims to assess the ocular pathological changes that may occur due to glycogen accumulation in tissues of GAA knockout mice, with the goal of establishing a biomarker for Pompe disease therapy.

Methods : Ocular morphology in GAA wild type and knockout mice (Regeneron pharmaceutical Inc) was evaluated with Heidelberg Spectralis optical coherence tomography (OCT). Corneal thickness and pupil size were measured at various ages. Electroretinogram (ERG) was conducted to assess the retina function change. Upon termination, eyeballs were collected for Periodic Acid-Schiff (PAS) staining to evaluate glycogen accumulation, while hearts and irises were harvested for glycogen measurement with bioassay kit.

Results : No difference was observed in anterior and posterior segment OCT compared KO to WT mice, respectively, except GAA knockout mice exhibited significantly smaller pupil sizes (p<0.01) at 6 and 8 months age, a trend that persisted at 11 months age. The ERG test didn’t show remarkable change in GAA KO mice. PAS staining revealed substantial glycogen accumulation in the ciliary body, lens epithelium, and neural retina of GAA knockout mice. Vacuolar myopathy was observed in the extraocular muscle of GAA knockout mice. Additionally, glycogen levels in iris of GAA knockout mice were significantly elevated.

Conclusions : Our data demonstrate GAA KO mice have smaller pupil size, this finding indicates that glycogen accumulation in ocular tissues, resulting from GAA gene mutation, can lead to pathological changes, and serve a potential non-invasive, easily obtainable biomarker of muscular damage in Pompe disease.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.