Adenovirus-Mediated Gene Therapy for Corneal Clouding in Mice with Mucopolysaccharidosis Type VII

Abstract

Recent advances in systemic treatments for mucopolysaccharidosis have led to therapies that improve the multiple somatic features of this disease, but the therapeutic effect on ocular manifestations such as corneal clouding is not satisfactory. Here, we administered an adenovirus expressing human beta-glucuronidase (AxCAhGUS) into the anterior chamber or intrastromal region of the cornea in mice with mucopolysaccharidosis type VII (B6/MPSVII), and successfully treated corneal clouding of MPSVII. When we injected AxCAhGUS into the anterior chamber of the eyes, cells expressing beta-glucuronidase (GUSB) were located mainly in the trabecular meshwork as well as in all corneal regions, and subsequent pathological corrections in the cornea were achieved. Widespread transgene expression was also observed when we administered AxCAhGUS inside the cornea after lamellar keratotomy, and rapid elimination of the lysosomal storage in the corneal keratocytes occurred. Furthermore, intrastromal vector administration did not generate significant levels of anti-adenovirus neutralizing antibodies, and secondary vector administration was effective. Based on these observations, we conclude that it is worth developing a treatment strategy for corneal clouding in mucopolysaccharidosis based on direct intraocular administration of adenoviral vectors.

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

“…[1][2][3][31][32][33] In this study, we have assessed the consequences of replication-defective and UV-inactivated Ad on secretory compartment organization and function in the acinar epithelial cells of the lacrimal gland. Exposure of lacrimal acini to replicationdefective Ad constructs at an MOI of 5 for 16-18 h Ad modulates epithelial secretory functions Y Wang et al elicited a marked dispersal of rab3D from its normally apical enrichment (Figures 3-5), a change independent of altered rab3D expression (Figure 4) or membrane association ( Figure 6).…”

Efficient lentiviral gene transfer into corneal stroma cells using a femtosecond laser

“…Alternative surgical approaches have also been proposed to enhance viral vector-mediated transduction of the corneal stroma. Vector application after lamellar keratotomy 22,23 or direct intrastromal injection 24 have led to the successful transduction of stromal cells, without reaching the efficiency reported in this study. Furthermore, such surgical approaches might be more traumatic than the femtosecond laser, and, most importantly, they do not allow to control vector diffusion as precisely as the femtosecond laser technique.…”

Prospects for gene therapy in corneal disease

“…This resulted in widespread distribution of GUSB expression in cells in the corneal stroma, epithelium, and endothelium at 5 and 30 days post-treatment. 14 Corneal expression of GUSB was associated with morphologic improvement as well as rapid and almost complete reversal of vacuolar histopathological changes. Even taking into account the shorter lifespan of mouse than man, these results must be considered short-term for an inherited disorder in which lifelong expression of a functionally active therapeutic gene would be necessary.…”