Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse

Abstract

Mutations in the beta-subunit of the cGMP phosphodiesterase gene (betaPDE) can cause photoreceptor degeneration leading to blindness in humans, dogs, and mice. Since intravitreal administration of trophic factors has been shown to reduce photoreceptor death in the Royal College of Surgeons rat and the light overexposure models of photoreceptor degeneration, we have tested the possibility of rescuing photoreceptors in the rd mouse using ciliary neurotrophic factor (CNTF). Following intravitreal injection of an adenoviral vector encoding a ngf/cntf fusion gene into one eye of rd/rd mice, many strong CNTF-immunoreactive profiles are detected in various cell types of the injected eyes. Semiquantitative analysis of the corresponding retinae reveals that the photoreceptor-containing layer (outer nuclear layer, or ONL) retains significantly more rows of photoreceptor nuclei than that of eyes treated with a control (LacZ) vector, or untreated, for at least 18 days after vector administration (the longest survival time analyzed). A smaller, but significant, protective effect was also seen 9 days after intravitreal injection of recombinant CNTF. Because apoptotic cell death has been shown to be the common terminal fate of photoreceptors in the rd mouse and many other animal models of retinitis pigmentosa, these results suggest the possibility that administration of neurotrophic factors may prove beneficial in reducing photoreceptor loss in multiple forms of retinitis pigmentosa.