CNTF Induces Regeneration of Cone Outer Segments in a Rat Model of Retinal Degeneration

Abstract

BackgroundCone photoreceptors are responsible for color and central vision. In the late stage of retinitis pigmentosa and in geographic atrophy associated with age-related macular degeneration, cone degeneration eventually causes loss of central vision. In the present work, we investigated cone degeneration secondary to rod loss in the S334ter-3 transgenic rats carrying the rhodopsin mutation S334ter.Methodology/Principal FindingsRecombinant human ciliary neurotrophic factor (CNTF) was delivered by intravitreal injection to the left eye of an animal, and vehicle to the right eye. Eyes were harvested 10 days after injection. Cone outer segments (COS), and cell bodies were identified by staining with peanut agglutinin and cone arrestin antibodies in whole-mount retinas. For long-term treatment with CNTF, CNTF secreting microdevices were implanted into the left eyes at postnatal day (PD) 20 and control devices into the right eyes. Cone ERG was recorded at PD 160 from implanted animals. Our results demonstrate that an early sign of cone degeneration is the loss of COS, which concentrated in many small areas throughout the retina and is progressive with age. Treatment with CNTF induces regeneration of COS and thus reverses the degeneration process in early stages of cone degeneration. Sustained delivery of CNTF prevents cones from degeneration and helps them to maintain COS and light-sensing function.Conclusions/SignificanceLoss of COS is an early sign of secondary cone degeneration whereas cell death occurs much later. At early stages, degenerating cones are capable of regenerating outer segments, indicating the reversal of the degenerative process. Sustained delivery of CNTF preserves cone cells and their function. Long-term treatment with CNTF starting at early stages of degeneration could be a viable strategy for preservation of central vision for patients with retinal degenerations.

Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration

“…Together, these data suggest that the increased retinal thickness reflects increased photoreceptor metabolic activity or an increased number of photoreceptors. Consistent with these findings, CNTF was recently shown to prolong cone photoreceptor survival and regenerate cone outer segments in a rat model of retinal degeneration (24). In this study, the CNTF cone rescue was most effective during early stage of the disease when the loss of cones was incomplete.…”

“…In this study, the CNTF cone rescue was most effective during early stage of the disease when the loss of cones was incomplete. Once complete cone loss had occurred during late stage of disease, CNTF could no longer bring the cone receptors back, suggesting the importance of early treatment (24). Consistent with observations in the animal studies, using adaptive optics scanning laser ophthalmoscopy (AOSLO), Talcott et al (25) recently reported cone preservation in CNTF-treated eyes compared with the sham-treated fellow eyes in patients with retinitis pigmentosa and Usher Syndrome Type 2.…”

Efficacy of Codelivery of Dual AAV2/5 Vectors in the Murine Retina and Hippocampus

“…Furthermore, spatial and temporal control of transgene expression could be mediated by a second AAV vector expressing, for example, inducible Cre recombinase (Li et al, 2006). In the case of therapies for mendelian diseases in which the underlying mutation is unknown, a combination therapy of antioxidants and/or growth factors may prolong cell survival and function (Komeima et al, 2007;Yang et al, 2009;Li et al, 2010). To treat patients with retinal degenerations it is possible that multivalent therapeutic strategies may be required.…”

Neuroprotektion geschädigter Photorezeptoren

“…Interessanterweise scheint CNTF seine protektive Wirkung indirekt über Müller-Gliazellen zu entfalten. CNTF ist vor allem deshalb interessant, weil der Faktor neben Stäb-chen auch Zapfen schützen kann und zudem die Regeneration der Zapfenaußensegmente fördert [27]. Vor diesem Hintergrund ist CNTF auch in Bezug auf den klinischen Einsatz attraktiv.…”