Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa

Fariss, Robert N.; Li, Zongyi; Milam, Ann H.

doi:10.1016/s0002-9394(99)00401-8

Cited by 246 publications

(186 citation statements)

References 17 publications

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“…Retinal remodeling associated with photorececeptor degeneration as been reported by several groups in humans with RP (Fariss et al, 2000;Jones et al, 2003), as well as in animal models (Strettoi and Pignatelli, 2000;Fisher and Lewis, 2003;Marc et al, 2003;Pignatelli et al, 2004;Jones et al, 2005;Beltran et al, 2006). In this study, a striking finding was the prominent remodeling that occurred in the peripheral retina of XLPRA2 dogs following intravitreal injection of CNTF.…”

Section: Discussionsupporting

confidence: 72%

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

Beltran

Wen

Acland

et al. 2007

Experimental Eye Research

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Ciliary neurotrophic factor (CNTF) rescues photoreceptors in several animal models of retinal degeneration and is currently being evaluated as a potential treatment for retinitis pigmentosa in humans. This study was conducted to test whether CNTF prevents photoreceptor cell loss in XLPRA2, an early onset canine model of X-linked retinitis pigmentosa caused by a frameshift mutation in RPGR exon ORF15.Four different treatment regimens of CNTF were tested in XLPRA2 dogs. Under anesthesia, the animals received at different ages an intravitreal injection of 12 μg of CNTF in the left eye. The right eye served as a control and was injected with a similar volume of phosphate buffered saline (PBS). Ocular examinations were performed regularly during the treatment periods. At termination, the dogs were euthanatized, eyes collected and the retinas were processed for embedding in optimal cutting temperature (OCT) medium. The outer nuclear layer (ONL) thickness was evaluated on H&E sections and values in both CNTF-and PBS-treated eyes were compared. Morphologic alterations in the peripheral retina were characterized by immunohistochemistry using cell-specific markers. Cell proliferation in the retinas was examined on semi-thin plastic sections, and by BrdU pulselabeling and Ki67 immunohistochemistry on cryosections.All CNTF-treated eyes showed early clinical signs of corneal epitheliopathy, subcapsular cataracts and uveitis. No statistically significant difference in ONL thickness was seen between the CNTFand PBS-injected eyes. Prominent retinal remodeling that consisted in an abnormal increase in the number of rods, and in misplacement of some rods, cones, bipolar and Müller cells, was observed in the peripheral retina of CNTF-treated eyes. This was only seen when CNTF was in injected before the age at which the canine retina reaches full maturation.In XLPRA2 dogs, intravitreal injections of CNTF failed to prevent photoreceptors from undergoing cell death in the central and mid-peripheral retina. CNTF also caused ocular side-effects and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Section: Discussionsupporting

confidence: 72%

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

Beltran

Wen

Acland

et al. 2007

Experimental Eye Research

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“…These may be analogous to projections observed in retinas of RP patients (sprouts) (Li et al, 1995;Fariss et al, 2000) or neurite outgrowth observed in cultured neurons (Craig and Banker, 1994). The development of these sprouts was also independent of rhodopsin signal transduction, because they occurred in both eRhoQ350Ter and eRhoK296R/Q350Ter retinas.…”

Section: Discussionsupporting

confidence: 56%

Mislocalized Rhodopsin Does Not Require Activation to Cause Retinal Degeneration and Neurite Outgrowth inXenopus laevis

Tam¹,

Xie²,

Oprian³

et al. 2006

J. Neurosci.

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Mutations in the C terminus of rhodopsin disrupt a rod outer segment localization signal, causing rhodopsin mislocalization and aggressive forms of retinitis pigmentosa (RP). Studies of cultured photoreceptors suggest that activated mislocalized rhodopsin can cause cell death via inappropriate G-protein-coupled signaling. To determine whether this pathway occurs in vivo, we developed a transgenic Xenopus laevis model of RP based on the class I rhodopsin mutation Q344Ter (Q350Ter in X. laevis). We used a second mutation, K296R, to block the ability of rhodopsin to bind chromophore and activate transducin. We compared the effects of expression of both mutants on X. laevis retinas alone and in combination. K296R did not significantly alter the cellular distribution of rhodopsin and did not induce retinal degeneration. Q350Ter caused rhodopsin mislocalization and induced an RP-like degeneration, including loss of rods and development of sprouts or neurites in some remaining rods, but did not affect the distribution of endogenous rhodopsin. The double mutant K296R/Q350Ter caused a similar degeneration and neurite outgrowth. In addition, we found no protective effects of dark rearing in these animals. Our results demonstrate that the degenerative effects of mislocalized rhodopsin are not mediated by the activated form of rhodopsin and therefore do not proceed via conventional G-protein-coupled signaling.

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“…Recent evidence indicates, however, that in addition to damage to www.intechopen.com Stem Cell Based Therapies for Glaucoma 273 the optic nerve, prolonged elevation of intraocular pressure may also induce degeneration or loss of function of other retinal neural cell types, most notably of amacrine cells (Hernandez et al, 2009). Similar observations have been made in other retinal degenerative diseases such as retinitis pigmentosa, which is characterized not only by the loss of rod, but also of cone photoreceptors and by major morphological changes of other surviving retinal neurons (Fariss et al, 2000). Therefore early intervention may be preferable, if cell replacement strategies are to succeed, in order to restrict the number of cells types which need to be transplanted.…”

Section: Potential Of Stem Cells For Retinal Ganglion Cell Replacementsupporting

confidence: 65%

Stem Cell Based Therapies for Glaucoma

Jayaram¹,

Becker²,

Limb³

2011

The Mystery of Glaucoma

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Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa

Cited by 246 publications

References 17 publications

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

Mislocalized Rhodopsin Does Not Require Activation to Cause Retinal Degeneration and Neurite Outgrowth inXenopus laevis

Stem Cell Based Therapies for Glaucoma

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