Effects of Adeno-associated Virus-vectored Ciliary Neurotrophic Factor on Retinal Structure and Function in Mice with a P216L rds/peripherin Mutation

Bok, Dean; Yasumura, Douglas; Matthes, Michael T.; Ruíz, Alexis Lorenzo; Duncan, Jacque L.; Chappelow, Aimee V.; Zolutukhin, Sergei; Hauswirth, William W.; LaVail, Matthew M.

doi:10.1006/exer.2002.1176

Cited by 194 publications

(170 citation statements)

References 43 publications

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“…This negative regulation in the expression of phototransduction proteins has been also reported in mature photoreceptors of the normal rat (Song et al, 2005), and rcd1 dog (Zeiss et al, 2006) following intravitreal administration of CNTF. Such an effect may be responsible for the electroretinographic alterations reported in rat and mouse models of retinal degeneration, as well as in the normal albino rabbit following intraocular delivery of CNTF (Bush et al, 2000;Liang et al, 2001;Bok et al, 2002;Schlichtenbrede et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Two recent reports clearly demonstrated that intraocular CNTF expression using rAAV-2/2-mediated gene delivery, in wild-type mice, in Prph2 Rd2/Rd2 mice and in mice with a P216L rds/peripherin mutation, resulted in a significant decrease of function, as assessed by ERG. 72,73 The mechanisms for these side effects should be determined before clinical trials involving CNTF are considered. Recombinant AAV-mediated gene transfer to the retina F Rolling…”

Section: Gene Transfer In Animal Models Of Retinal Degenerationmentioning

confidence: 99%

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Rolling

2004

Gene Ther

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“…Furthermore, CNTF overexpression might stimulate remodelling of the inner retina, leading to a change in cell function, a decrease in b-wave amplitude and subsequently to dedifferentiation of the photoreceptor cell, as reflected by the changes in chromatin staining. 13 It has been suggested that in the course of retinal degeneration, loss of input from photoreceptors leads to input-dependent secondary neurons of the inner retina 'seeking replacement' for the input of lost photoreceptors. 19 It would appear that the remodeling of the inner retina that normally occurs in the course of degeneration is exacerbated by the expression of CNTF.…”

mentioning

confidence: 99%

Intraocular gene delivery of ciliary neurotrophic factor results in significant loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal degeneration

et al. 2003

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Intraocular delivery of a variety of neurotrophic factors has been widely investigated as a potential treatment for retinal dystrophy (RD). The most commonly studied factor, ciliary neurotrophic factor (CNTF), has been shown to preserve retinal morphology and to promote cell survival in a variety of models of RD. In order to evaluate CNTF as a potential treatment for RD, we used the Prph2 Rd2/Rd2 mouse. CNTF was expressed intraocularly using AAV-mediated gene delivery either by itself or, in a second treatment group, combined with AAV-mediated gene replacement therapy of peripherin2, which we have previously shown to improve photoreceptor structure and function. We confirmed in both groups of animals that CNTF reduces the loss of photoreceptor cells. Visual function, however, as assessed over a time course by electroretinography (ERG), was significantly reduced compared with untreated controls. Furthermore, CNTF gene expression negated the effects on function of gene replacement therapy. In order to test whether this deleterious effect is only seen when degenerating retina is treated, we recorded ERGs from wild-type mice following intraocular injection of AAV expressing CNTF. Here a marked deleterious effect was noted, in which the b-wave amplitude was reduced by at least 50%. Our results demonstrate that intraocular CNTF gene delivery may have a deleterious effect on the retina and caution against its application in clinical trials.

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Effects of Adeno-associated Virus-vectored Ciliary Neurotrophic Factor on Retinal Structure and Function in Mice with a P216L rds/peripherin Mutation

Cited by 194 publications

References 43 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

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Intraocular gene delivery of ciliary neurotrophic factor results in significant loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal degeneration

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