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

Abstract

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.

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

“…The disorganization in the normal retinal layering was associated with the loss of inner and outer segments, which has been also observed by others (Schlichtenbrede et al, 2003;Song et al, 2005), Similar alterations were found in the retinas of transgenic mice that constitutively express leukemia inhibitory factor Sherry et al, 2005). Although IS are beginning to bud in the 4 week-old canine peripheral retina, IS and OS are fully formed when the retina has reached maturity at 7-8 weeks of age.…”

“…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).…”

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

“…32,33 Of course, increased transduction and stronger transgene expression from gene therapy applications may not necessarily lead to better outcomes, and there is likely to be a fine balance between therapeutic and detrimental expression levels, especially for genes that encode secretable proteins. [34][35][36] This should also be taken into account when choosing promoters that may increase the specificity of transgene expression [37][38][39] and when designing vector systems that allow the temporal regulation of transgene expression. [40][41][42][43] Although comparable in terms of overall transduction efficiency, the tropism profile between rAAV2/2 and rAAV2/6 was considerably different.…”

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

“…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…”