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P. Buch, K.S. Balaggan, Y. Durán, A.J. Smith, C. Broderick, R.R. Ali; AAV–Mediated GDNF Expression in Combination With Gene Replacement Therapy to Treat Rodent Models of Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5226.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: AAV– and lentivirus–mediated gene replacement therapy has been used to rescue various animal models of inherited retinal degeneration (RD). However, replacing the mutated gene does not always significantly slow apoptotic loss of photoreceptors (PRs). Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and glial cell line–derived neurotrophic factor (GDNF) have been shown to enhance photoreceptor (PR) survival in rodent models of RD on their own, but AAV–mediated CNTF expression results in suppression of electrophysiological response in both wild–type and degenerating retinae. Here we investigate the ability of AAV–mediated delivery of GDNF to delay apoptosis in two rodent models of RD, and prolong functional rescue in combination with the relevant gene replacement therapy. Methods: Rds mice, homozygous for a null mutation in the Peripherin gene, were given sub–retinal injections of an AAV2 vector encoding the Peripherin gene driven by a rhodopsin promoter (AAV.Rho.Prph2, left eye). A combination of the AAV.Rho.Prph2 construct and AAV.CBA.GDNF was injected sub–retinally into the contralateral (right) eyes. A group of Rds mice received sub–retinal injections of AAV.CBA.GDNF only, to assess neuroprotective effect of the growth factor alone. RCS rats, homozygous for a null mutation in the MERTK gene, received sub–retinal injections of Lenti.MERTK (left eye) or Lenti.MERTK and AAV.CBA.GDNF (right eye). ERG was performed at various time points, and paraffin histology was carried out on Rds eyes treated with GDNF. Results: Preliminary functional data show that GDNF expression both in Rds mice (4 and 6 weeks post–injection) and in RCS rats (4 weeks post injection) has no detrimental effect on ERG in combination with gene replacement, unlike the ERG suppression seen previously after AAV–mediated ciliary neurotrophic factor (CNTF) expression. Long–term follow up of these rodents will show whether GDNF–treated eyes show prolonged rescue once Prhp2– and MERTK–only treated eyes have lost their function. Histological analysis on GDNF–only treated Rds eyes at four months post–injection shows 25% more photoreceptors surviving in the outer nuclear layer in treated vs. non–treated eyes (p=0.009). Conclusions: These results show that AAV–mediated delivery of GDNF delays PR cell death, without disrupting their function, and that this approach warrants further investigation as a neuroprotective treatment. We will now investigate whether AAV–mediated delivery of GDNF enhances gene replacement therapy.
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