gms | German Medical Science

102. Jahrestagung der DOG

Deutsche Ophthalmologische Gesellschaft e. V.

23. bis 26.09.2004, Berlin

The potential of gene therapy for the treatment of retinal degenerative diseases

Meeting Abstract

Search Medline for

  • corresponding author G. Aguirre - University of Pennsylvania, College of Veterinary Medicine, Philadelphia/USA

Evidenzbasierte Medizin - Anspruch und Wirklichkeit. 102. Jahrestagung der Deutschen Ophthalmologischen Gesellschaft. Berlin, 23.-26.09.2004. Düsseldorf, Köln: German Medical Science; 2004. Doc04dogSA.11.02

The electronic version of this article is the complete one and can be found online at:

Published: September 22, 2004

© 2004 Aguirre.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Retinal degenerations are a large group of diseases that are a major cause of blindness worldwide. While the causes and the phenotypes of these diseases can vary, they all share a common feature: the degeneration and death of the photoreceptor cells. No form of treatment that prevents or stops the degeneration of photoreceptor is currently available, thus, patients diagnosed with retinal degeneration are bound to experience visual impairment or blindness.

Different approaches for treatment of retinal degenerations are under development; among these are corrective gene therapy, survival factors, transplantation of retinal tissue or stem cells, subretinal or epiretinal implantations of chips and others. In order to develop a new generation of treatment modalities, the use of animal models is essential. In this discussion, I will presents studies using gene augmentation therapy in the experimental treatment of retinal diseases.

The RPE65 mutant dog has an autosomal recessive congenital blindness caused by a 4 basepair deletion in the RPE65 gene, and is a natural model of human Leber Congenital Amaurosis (LCA). The affected animal has markedly elevated ERG thresholds, reduced b-wave amplitude,s and no detectable a-wave. To determine if this disease was amenable to genetic manipulation, we carried out intraocular injections of AAV vectors carrying a chicken beta-actin-driven canine cDNA encoding wildtype RPE65, and examined the resultant phenotype using methods of assessment such as ERG, pupillometry, vision testing, morphology, gene expression, immunocytochemistry and retinoid analysis. This work is being done as part of an NEI/NIH consortium in which several laboratories and investigators participate (G.D. Aguirre, S. Jacobson, A. Maguire, J. Bennett, S. Pearce-Kelling, K. Palczewski ,T. Aleman, A. Cideciyan, W. Hauswirth G.K. Aguirre and G. Acland).

In the first study, restoration of visual function was demonstrated 3 months after subretinal injection in dogs treated at 3-4 months of age; intravitreal delivery was not effective. ERG b-wave thresholds were improved by ~3 log units, ERG a- and b-wave amplitudes were markedly increased, and waveform shape approximated that of normal controls. As well, cortical evoked potentials and behavioral assessment supported the ERG evidence of restored visual function. Two of these dogs have been studied post-treatment, and the improvement in ERG parameters and visual function (3+ years) has remained unchanged.

Additional dogs ranging in age from 4-11 months have injected with AAV-RPE65 vector either subretinally or intravitreally. The injections were well tolerated, and treated dogs showed no evidence of intraocular inflammation except a small number of dogs that received a vector preparation that was not subjected to rigorous purification. The results confirmed the findings in the initial study. In general, pupillometry response threshold, dark adapted ERG b-wave amplitudes, light adapted 29 Hz cone flicker amplitudes and cortical responses assessed by fMRI improved in subretinally injected eyes, but not in eyes receiving AAV-RPE65 by the intravitreal route. The treated eyes showed expression of RPE65 protein in the RPE of the treated regions, and no expression in any other cells. Retinoid analysis showed that 11-cis retinal, the photoactive chromophore of opsin, is present in treated areas following subretinal injection, but the accumulating retinyl esters of the RPE do not show any reductions.

In conclusion, the restoration of visual function in the LCA mutant dog model following subretinal injection of AAV-RPE65 is stable, an indication of long-term expression of the transferred cDNA. The effect is critically dependent on subretinal delivery of the vector, and fails following intravitreal administration.