Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness
- PMID: 16226919
- PMCID: PMC3647373
- DOI: 10.1016/j.ymthe.2005.08.008
Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness
Abstract
The short- and long-term effects of gene therapy using AAV-mediated RPE65 transfer to canine retinal pigment epithelium were investigated in dogs affected with disease caused by RPE65 deficiency. Results with AAV 2/2, 2/1, and 2/5 vector pseudotypes, human or canine RPE65 cDNA, and constitutive or tissue-specific promoters were similar. Subretinally administered vectors restored retinal function in 23 of 26 eyes, but intravitreal injections consistently did not. Photoreceptoral and postreceptoral function in both rod and cone systems improved with therapy. In dogs followed electroretinographically for 3 years, responses remained stable. Biochemical analysis of retinal retinoids indicates that mutant dogs have no detectable 11-cis-retinal, but markedly elevated retinyl esters. Subretinal AAV-RPE65 treatment resulted in detectable 11-cis-retinal expression, limited to treated areas. RPE65 protein expression was limited to retinal pigment epithelium of treated areas. Subretinal AAV-RPE65 vector is well tolerated and does not elicit high antibody levels to the vector or the protein in ocular fluids or serum. In long-term studies, wild-type cDNA is expressed only in target cells. Successful, stable restoration of rod and cone photoreceptor function in these dogs has important implications for treatment of human patients affected with Leber congenital amaurosis caused by RPE65 mutations.
Figures
![FIG. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3647373/bin/nihms-176451-f0001.gif)
![FIG. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3647373/bin/nihms-176451-f0002.gif)
![FIG. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3647373/bin/nihms-176451-f0003.gif)
Similar articles
-
The Status of RPE65 Gene Therapy Trials: Safety and Efficacy.Cold Spring Harb Perspect Med. 2015 Jan 29;5(9):a017285. doi: 10.1101/cshperspect.a017285. Cold Spring Harb Perspect Med. 2015. PMID: 25635059 Free PMC article. Review.
-
RPE65: role in the visual cycle, human retinal disease, and gene therapy.Ophthalmic Genet. 2009 Jun;30(2):57-62. doi: 10.1080/13816810802626399. Ophthalmic Genet. 2009. PMID: 19373675 Free PMC article. Review.
-
Gene therapeutic prospects in early onset of severe retinal dystrophy: restoration of vision in RPE65 Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium.Bull Mem Acad R Med Belg. 2006;161(10-12):497-508; discussion 508-9. Bull Mem Acad R Med Belg. 2006. PMID: 17503728
-
Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium.Gene Ther. 2007 Feb;14(4):292-303. doi: 10.1038/sj.gt.3302861. Epub 2006 Oct 5. Gene Ther. 2007. PMID: 17024105
-
Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis.Hum Gene Ther. 2006 Aug;17(8):845-58. doi: 10.1089/hum.2006.17.845. Hum Gene Ther. 2006. PMID: 16942444
Cited by
-
Fine-tuning FAM161A gene augmentation therapy to restore retinal function.EMBO Mol Med. 2024 Apr;16(4):805-822. doi: 10.1038/s44321-024-00053-x. Epub 2024 Mar 19. EMBO Mol Med. 2024. PMID: 38504136 Free PMC article.
-
Retinal response to light exposure in BEST1-mutant dogs evaluated with ultra-high resolution OCT.Vision Res. 2024 May;218:108379. doi: 10.1016/j.visres.2024.108379. Epub 2024 Mar 8. Vision Res. 2024. PMID: 38460402
-
ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells.Nat Commun. 2023 Dec 20;14(1):8463. doi: 10.1038/s41467-023-44319-3. Nat Commun. 2023. PMID: 38123547 Free PMC article.
-
The rod synapse in aging wildtype and Dscaml1 mutant mice.PLoS One. 2023 Nov 1;18(11):e0290257. doi: 10.1371/journal.pone.0290257. eCollection 2023. PLoS One. 2023. PMID: 37910517 Free PMC article.
-
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.Nat Commun. 2023 Jul 5;14(1):3962. doi: 10.1038/s41467-023-39552-9. Nat Commun. 2023. PMID: 37407555 Free PMC article.
References
-
- Hanein S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype–phenotype correlations as a strategy for molecular diagnosis. Hum. Mutat. 2004;23:306–317. - PubMed
-
- Preising MN, Heegard S. Recent advances in early-onset severe retinal degeneration: more than just basic research. Trends Mol. Med. 2004;10:51–54. - PubMed
-
- Cremers FP, van den Hurk JA, den Hollander AI. Molecular genetics of Leber congenital amaurosis. Hum. Mol. Genet. 2002;11:1169–1176. - PubMed
-
- Thompson DA, Gal A. Vitamin A metabolism in the retinal pigment epithelium: genes, mutations, and diseases. Prog. Retinal Eye Res. 2003;22:683–703. - PubMed
-
- Baehr W, et al. The retinoid cycle and retinal disease. Vision Res. 2003;43:2957–2958. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- EY 08061/EY/NEI NIH HHS/United States
- EY 06855/EY/NEI NIH HHS/United States
- R01 EY006855/EY/NEI NIH HHS/United States
- EY 11123/EY/NEI NIH HHS/United States
- R01 EY008061/EY/NEI NIH HHS/United States
- EY 13385/EY/NEI NIH HHS/United States
- R01 EY013132/EY/NEI NIH HHS/United States
- R01 EY010820-11/EY/NEI NIH HHS/United States
- U10 EY 13729/EY/NEI NIH HHS/United States
- U10 EY013729/EY/NEI NIH HHS/United States
- U10 EY013729-01/EY/NEI NIH HHS/United States
- R01 EY011123/EY/NEI NIH HHS/United States
- R01 EY010820-12/EY/NEI NIH HHS/United States
- P30 EY021721/EY/NEI NIH HHS/United States
- R01 EY010820/EY/NEI NIH HHS/United States
- EY 13132/EY/NEI NIH HHS/United States
- R01 EY013385/EY/NEI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical