Abstract | PURPOSE: AAV-mediated gene therapy in the rd10 mouse, with retinal degeneration caused by mutation in the rod cyclic guanosine monophosphate phosphodiesterase β-subunit (PDEβ) gene, produces significant, but transient, rescue of photoreceptor structure and function. This study evaluates the ability of AAV-mediated delivery of X-linked inhibitor of apoptosis (XIAP) to enhance and prolong the efficacy of PDEβ gene-replacement therapy. METHODS: Rd10 mice were bred and housed in darkness. Two groups of animals were generated: Group 1 received sub- retinal AAV5-XIAP or AAV5-GFP at postnatal age (P) 4 or 21 days; Group 2 received sub- retinal AAV5-XIAP plus AAV5- PDEβ, AAV5-GFP plus AAV5- PDEβ, or AAV- PDEβ alone at age P4 or P21. Animals were maintained for an additional 4 weeks in darkness before being moved to a cyclic-light environment. A subset of animals from Group 1 received a second sub- retinal injection of AAV8-733-PDEβ two weeks after being moved to the light. Histology, immunohistochemistry, Western blots, and electroretinograms were performed at different times after moving to the light. RESULTS: Injection of AAV5-XIAP alone at P4 and 21 resulted in significant slowing of light-induced retinal degeneration, as measured by outer nuclear thickness and cell counts, but did not result in improved outer segment structure and rhodopsin localization. In contrast, co-injection of AAV5-XIAP and AAV5-PDEβ resulted in increased levels of rescue and decreased rates of retinal degeneration compared to treatment with AAV5-PDEβ alone. Mice treated with AAV5-XIAP at P4, but not P21, remained responsive to subsequent rescue by AAV8-733-PDEβ when injected two weeks after moving to a light-cycling environment. CONCLUSIONS: Adjunctive treatment with the anti-apoptotic gene XIAP confers additive protective effect to gene-replacement therapy with AAV5-PDEβ in the rd10 mouse. In addition, AAV5-XIAP, when given early, can increase the age at which gene-replacement therapy remains effective, thus effectively prolonging the window of opportunity for therapeutic intervention.
|
Authors | Jingyu Yao, Lin Jia, Naheed Khan, Qiong-Duan Zheng, Ashley Moncrief, William W Hauswirth, Debra A Thompson, David N Zacks |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 5
Pg. e37197
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 22615940
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Caspase Inhibitors
- X-Linked Inhibitor of Apoptosis Protein
- Cyclic Nucleotide Phosphodiesterases, Type 6
- Pde6b protein, mouse
|
Topics |
- Animals
- Caspase Inhibitors
- Cyclic Nucleotide Phosphodiesterases, Type 6
(biosynthesis, genetics)
- Dependovirus
(genetics)
- Disease Models, Animal
- Electroretinography
- Genetic Therapy
(methods)
- Genetic Vectors
- Light
(adverse effects)
- Mice
- Mice, Inbred C57BL
- Photoreceptor Cells, Vertebrate
(metabolism)
- Retinal Degeneration
(genetics, therapy)
- X-Linked Inhibitor of Apoptosis Protein
(therapeutic use)
|