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Caspase inhibition with XIAP as an adjunct to AAV vector gene-replacement therapy: improving efficacy and prolonging the treatment window.

AbstractPURPOSE:
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.
AuthorsJingyu Yao, Lin Jia, Naheed Khan, Qiong-Duan Zheng, Ashley Moncrief, William W Hauswirth, Debra A Thompson, David N Zacks
JournalPloS one (PLoS One) Vol. 7 Issue 5 Pg. e37197 ( 2012) ISSN: 1932-6203 [Electronic] United States
PMID22615940 (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)

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