Rod Outer Segment Development Influences AAV-Mediated Photoreceptor Transduction After Subretinal Injection

Autor: Claudio Punzo, Shan Ma, Lolita Petit, Shun-Yun Cheng, Guangping Gao
Rok vydání: 2017
Předmět:
0301 basic medicine
Retinal degeneration
retina
genetic structures
Cellular differentiation
viruses
Cytomegalovirus
chemistry.chemical_compound
Transduction (genetics)
Mice
cones
Genes
Reporter
Transduction
Genetic
Promoter Regions
Genetic
Research Articles
Retinal Degeneration
Cell Differentiation
AAV
photoreceptors
Rod Cell Outer Segment
Dependovirus
gene therapy
Cell biology
medicine.anatomical_structure
Organ Specificity
Intravitreal Injections
Retinal Cone Photoreceptor Cells
Molecular Medicine
Expression cassette
Injections
Intraocular
Genetic Engineering
Genetic Vectors
Green Fluorescent Proteins
Mice
Transgenic
CHO Cells
Biology
Gene delivery
03 medical and health sciences
Cricetulus
rods
Genetics
medicine
Animals
Molecular Biology
Retina
Retinal
medicine.disease
Virology
Disease Models
Animal
030104 developmental biology
chemistry
sense organs
Zdroj: Human Gene Therapy
ISSN: 1557-7422
Popis: Vectors based on the adeno-associated virus (AAV) are currently the preferred tools for delivering genes to photoreceptors (PR) in small and large animals. AAVs have been applied successfully in various models of PR dystrophies. However, unknown barriers still limit AAV's efficient application in several forms of severe PR degenerations due to insufficient transgene expression and/or treated cells at the time of injection. Optimizations of PR gene therapy strategies will likely benefit from the identification of the cellular factors that influence PR transduction. Interestingly, recent studies have shown that the AAV transduction profile of PRs differs significantly between neonatal and adult mouse retinas after subretinal injection. This phenomenon may provide clues to identify host factors that influence the efficiency of AAV-mediated PR transduction. This study demonstrates that rod outer segments are critical modulators of efficient AAV-mediated rod transduction. During retinal development, rod transduction correlated temporally and spatially with the differentiation order of PRs when vectors were introduced subretinally but not when introduced intravitreally. All subretinally injected vectors had an initial preference to transduce cones in the absence of formed rod outer segments and then displayed a preference for rods as the cells matured, independently of the expression cassette or AAV serotype. Consistent with this observation, altered development of rod outer segments was associated with a strong reduction of rod transduction and an increase in the percentage of transduced cones by 2- to 2.8-fold. A similar increase of cone transduction was observed in the adult retinal degeneration 1 (rd1) retina compared to wild-type mice. These results suggest that the loss of rod outer segments in diseased retinas could markedly affect gene transfer efficiency of AAV vectors by limiting the ability of AAVs to infect dying rods efficiently. This information could be exploited for the development of more efficient AAV-based PR gene delivery procedures.
Databáze: OpenAIRE
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