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001     155698
005     20230915092337.0
024 7 _ |a 10.1089/hum.2020.321
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024 7 _ |a 1557-7422
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037 _ _ |a DZNE-2021-00866
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Völkner, Manuela
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245 _ _ |a Optimized Adeno-Associated Virus Vectors for Efficient Transduction of Human Retinal Organoids.
260 _ _ |a New York, NY
|c 2021
|b Liebert
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520 _ _ |a The most widely used vectors for gene delivery in the retina are recombinant adeno-associated virus (rAAV) vectors. They have proven to be safe and effective in retinal gene therapy studies aimed to treat inherited retinal dystrophies, although with various limitations in transduction efficiency. Novel variants with modified capsid sequences have been engineered to improve transduction and overcome limitations of naturally occurring variants. Although preclinical evaluation of rAAV vectors based on such novel capsids is mostly done in animal models, the use of human induced pluripotent stem cell (hiPSC)-derived organoids offers an accessible and abundant human testing platform for rAAV evaluation. In this study, we tested the novel capsids, AAV9.GL and AAV9.NN, for their tropism and transduction efficiency in hiPSC-derived human retinal organoids (HROs) with all major neuronal and glial cell types in a laminated structure. These variants are based on the AAV9 capsid and were engineered to display specific surface-exposed peptide sequences, previously shown to improve the retinal transduction properties in the context of AAV2. To this end, HROs were transduced with increasing concentrations of rAAV9, rAAV9.GL, or rAAV9.NN carrying a self-complementary genome with a cytomegalovirus-enhanced green fluorescent protein (eGFP) cassette and were monitored for eGFP expression. The rAAV vectors transduced HROs in a dose-dependent manner, with rAAV9.NN achieving the highest efficiency and fastest onset kinetics, leading to detectable eGFP signals in photoreceptors, some interneurons, and Müller glia already at 2 days post-transduction. The potency-enhancing effect of the NN peptide insert was replicated when using the corresponding AAV2-based version (rAAV2.NN). Taken together, we report the application of an HRO system for screening novel AAV vectors and introduce novel vector candidates with enhanced transduction efficiency for human retinal cells.
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650 _ 7 |a adeno-associated virus
|2 Other
650 _ 7 |a engineered AAV vector
|2 Other
650 _ 7 |a human retinal organoids
|2 Other
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Dependovirus: genetics
|2 MeSH
650 _ 2 |a Gene Transfer Techniques
|2 MeSH
650 _ 2 |a Genetic Vectors: genetics
|2 MeSH
650 _ 2 |a Green Fluorescent Proteins: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells
|2 MeSH
650 _ 2 |a Organoids
|2 MeSH
650 _ 2 |a Retina
|2 MeSH
650 _ 2 |a Transduction, Genetic
|2 MeSH
700 1 _ |a Pavlou, Marina
|b 1
700 1 _ |a Büning, Hildegard
|b 2
700 1 _ |a Michalakis, Stylianos
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700 1 _ |a Karl, Mike Oliver
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773 _ _ |a 10.1089/hum.2020.321
|g Vol. 32, no. 13-14, p. 694 - 706
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