Journal article
The degree of AAV-induced retinal inflammation varies based on serotype and route of delivery: intravitreal, subretinal or suprachoroidal
Human gene therapy, Vol.34(11-12), pp.530-539
06/2023
DOI: 10.1089/hum.2022.222
PMCID: PMC10282814
PMID: 36793189
Abstract
Adeno-associated virus (AAV) mediated gene therapy has great potential for treating a wide range of retinal degenerative diseases. However, some initial enthusiasm for gene therapy has been tempered by emerging evidence of AAV-associated inflammation, which in several instances has contributed to clinical trial discontinuation. Currently, there is a paucity of data describing the variable immune responses to different AAV serotypes, and similarly, little is known regarding how these responses differ depending on route of ocular delivery, including in animal models of disease. In this study, we characterize the severity and retinal distribution of AAV-associated inflammation in rats triggered by delivery of 5 different AAV vectors (AAV1, AAV2, AAV6, AAV8, AAV9), each of which contained eGFP driven under control of the constitutively active CMV promoter. We further compare the inflammation across 3 different potential routes (intravitreal, subretinal, suprachoroidal) of ocular delivery. Compared to buffer-injected controls for each route of delivery, AAV2 and AAV6 induced the most inflammation across all routes of delivery of the vectors tested, with AAV6 inducing the highest levels of inflammation when delivered suprachoroidally. AAV1-induced inflammation was highest when delivered suprachoroidally, whereas minimal inflammation was seen with intravitreal delivery. AAV8 and AAV9 induced minimal inflammation across all routes of delivery. Importantly, the degree of inflammation was not correlated with vector-mediated transduction and expression of eGFP. These data emphasize the importance of considering ocular inflammation when selecting AAV serotypes and ocular delivery routes for the development of gene therapy strategies.
Details
- Title: Subtitle
- The degree of AAV-induced retinal inflammation varies based on serotype and route of delivery: intravitreal, subretinal or suprachoroidal
- Creators
- Luke Aaron Wiley - University of IowaTimothy M Boyce - University of IowaEmily E Meyering - University of IowaDalyz Ochoa - University of IowaKatie M Sheehan - University of IowaEdwin Stone - University of IowaRobert F Mullins - University of IowaBudd A Tucker - University of IowaIan C Han - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.34(11-12), pp.530-539
- DOI
- 10.1089/hum.2022.222
- PMID
- 36793189
- PMCID
- PMC10282814
- NLM abbreviation
- Hum Gene Ther
- eISSN
- 1557-7422
- Language
- English
- Electronic publication date
- 02/15/2023
- Date published
- 06/2023
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; John and Marcia Carver Nonprofit Genetic Testing Laboratory; Ophthalmology and Visual Sciences
- Record Identifier
- 9984367186302771
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