Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates.

Autor:	Seitz IP; University Eye Hospital, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Michalakis S; Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany., Wilhelm B; STZ Eyetrial at the Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Reichel FF; University Eye Hospital, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Ochakovski GA; University Eye Hospital, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Zrenner E; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Ueffing M; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Biel M; Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany., Wissinger B; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Bartz-Schmidt KU; University Eye Hospital, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Peters T; STZ Eyetrial at the Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Fischer MD; University Eye Hospital, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; STZ Eyetrial at the Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2017 Nov 01; Vol. 58 (13), pp. 5792-5801.
DOI:	10.1167/iovs.17-22473
Abstrakt:	Purpose: To investigate shedding and biodistribution characteristics of recombinant adeno-associated virus serotype 8 (rAAV8) after single-dose subretinal or intravitreal injection in nonhuman primates (NHP, Macaca fascicularis) as a surrogate for environmental hazard and patient safety. Methods: In a study for regulatory submission, 22 NHP were divided into four cohorts receiving either single subretinal injections of vehicle or clinical grade rAAV8 (1 × 1011 or 1 × 1012 vector genomes [vg]) versus single intravitreal application of 1 × 1012 vg. Viral shedding and biodistribution were monitored in biofluids for up to 91 days, followed by necropsy and tissue harvesting of all major organs, the visual pathway, and lymphatic tissue. Quantification of vector genomes was done by quantitative (q)PCR. Results: Shedding occurred in a dose-dependent manner in all biofluids and persisted for a maximum of 7 days. Intravitreal delivery led to increased and persistent (up to 13 weeks) distribution of vector genomes in blood and draining lymphatic tissue, increased off-target deposition, and inefficient gene transfer to the retina. No vector targeting of the germ line was observed in any cohort. Conclusions: These data illustrate that subretinal application of rAAV8 leads to a more favorable biodistribution profile compared to intravitreal injections. Extraocular biodistribution is limited after subretinal delivery, while intravitreal injection leads to both greater and more persistent systemic exposure, evident in blood and lymphatic tissues. With the knowledge on the dynamics of shedding in a setting mimicking clinical application, guidelines can be developed to refine clinical trial protocols to reduce the risk for trial subjects and their environment.
Databáze:	MEDLINE
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