アデノ随伴ウイルス
The virus is known to instigate robust humoral immunity in animal models and in the human population where up to 80% of individuals are thought to be seropositive for AAV2. Antibodies are known to be neutralising and for gene therapy applications these do impact on vector transduction efficiency via some routes of administration. As well as persistent AAV specific antibody levels, it appears from both prime-boost studies in animals and from clinical trials that the B-cell memory is also strong. In seropositive humans, circulating IgG antibodies for AAV2 appear to be primarily composed of the IgG1 and IgG2 subclasses, with little or no IgG3 or IgG4 present.
Replication of the virus can also vary in one cell type, depending on the cell's current cell cycle phase.[71] The characteristic feature of the adeno-associated virus is a deficiency in replication and thus its inability to multiply in unaffected cells. The first factor that was described as providing successful generation of new AAV particles, was the adenovirus, from which the AAV name originated. It was then shown that AAV replication can be facilitated by selected proteins derived from the adenovirus genome, by other viruses such as HSV, or by genotoxic agents, such as UV irradiation or hydroxyurea.
The minimal set of the adenoviral genes required for efficient generation of progeny AAV particles, was discovered by Matsushita, Ellinger et al.
doi:10.1056/NEJMoa1108046
↑ Jessup, M; Greenberg B, Mancini DM, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo K, Dittrich H, Hajjar, RJ (June 2011). “Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure”. Circulation 124 (3): 304–313. doi:10.1161/CIRCULATIONAHA.111.022889. ISSN 1524-4539. PMID 21709064. http://circ.ahajournals.org/content/124/3/304.long 2012年3月24日閲覧。.
↑ LeWitt, P. A., Rezai, A. R., Leehey, M. A., Ojemann, S. G., Flaherty, A. W., Eskandar, E. N., Kostyk, S. K., et al. (2011).
AAVベクターに対する自然免疫反応はの特徴は、動物モデルで明らかにされている。
The innate immune response to the AAV vectors has been characterised in animal models. Intravenous administration in mice causes transient production of pro-inflammatory cytokines and some infiltration of neutrophils and other leukocytes into the liver, which seems to sequester a large percentage of the injected viral particles. Both soluble factor levels and cell infiltration appear to return to baseline within six hours. By contrast, more aggressive viruses produce innate responses lasting 24 hours or longer.
Effect of gene therapy on visual function in Leber's congenital amaurosis The New England journal of medicine, 358(21), 2231–2239. doi:10.1056/NEJMoa0802268 PMID 18441371
↑ Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., et al. (2008). Treatment of Leber Congenital Amaurosis Due to RPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial. Human gene therapy, 19(10), 979–990. doi:10.1089/hum.2008.107 PMID 18774912
↑ Nathwani, A. C., Tuddenham, E. G. D., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C., Chowdary, P., et al. (2011). Adenovirus-associated virus vector-mediated gene transfer in hemophilia B The New England journal of medicine, 365(25), 2357–2365.
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↑ Wu P, Xiao W, Conlon T, et al. (September 2000). “Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism”. Journal of Virology 74 (18): 8635–47. doi:10.1128/JVI.74.18.8635-8647.2000. PMC 102071. PMID 10954565. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102071/.
↑ Manno CS, Chew AJ, Hutchison S, et al. (April 2003). “AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B”. Blood 101 (8): 2963–72. doi:10.1182/blood-2002-10-3296. PMID 12515715.
↑ Richter M, Iwata A, Nyhuis J, et al. (April 2000). “Adeno-associated virus vector transduction of vascular smooth muscle cells in vivo”.
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↑ Di Pasquale G, Davidson BL, Stein CS, et al. (October 2003). “Identification of PDGFR as a receptor for AAV-5 transduction”. Nature Medicine 9 (10): 1306–12. doi:10.1038/nm929. PMID 14502277.
↑ Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA (May 2002). “Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors”. Journal of Virology 76 (9): 4580–90. doi:10.1128/JVI.76.9.4580-4590.2002. PMC 155101. PMID 11932423. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC155101/.
1 2 Zaiss AK, Muruve DA (June 2005).
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↑ Tullis GE, Shenk T (December 2000). “Efficient replication of adeno-associated virus type 2 vectors: a cis-acting element outside of the terminal repeats and a minimal size”. Journal of Virology 74 (24): 11511–21. doi:10.1128/JVI.74.24.11511-11521.2000. PMC 112431. PMID 11090148. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112431/.
1 2 Kyöstiö SR, Owens RA, Weitzman MD, Antoni BA, Chejanovsky N, Carter BJ (May 1, 1994). “Analysis of adeno-associated virus (AAV) wild-type and mutant Rep proteins for their abilities to negatively regulate AAV p5 and p19 mRNA levels”. Journal of Virology 68 (5): 2947–57. PMC 236783. PMID 8151765. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=8151765.