Abstract
No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8 and 9, but unlike these parental serotypes after intravenous administration Olig001 has very low affinity for peripheral organs, especially the liver. Furthermore, in mixed glial cell cultures, Olig001 exhibits a 9-fold greater binding when compared with AAV8. This novel oligodendrocyte-preferring AAV vector exhibits characteristics that are a marked departure from previously described AAV serotypes.
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References
Hadaczek P, Eberling JL, Pivirotto P, Bringas J, Forsayeth J, Bankiewicz KS . Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther 2010; 18: 1458–1461.
Kantor B, McCown T, Leone P, Gray SJ . Clinical applications involving CNS gene transfer. Adv Genet 2014; 87: 71–124.
Kantor B, Bailey RM, Wimberly K, Kalburgi SN, Gray SJ . Methods for gene transfer to the central nervous system. Adv Genet 2014; 87: 125–197.
McPhee SW, Janson CG, Li C, Samulski RJ, Camp AS, Francis J et al. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006; 8: 577–588.
Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther 2010; 18: 1731–1735.
Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 2014; 10: 571–581.
Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 2004; 10: 302–317.
Davidson BL, Stein CS, Heth JA, Martins I, Kotin RM, Derksen TA et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000; 97: 3428–3432.
Harding TC, Dickinson PJ, Roberts BN, Yendluri S, Gonzalez-Edick M, Lecouteur RA et al. Enhanced gene transfer efficiency in the murine striatum and an orthotopic glioblastoma tumor model, using AAV-7- and AAV-8-pseudotyped vectors. Hum Gene Ther 2006; 17: 807–820.
Klein RL, Dayton RD, Leidenheimer NJ, Jansen K, Golde TE, Zweig RM . Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins. Mol Ther 2006; 13: 517–527.
Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 2009; 27: 59–65.
Cearley CN, Wolfe JH . Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther 2006; 13: 528–537.
Cearley CN, Vandenberghe LH, Parente MK, Carnish ER, Wilson JM, Wolfe JH . Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol Ther 2008; 16: 1710–1718.
San Sebastian W, Samaranch L, Heller G, Kells AP, Bringas J, Pivirotto P et al. Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. Gene Therapy 2013; 20: 1178–1183.
Chen H, McCarty DM, Bruce AT, Suzuki K, Suzuki K . Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus. Gene Therapy 1998; 5: 50–58.
Lawlor PA, Bland RJ, Mouravlev A, Young D, During MJ . Efficient gene delivery and selective transduction of glial cells in the mammalian brain by AAV serotypes isolated from nonhuman primates. Mol Ther 2009; 17: 1692–1702.
Gray SJ, Blake BL, Criswell HE, Nicolson SC, Samulski RJ, McCown TJ et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther 2010; 18: 570–578.
Agbandje-McKenna M, Kleinschmidt J . AAV capsid structure and cell interactions. Methods Mol Biol 2011; 807: 47–92.
Govindasamy L, Padron E, McKenna R, Muzyczka N, Kaludov N, Chiorini JA et al. Structurally mapping the diverse phenotype of adeno-associated virus serotype 4. J Virol 2006; 80: 11556–11570.
Nonnenmacher M, Weber T . Intracellular transport of recombinant adeno-associated virus vectors. Gene Therapy 2012; 19: 649–658.
Asokan A, Conway JC, Phillips JL, Li C, Hegge J, Sinnott R et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 2010; 28: 79–82.
Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 2012; 20: 443–455.
Pulicherla N, Shen S, Yadav S, Debbink K, Govindasamy L, Agbandje-McKenna M et al. Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol Ther 2011; 19: 1070–1078.
Hughes EG, Kang SH, Fukaya M, Bergles DE . Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci 2013; 16: 668–676.
Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 2013; 16: 571–579.
Gray SJ, Foti SB, Schwartz JW, Bachaboina L, Taylor-Blake B, Coleman J et al. Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther 2011; 22: 1143–1153.
Sondhi D, Hackett NR, Peterson DA, Stratton J, Baad M, Travis KM et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Ther 2007; 15: 481–491.
Taymans JM, Vandenberghe LH, Haute CV, Thiry I, Deroose CM, Mortelmans L et al. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 2007; 18: 195–206.
Klein RL, Dayton RD, Tatom JB, Henderson KM, Henning PP . AAV8, 9, Rh10, Rh43 vector gene transfer in the rat brain: effects of serotype, promoter and purification method. Mol Ther 2008; 16: 89–96.
Paneda A, Vanrell L, Mauleon I, Crettaz JS, Berraondo P, Timmermans EJ et al. Effect of adeno-associated virus serotype and genomic structure on liver transduction and biodistribution in mice of both genders. Hum Gene Ther 2009; 20: 908–917.
Xiao PJ, Li C, Neumann A, Samulski RJ . Quantitative 3D tracing of gene-delivery viral vectors in human cells and animal tissues. Mol Ther 2012; 20: 317–328.
Li W, Asokan A, Wu Z, Van Dyke T, DiPrimio N, Johnson JS et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther 2008; 16: 1252–1260.
Gray SJ, Nagabhushan Kalburgi S, McCown TJ, Jude Samulski R . Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Therapy 2013; 20: 450–459.
Paxinos G, Watson C The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego, CA, USA, 2014.
McCarthy KD, de Vellis J . Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 1980; 85: 890–902.
Acknowledgements
These studies were supported by Michael J. Fox Foundation and Target ALS grants to TJM, as well as a grant from the Legacy of Angels to SJG. Indirect administrative support for SJG was provided by Research to Prevent Blindness to the UNC Department of Ophthalmology.
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SJG and TJM are inventors for a filed patent by UNC that includes the Olig001 capsid and is licensed to Asklepios Biopharmaceutical. They have received royalties from Asklepios Biopharmaceutical for this patent. RJS is a scientific co-founder of Asklepios Biopharmaceutical. The remaining authors declare no conflict of interest.
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Powell, S., Khan, N., Parker, C. et al. Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism. Gene Ther 23, 807–814 (2016). https://doi.org/10.1038/gt.2016.62
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DOI: https://doi.org/10.1038/gt.2016.62
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