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Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates


Autoři: Jeff L. Ellsworth aff001;  Jacinthe Gingras aff001;  Laura J. Smith aff001;  Hillard Rubin aff001;  Tania A. Seabrook aff001;  Kruti Patel aff001;  Nicole Zapata aff001;  Kevin Olivieri aff001;  Michael O’Callaghan aff001;  Elizabeth Chlipala aff002;  Pablo Morales aff003;  Albert Seymour aff001
Působiště autorů: Homology Medicines, Inc., Bedford, Massachusetts, United States of America aff001;  Premier Laboratory, LLC., Boulder, Colorado, United States of America aff002;  Mannheimer Foundation, Inc., Homestead, Florida, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225582

Souhrn

The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis). Animals received a single intravenous (IV) injection of a self-complementary AAVHSC-enhanced green fluorescent protein (eGFP) vector and tissues were harvested at two weeks post-dose for anti-eGFP immunohistochemistry and vector genome analyses. IV delivery of AAVHSC vectors produced widespread distribution of eGFP staining in glial cells throughout the central nervous system, with the highest levels seen in the pons and lateral geniculate nuclei (LGN). eGFP-positive neurons were also observed throughout the central and peripheral nervous systems for all three AAVHSC vectors including brain, spinal cord, and dorsal root ganglia (DRG) with staining evident in neuronal cell bodies, axons and dendritic arborizations. Co-labeling of sections from brain, spinal cord, and DRG with anti-eGFP antibodies and cell-specific markers confirmed eGFP-staining in neurons and glia, including protoplasmic and fibrous astrocytes and oligodendrocytes. For all capsids tested, 50 to 70% of glial cells (S100-β+) and on average 8% of neurons (NeuroTrace+) in the LGN were positive for eGFP expression. In the DRG, 45 to 62% of neurons and 8 to 12% of satellite cells were eGFP-positive for the capsids tested. eGFP staining was also observed in peripheral tissues with abundant staining in hepatocytes, skeletal- and cardio-myocytes and in acinar cells of the pancreas. Biodistribution of AAVHSC vector genomes in the central and peripheral organs generally correlated with eGFP staining and were highest in the liver for all AAVHSC vectors tested. These data demonstrate that AAVHSCs have broad tissue tropism and cross the blood-nerve and blood-brain-barriers following systemic delivery in nonhuman primates, making them suitable gene editing or gene transfer vectors for therapeutic application in human genetic diseases.

Klíčová slova:

Cell staining – Central nervous system – Cytoplasmic staining – Intravenous injections – Macaque – Neurons – Primates


Zdroje

1. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015;372(20):1887–97. Epub 2015/05/06. doi: 10.1056/NEJMoa1414221 25938638; PubMed Central PMCID: PMC4497809.

2. Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, et al. Visual Acuity after Retinal Gene Therapy for Choroideremia. N Engl J Med. 2016;374(20):1996–8. Epub 2016/04/28. doi: 10.1056/NEJMc1509501 27120491; PubMed Central PMCID: PMC4996318.

3. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med. 2017;377(23):2215–27. Epub 2017/12/07. doi: 10.1056/NEJMoa1708538 29211678; PubMed Central PMCID: PMC6029626.

4. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr., Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358(21):2240–8. Epub 2008/04/29. doi: 10.1056/NEJMoa0802315 18441370; PubMed Central PMCID: PMC2829748.

5. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1713–22. Epub 2017/11/02. doi: 10.1056/NEJMoa1706198 29091557.

6. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017;377(26):2519–30. Epub 2017/12/12. doi: 10.1056/NEJMoa1708483 29224506.

7. Patricio MI, Barnard AR, Xue K, MacLaren RE. Choroideremia: molecular mechanisms and development of AAV gene therapy. Expert Opin Biol Ther. 2018:1–14. Epub 2018/06/23. doi: 10.1080/14712598.2018.1484448 29932012.

8. Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643–50. Epub 2009/12/03. doi: 10.1038/mt.2009.277 19953081; PubMed Central PMCID: PMC2839440.

9. Penaud-Budloo M, Francois A, Clement N, Ayuso E. Pharmacology of Recombinant Adeno-associated Virus Production. Mol Ther Methods Clin Dev. 2018;8:166–80. Epub 2018/04/25. doi: 10.1016/j.omtm.2018.01.002 29687035; PubMed Central PMCID: PMC5908265.

10. Smith LJ, Ul-Hasan T, Carvaines SK, Van Vliet K, Yang E, Wong KK Jr., et al. Gene transfer properties and structural modeling of human stem cell-derived AAV. Mol Ther. 2014;22(9):1625–34. Epub 2014/06/14. doi: 10.1038/mt.2014.107 24925207; PubMed Central PMCID: PMC4435483.

11. Smith LJ, Wright J, Clark G, Ul-Hasan T, Jin X, Fong A, et al. Stem cell-derived clade F AAVs mediate high-efficiency homologous recombination-based genome editing. Proc Natl Acad Sci U S A. 2018;115:E7379–E88. Epub 2018/07/19. doi: 10.1073/pnas.1802343115 30018062.

12. Ahmed S, Ellsworth JL, Francone O, Faulkner D, Sengooba A, Dollive S, et al. Sustained Correction of Phenylketonuria by a Single Dose of AAVHSC Packaging a Human Phenylalanine Hydroxylase Transgene. Molecular Therapy. 2018;26(5S1):252.

13. Ellsworth JL, Smith LJ, Rubin H, Seymour A, Morales PR, Chlipala E, et al. Widespread Transduction of the Central Nervous System Following Systemic Delivery of AAVHSC17 in Non-Human Primates. Mol Ther. 2017;25(5S1):262.

14. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381–8. Epub 2004/05/28. doi: 10.1128/JVI.78.12.6381-6388.2004 15163731; PubMed Central PMCID: PMC416542.

15. 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(1):59–65. Epub 2008/12/23. doi: 10.1038/nbt.1515 19098898; PubMed Central PMCID: PMC2895694.

16. Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar AM, et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther. 2009;17(7):1187–96. Epub 2009/04/16. doi: 10.1038/mt.2009.71 19367261; PubMed Central PMCID: PMC2835208.

17. Jackson KL, Dayton RD, Klein RL. AAV9 supports wide-scale transduction of the CNS and TDP-43 disease modeling in adult rats. Mol Ther Methods Clin Dev. 2015;2:15036. Epub 2015/10/09. doi: 10.1038/mtm.2015.36 26445725; PubMed Central PMCID: PMC4588447.

18. Bevan AK, Duque S, Foust KD, Morales PR, Braun L, Schmelzer L, et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther. 2011;19(11):1971–80. Epub 2011/08/04. doi: 10.1038/mt.2011.157 21811247; PubMed Central PMCID: PMC3222525.

19. Gray SJ, Matagne V, Bachaboina L, Yadav S, Ojeda SR, Samulski RJ. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther. 2011;19(6):1058–69. Epub 2011/04/14. doi: 10.1038/mt.2011.72 21487395; PubMed Central PMCID: PMC3129805.

20. AveXis receives FDA approval for Zolgensma®, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA) [Website]. 2019 [updated May 24, 2019]. Available from: http://www.novartis.com.

21. Hordeaux J, Wang Q, Katz N, Buza EL, Bell P, Wilson JM. The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice. Mol Ther. 2018;26(3):664–8. Epub 2018/02/13. doi: 10.1016/j.ymthe.2018.01.018 29428298; PubMed Central PMCID: PMC5911151.

22. Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD, Mollgard K, et al. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci. 2014;8:404. Epub 2015/01/08. doi: 10.3389/fnins.2014.00404 25565938; PubMed Central PMCID: PMC4267212.

23. Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol. 2012;3:46. Epub 2012/04/06. doi: 10.3389/fphar.2012.00046 22479246; PubMed Central PMCID: PMC3314990.

24. Smith L, Kauss A, Wong KK Jr., Chatterjee S. Enhanced Hepatic Transgene Expression Following Intravenous Delivery of Novel Stem Cell-Derived Recombinant AAV Vectors. Mol Ther. 2010;18(supplement 1):S1–S2.

25. Ojala DS, Amara DP, Schaffer DV. Adeno-associated virus vectors and neurological gene therapy. Neuroscientist. 2015;21(1):84–98. Epub 2014/02/22. doi: 10.1177/1073858414521870 24557878.

26. Murlidharan G, Samulski RJ, Asokan A. Biology of adeno-associated viral vectors in the central nervous system. Front Mol Neurosci. 2014;7:76. Epub 2014/10/07. doi: 10.3389/fnmol.2014.00076 25285067; PubMed Central PMCID: PMC4168676.

27. Saraiva J, Nobre RJ, Pereira de Almeida L. Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9. J Control Release. 2016;241:94–109. Epub 2016/10/19. doi: 10.1016/j.jconrel.2016.09.011 27637390.

28. Wang D, Gao G. Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB. Mol Ther. 2018;26(2):336–8. Epub 2018/02/06. doi: 10.1016/j.ymthe.2018.01.005 29398483; PubMed Central PMCID: PMC5835224.

29. Albright BH, Storey CM, Murlidharan G, Castellanos Rivera RM, Berry GE, Madigan VJ, et al. Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol Ther. 2018;26(2):510–23. Epub 2017/11/28. doi: 10.1016/j.ymthe.2017.10.017 29175157; PubMed Central PMCID: PMC5835146.

30. Hudry E, Andres-Mateos E, Lerner EP, Volak A, Cohen O, Hyman BT, et al. Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65. Mol Ther Methods Clin Dev. 2018;10:197–209. Epub 2018/08/16. doi: 10.1016/j.omtm.2018.07.006 30109242; PubMed Central PMCID: PMC6083902.

31. Kanaan NM, Sellnow RC, Boye SL, Coberly B, Bennett A, Agbandje-McKenna M, et al. Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS. Mol Ther Nucleic Acids. 2017;8:184–97. Epub 2017/09/18. doi: 10.1016/j.omtn.2017.06.011 28918020; PubMed Central PMCID: PMC5503098.

32. Wang D, Li S, Gessler DJ, Xie J, Zhong L, Li J, et al. A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates. Mol Ther Methods Clin Dev. 2018;9:234–46. Epub 2018/05/17. doi: 10.1016/j.omtm.2018.03.004 29766031; PubMed Central PMCID: PMC5948233.

33. Yang B, Li S, Wang H, Guo Y, Gessler DJ, Cao C, et al. Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. Mol Ther. 2014;22(7):1299–309. Epub 2014/05/02. doi: 10.1038/mt.2014.68 24781136; PubMed Central PMCID: PMC4089005.

34. Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY, Banerjee A, et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol. 2016;34(2):204–9. Epub 2016/02/02. doi: 10.1038/nbt.3440 26829320; PubMed Central PMCID: PMC5088052.

35. Matsuzaki Y, Konno A, Mochizuki R, Shinohara Y, Nitta K, Okada Y, et al. Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci Lett. 2018;665:182–8. Epub 2017/11/28. doi: 10.1016/j.neulet.2017.11.049 29175632.

36. Merkel SF, Andrews AM, Lutton EM, Mu D, Hudry E, Hyman BT, et al. Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells. J Neurochem. 2017;140(2):216–30. Epub 2016/10/09. doi: 10.1111/jnc.13861 27718541; PubMed Central PMCID: PMC5298820.

37. Shen S, Bryant KD, Brown SM, Randell SH, Asokan A. Terminal N-linked galactose is the primary receptor for adeno-associated virus 9. J Biol Chem. 2011;286(15):13532–40. Epub 2011/02/19. doi: 10.1074/jbc.M110.210922 21330365; PubMed Central PMCID: PMC3075699.

38. Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther. 2012;19(6):649–58. Epub 2012/02/24. doi: 10.1038/gt.2012.6 22357511; PubMed Central PMCID: PMC4465241.

39. Pillay S, Meyer NL, Puschnik AS, Davulcu O, Diep J, Ishikawa Y, et al. An essential receptor for adeno-associated virus infection. Nature. 2016;530(7588):108–12. Epub 2016/01/28. doi: 10.1038/nature16465 26814968; PubMed Central PMCID: PMC4962915.

40. Dudek AM, Pillay S, Puschnik AS, Nagamine CM, Cheng F, Qiu J, et al. An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor. J Virol. 2018;92(7). Epub 2018/01/19. doi: 10.1128/JVI.02213-17 29343568; PubMed Central PMCID: PMC5972900.

41. Weber-Adrian D, Heinen S, Silburt J, Noroozian Z, Aubert I. The human brain endothelial barrier: transcytosis of AAV9, transduction by AAV2: An Editorial Highlight for 'Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells'. J Neurochem. 2017;140(2):192–4. Epub 2016/12/16. doi: 10.1111/jnc.13898 27976378.

42. Hordeaux J, Yuan Y, Clark PM, Wang Q, Martino RA, Sims JJ, et al. The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier. Mol Ther. 2019;27(5):912–21. Epub 2019/03/02. doi: 10.1016/j.ymthe.2019.02.013 30819613; PubMed Central PMCID: PMC6520463.

43. Metzner C, Salmons B, Gunzburg WH, Dangerfield JA. Rafts, anchors and viruses—a role for glycosylphosphatidylinositol anchored proteins in the modification of enveloped viruses and viral vectors. Virology. 2008;382(2):125–31. Epub 2008/10/31. doi: 10.1016/j.virol.2008.09.014 18962809.

44. Smith LJ, Kauss A, Wong KK, Chatterjee S. Enhanced Hepatic Transgene Expression Following Intravenous Delivery of Novel Stem Cell-Derived Recombinant AAV Vectors. Molecular Therapy. 2010;18(Supplement 1):S1–S2.

45. Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, et al. Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hum Gene Ther. 2018;29(3):285–98. Epub 2018/01/31. doi: 10.1089/hum.2018.015 29378426; PubMed Central PMCID: PMC5865262.

46. Colella P, Ronzitti G, Mingozzi F. Emerging Issues in AAV-Mediated In Vivo Gene Therapy. Mol Ther Methods Clin Dev. 2018;8:87–104. Epub 2018/01/13. doi: 10.1016/j.omtm.2017.11.007 29326962; PubMed Central PMCID: PMC5758940.

47. Ellsworth JL, O'Callaghan M, Rubin H, Seymour A. Low Seroprevalence of Neutralizing Antibodies Targeting Two Clade F AAV in Humans. Hum Gene Ther Clin Dev. 2018;29(1):60–7. Epub 2018/04/07. doi: 10.1089/humc.2017.239 29624457.


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