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Pharmaceutical Development of AAV-Based Gene Therapy Products for the Eye

Gerard A. Rodrigues, Evgenyi Shalaev, Thomas K. Karami and 3 more

Pharmaceutical Research · 2018 · Review · CC BY

doi:10.1007/s11095-018-2554-7

Abstract

A resurgence of interest and investment in the field of gene therapy, driven in large part by advances in viral vector technology, has recently culminated in United States Food and Drug Administration approval of the first gene therapy product targeting a disease caused by mutations in a single gene. This product, LUXTURNA™ (voretigene neparvovec-rzyl; Spark Therapeutics, Inc., Philadelphia, PA), delivers a normal copy of the RPE65 gene to retinal cells for the treatment of biallelic RPE65 mutation–associated retinal dystrophy, a blinding disease. Many additional gene therapy programs targeting both inherited retinal diseases and other ocular diseases are in development, owing to an improved understanding of the genetic basis of ocular disease and the unique properties of the ocular compartment that make it amenable to local gene therapy. Here we review the growing body of literature that describes both the design and development of ocular gene therapy products, with a particular emphasis on target and vector selection, and chemistry, manufacturing, and controls.

References 135

  1. 1.

    Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018;359(6372):eaan4672.

    Not in our library10.1126/science.aan4672

  2. 2.

    Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358(21):2231-2239.

    Not in our library10.1056/nejmoa0802268

  3. 3.

    Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979-990.

    Not in our library10.1089/hum.2008.107

  4. 4.

    Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358(21):2240-2248.

    Not in our library10.1056/nejmoa0802315

  5. 5.

    Naldini L. Medicine. A comeback for gene therapy. Science. 2009;326(5954):805-806.

    Not in our library10.1126/science.1181937

  6. 6.

    Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Mol Ther. 2013;21(3):509-519.

    Not in our library10.1038/mt.2012.280

  7. 7.

    Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Pang JJ, Roman AJ, Byrne BJ, Jacobson SG. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009;20(9):999-1004.

    Not in our library10.1089/hum.2009.086

  8. 8.

    Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9-24.

    Not in our library10.1001/archophthalmol.2011.298

  9. 9.

    Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643-650.

    Not in our library10.1038/mt.2009.277

  10. 10.

    Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology. 2013;120(6):1283-1291.

    Not in our library10.1016/j.ophtha.2012.11.048

  11. 11.

    Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying GS, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA. Maguire AM. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4(120):120ra115.

    Not in our library10.1126/scitranslmed.3002865

  12. 12.

    Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015;372(20):1887-1897.

    Not in our library10.1056/nejmoa1414221

  13. 13.

    Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372(20):1920-1926.

    Not in our library10.1056/nejmoa1412965

  14. 14.

    Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.

    Not in our library10.1016/s0140-6736(17)31868-8

  15. 15.

    MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129-1137.

    Not in our library10.1016/s0140-6736(13)62117-0

  16. 16.

    Solinís MÁ, del Pozo-Rodríguez A, Apaolaza PS, Rodríguez-Gascón A. Treatment of ocular disorders by gene therapy. Eur J Pharm Biopharm. 2015;95(Pt B):331-342.

    Not in our library10.1016/j.ejpb.2014.12.022

  17. 17.

    Farrar GJ, Carrigan M, Dockery A, Millington-Ward S, Palfi A, Chadderton N, Humphries M, Kiang AS, Kenna PF, Humphries P. Toward an elucidation of the molecular genetics of inherited retinal degenerations. Hum Mol Genet. 2017;26(R1):R2-R11.

    Not in our library10.1093/hmg/ddx185

  18. 18.

    Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation. Genet Med. 2016;18(4):283-289.

    Not in our library10.1038/gim.2015.70

  19. 19.

    Khan AO. Genetics of primary glaucoma. Curr Opin Ophthalmol. 2011;22(5):347-355.

    Not in our library10.1097/icu.0b013e32834922d2

  20. 20.

    Eghrari AO, Riazuddin SA, Gottsch JD. Fuchs corneal dystrophy. Prog Mol Biol Transl Sci. 2015;134:79-97.

    Not in our library10.1016/bs.pmbts.2015.04.005

  21. 21.

    Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2):132-141.

    Not in our library10.1111/cge.12203

  22. 22.

    RetNet™ Retinal Information Network. Available from: https://sph.uth.edu/retnet/. Accessed 20 Nov 2018.

    Not in our library

  23. 23.
    Biology and therapy of inherited retinal degenerative disease: insights from mouse models · 2015
    No notice
  24. 24.

    Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124(9):1314-1331.

    Not in our library10.1016/j.ophtha.2017.04.008

  25. 25.
    Retinitis Pigmentosa: Genes and Disease Mechanisms · 2011
    No notice
  26. 26.

    Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HP, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YT, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GH, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Said S, Sahel JA, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze JF, Igo RP, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith RT, Khan JC, Shahid H, Moore AT, McGrath JA, Laux R, Brantley MA, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NT, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CC, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JR, Allikmets R, Wang JJ, Schaumberg DA, Klein BE, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BH, Abecasis GR, Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134-143.

    Not in our library10.1038/ng.3448

  27. 27.

    Schramm EC, Clark SJ, Triebwasser MP, Raychaudhuri S, Seddon JM, Atkinson JP. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol Immunol. 2014;61(2):118-125.

    Not in our library10.1016/j.molimm.2014.06.032

  28. 28.

    Bhisitkul RB. Vascular endothelial growth factor biology: clinical implications for ocular treatments. Br J Ophthalmol. 2006;90(12):1542-1547.

    Not in our library10.1136/bjo.2006.098426

  29. 29.

    Constable IJ, Lai CM, Magno AL, French MA, Barone SB, Schwartz SD, Blumenkranz MS, Degli-Esposti MA, Rakoczy EP. Gene therapy in neovascular age-related macular degeneration: three-year follow-up of a phase 1 randomized dose escalation trial. Am J Ophthalmol. 2017;177:150-158.

    Not in our library10.1016/j.ajo.2017.02.018

  30. 30.

    Heier JS, Kherani S, Desai S, Dugel P, Kaushal S, Cheng SH, Delacono C, Purvis A, Richards S, Le-Halpere A, Connelly J, Wadsworth SC, Varona R, Buggage R, Scaria A, Campochiaro PA. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet. 2017;390(10089):50-61.

    Not in our library10.1016/s0140-6736(17)30979-0

  31. 31.

    Bloquel C, Bourges JL, Touchard E, Berdugo M, BenEzra D, Behar-Cohen F. Non-viral ocular gene therapy: potential ocular therapeutic avenues. Adv Drug Deliv Rev. 2006;58(11):1224-1242.

    Not in our library10.1016/j.addr.2006.07.023

  32. 32.

    Cheng HC, Yeh SI, Tsao YP, Kuo PC. Subconjunctival injection of recombinant AAV-angiostatin ameliorates alkali burn induced corneal angiogenesis. Mol Vis. 2007;13:2344-2352.

    Not in our library

  33. 33.

    Yoon KC, Bae JA, Park HJ, Im SK, Oh HJ, Lin XH, Kim MY, Lee JH, Lee SE, Ahn KY, Kim KK. Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model. Gene Ther. 2009;16(8):973-981.

    Not in our library10.1038/gt.2009.50

  34. 34.

    Gerometta R, Spiga MG, Borras T, Candia OA. Treatment of sheep steroid-induced ocular hypertension with a glucocorticoid-inducible MMP1 gene therapy virus. Invest Ophthalmol Vis Sci. 2010;51(6):3042-3048.

    Not in our library10.1167/iovs.09-4920

  35. 35.

    Dalkara D, Kolstad KD, Caporale N, Visel M, Klimczak RR, Schaffer DV, Flannery JG. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther. 2009;17(12):2096-2102.

    Not in our library10.1038/mt.2009.181

  36. 36.

    Takahashi K, Igarashi T, Miyake K, Kobayashi M, Yaguchi C, Iijima O, Yamazaki Y, Katakai Y, Miyake N, Kameya S, Shimada T, Takahashi H, Okada T. Improved intravitreal AAV-mediated inner retinal gene transduction after surgical internal limiting membrane peeling in cynomolgus monkeys. Mol Ther. 2017;25(1):296-302.

    Not in our library10.1016/j.ymthe.2016.10.008

  37. 37.
    Evaluation of lateral spread of transgene expression following subretinal AAV-mediated gene delivery in dogs. · 2013
    Not checked
  38. 38.

    Peden MC, Min J, Meyers C, Lukowski Z, Li Q, Boye SL, Levine M, Hauswirth WW, Ratnakaram R, Dawson W, Smith WC, Sherwood MB. Ab-externo AAV-mediated gene delivery to the suprachoroidal space using a 250 micron flexible microcatheter. PLoS One. 2011;6(2):e17140.

    Not in our library10.1371/journal.pone.0017140

  39. 39.
    Non Viral Vectors in Gene Therapy- An Overview · 2015
    Not checked
  40. 40.

    Kachi S, Oshima Y, Esumi N, Kachi M, Rogers B, Zack DJ, Campochiaro PA. Nonviral ocular gene transfer. Gene Ther. 2005;12(10):843-851.

    Not in our library10.1038/sj.gt.3302475

  41. 41.

    Delgado D, del Pozo-Rodriguez A, Solinís MÁ, Avilés-Triqueros M, Weber BH, Fernández E, Gascón AR. Dextran and protamine-based solid lipid nanoparticles as potential vectors for the treatment of X-linked juvenile retinoschisis. Hum Gene Ther. 2012;23(4):345-355.

    Not in our library10.1089/hum.2011.115

  42. 42.

    Pitkanen L, Ruponen M, Nieminen J, Urtti A. Vitreous is a barrier in nonviral gene transfer by cationic lipids and polymers. Pharm Res. 2003;20(4):576-583.

    Not in our library10.1023/a:1023238530504

  43. 43.

    Bejjani RA, BenEzra D, Cohen H, Rieger J, Andrieu C, Jeanny JC, Gollomb G, Behar-Cohen FF. Nanoparticles for gene delivery to retinal pigment epithelial cells. Mol Vis. 2005;11:124-132.

    Not in our library

  44. 44.

    Bourges JL, Gautier SE, Delie F, Bejjani RA, Jeanny JC, Gurny R, BenEzra D, Behar-Cohen FF. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci. 2003;44(8):3562-3569.

    Not in our library10.1167/iovs.02-1068

  45. 45.

    Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108-128.

    Not in our library10.1016/j.preteyeres.2014.08.001

  46. 46.

    Kong J, Kim SR, Binley K, Pata I, Doi K, Mannik J, Zernant-Rajang J, Kan O, Iqball S, Naylor S, Sparrow JR, Gouras P, Allikmets R. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther. 2008;15(19):1311-1320.

    Not in our library10.1038/gt.2008.78

  47. 47.

    Auricchio A, Kobinger G, Anand V, Hildinger M, O'Connor E, Maguire AM, Wilson JM, Bennett J. Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model. Hum Mol Genet. 2001;10(26):3075-3081.

    Not in our library10.1093/hmg/10.26.3075

  48. 48.

    Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol. 1998;72(12):9873-9880.

    Not in our library10.1128/jvi.72.12.9873-9880.1998

  49. 49.

    Yáñez-Muñoz RJ, Balaggan KS, MacNeil A, Howe SJ, Schmidt M, Smith AJ, Buch P, MacLaren RE, Anderson PN, Barker SE, Duran Y, Bartholomae C, von Kalle C, Heckenlively JR, Kinnon C, Ali RR, Thrasher AJ. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med. 2006;12(3):348-353.

    Not in our library10.1038/nm1365

  50. 50.

    Chen Y, Moiseyev G, Takahashi Y, Ma JX. RPE65 gene delivery restores isomerohydrolase activity and prevents early cone loss in Rpe65−/− mice. Invest Ophthalmol Vis Sci. 2006;47(3):1177-1184.

    Not in our library10.1167/iovs.05-0965

  51. 51.

    Vollrath D, Feng W, Duncan JL, Yasumura D, D'Cruz PM, Chappelow A, Matthes MT, Kay MA, LaVail MM. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A. 2001;98(22):12584-12589.

    Not in our library10.1073/pnas.221364198

  52. 52.

    Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J, DiBartolomeo R, Wei LL. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther. 2006;17(2):167-176.

    Not in our library10.1089/hum.2006.17.167

  53. 53.

    Reichel MB, Ali RR, Thrasher AJ, Hunt DM, Bhattacharya SS, Baker D. Immune responses limit adenovirally mediated gene expression in the adult mouse eye. Gene Ther. 1998;5(8):1038-1046.

    Not in our library10.1038/sj.gt.3300691

  54. 54.
    A helper-dependent adenovirus vector system: Removal of helper virus by Cre-mediated excision of the viral packaging signal · 1996
    Not checked
  55. 55.

    Schön C, Biel M, Michalakis S. Retinal gene delivery by adeno-associated virus (AAV) vectors: strategies and applications. Eur J Pharm Biopharm. 2015;95(Pt B):343-352.

    Not in our library10.1016/j.ejpb.2015.01.009

  56. 56.

    Lotery AJ, Yang GS, Mullins RF, Russell SR, Schmidt M, Stone EM, Lindbloom JD, Chiorini JA, Kotin RM, Davidson BL. Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina. Hum Gene Ther. 2003;14(17):1663-1671.

    Not in our library10.1089/104303403322542301

  57. 57.

    Yang GS, Schmidt M, Yan Z, Lindbloom JD, Harding TC, Donahue BA, Engelhardt JF, Kotin R, Davidson BL. Virus-mediated transduction of murine retina with adeno-associated virus: effects of viral capsid and genome size. J Virol. 2002;76(15):7651-7660.

    Not in our library10.1128/jvi.76.15.7651-7660.2002

  58. 58.

    Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D, Chérel Y, Chenuaud P, Samulski J, Moullier P, Rolling F. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther. 2003;7(6):774-781.

    Not in our library10.1016/s1525-0016(03)00098-4

  59. 59.

    Madigan VJ, Asokan A. Engineering AAV receptor footprints for gene therapy. Curr Opin Virol. 2016;18:89-96.

    Not in our library10.1016/j.coviro.2016.05.001

  60. 60.

    Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5(3):285-297.

    Not in our library10.2174/1566523054065057

  61. 61.

    Vandenberghe LH, Bell P, Maguire AM, Cearley CN, Xiao R, Calcedo R, Wang L, Castle MJ, Maguire AC, Grant R, Wolfe JH, Wilson JM, Bennett J. Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011;3(88):88ra54.

    Not in our library10.1126/scitranslmed.3002103

  62. 62.

    Auricchio A. Pseudotyped AAV vectors for constitutive and regulated gene expression in the eye. Vis Res. 2003;43(8):913-918.

    Not in our library10.1016/s0042-6989(02)00676-4

  63. 63.

    Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199(3):381-390.

    Not in our library10.1086/595830

  64. 64.

    Allocca M, Mussolino C, Garcia-Hoyos M, Sanges D, Iodice C, Petrillo M, Vandenberghe LH, Wilson JM, Marigo V, Surace EM, Auricchio A. Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. J Virol. 2007;81(20):11372-11380.

    Not in our library10.1128/jvi.01327-07

  65. 65.

    Lebherz C, Maguire A, Tang W, Bennett J, Wilson JM. Novel AAV serotypes for improved ocular gene transfer. J Gene Med. 2008;10(4):375-382.

    Not in our library10.1002/jgm.1126

  66. 66.

    Manfredi A, Marrocco E, Puppo A, Cesi G, Sommella A, Della Corte M, Rossi S, Giunti M, Craft CM, Bacci ML, Simonelli F, Surace EM, Auricchio A. Combined rod and cone transduction by adeno-associated virus 2/8. Hum Gene Ther. 2013;24(12):982-992.

    Not in our library10.1089/hum.2013.154

  67. 67.

    Mussolino C, della Corte M, Rossi S, Viola F, Di Vicino U, Marrocco E, Neglia S, Doria M, Testa F, Giovannoni R, Crasta M, Giunti M, Villani E, Lavitrano M, Bacci ML, Ratiglia R, Simonelli F, Auricchio A, Surace EM. AAV-mediated photoreceptor transduction of the pig cone-enriched retina. Gene Ther. 2011;18(7):637-645.

    Not in our library10.1038/gt.2011.3

  68. 68.

    Alexander JJ, Umino Y, Everhart D, Chang B, Min SH, Li Q, Timmers AM, Hawes NL, Pang JJ, Barlow RB, Hauswirth WW. Restoration of cone vision in a mouse model of achromatopsia. Nat Med. 2007;13(6):685-687.

    Not in our library10.1038/nm1596

  69. 69.

    Komaromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, Hauswirth WW, Aguirre GD. Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet. 2010;19(13):2581-2593.

    Not in our library10.1093/hmg/ddq136

  70. 70.

    Mancuso K, Hauswirth WW, Li Q, Connor TB, Kuchenbecker JA, Mauck MC, Neitz J, Neitz M. Gene therapy for red-green colour blindness in adult primates. Nature. 2009;461(7265):784-787.

    Not in our library10.1038/nature08401

  71. 71.

    Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15(7):445-451.

    Not in our library10.1038/nrg3742

  72. 72.

    Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M, Herzog RW, Zolotukhin I, Warrington KH, Weigel-Van Aken KA, Hobbs JA, Zolotukhin S, Muzyczka N, Srivastava A. Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci U S A. 2008;105(22):7827-7832.

    Not in our library10.1073/pnas.0802866105

  73. 73.

    Petrs-Silva H, Dinculescu A, Li Q, Min SH, Chiodo V, Pang JJ, Zhong L, Zolotukhin S, Srivastava A, Lewin AS, Hauswirth WW. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther. 2009;17(3):463-471.

    Not in our library10.1038/mt.2008.269

  74. 74.

    Martino AT, Basner-Tschakarjan E, Markusic DM, Finn JD, Hinderer C, Zhou S, Ostrov DA, Srivastava A, Ertl HC, Terhorst C, High KA, Mingozzi F, Herzog RW. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood. 2013;121(12):2224-2233.

    Not in our library10.1182/blood-2012-10-460733

  75. 75.

    Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, Flannery JG, Schaffer DV. In vivo–directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med 2013;5(189):189ra176.

    Not in our library10.1126/scitranslmed.3005708

  76. 76.

    Dalkara D, Kolstad KD, Guerin KI, Hoffmann NV, Visel M, Klimczak RR, Schaffer DV, Flannery JG. AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. Mol Ther. 2011;19(9):1602-1608.

    Not in our library10.1038/mt.2011.62

  77. 77.
    A Novel Adeno-Associated Viral Variant for Efficient and Selective Intravitreal Transduction of Rat Müller Cells · 2009
    No notice
  78. 78.

    Young JE, Vogt T, Gross KW, Khani SC. A short, highly active photoreceptor-specific enhancer/promoter region upstream of the human rhodopsin kinase gene. Invest Ophthalmol Vis Sci. 2003;44(9):4076-4085.

    Not in our library10.1167/iovs.03-0197

  79. 79.

    Beltran WA, Cideciyan AV, Lewin AS, Iwabe S, Khanna H, Sumaroka A, Chiodo VA, Fajardo DS, Román AJ, Deng WT, Swider M, Alemán TS, Boye SL, Genini S, Swaroop A, Hauswirth WW, Jacobson SG, Aguirre GD. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci U S A. 2012;109(6):2132-2137.

    Not in our library10.1073/pnas.1118847109

  80. 80.

    Flannery JG, Zolotukhin S, Vaquero MI, LaVail MM, Muzyczka N, Hauswirth WW. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Natl Acad Sci U S A. 1997;94(13):6916-6921.

    Not in our library10.1073/pnas.94.13.6916

  81. 81.

    Carvalho LS, Xu J, Pearson RA, Smith AJ, Bainbridge JW, Morris LM, Fliesler SJ, Ding XQ, Ali RR. Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Hum Mol Genet. 2011;20(16):3161-3175.

    Not in our library10.1093/hmg/ddr218

  82. 82.

    Michalakis S, Mühlfriedel R, Tanimoto N, Krishnamoorthy V, Koch S, Fischer MD, Becirovic E, Bai L, Huber G, Beck SC, Fahl E, Büning H, Paquet-Durand F, Zong X, Gollisch T, Biel M, Seeliger MW. Restoration of cone vision in the CNGA3−/− mouse model of congenital complete lack of cone photoreceptor function. Mol Ther. 2010;18(12):2057-2063.

    Not in our library10.1038/mt.2010.149

  83. 83.

    Komáromy AM, Alexander JJ, Cooper AE, Chiodo VA, Glushakova LG, Acland GM, Hauswirth WW, Aguirre GD. Targeting gene expression to cones with human cone opsin promoters in recombinant AAV. Gene Ther. 2008;15(14):1049-1055.

    Not in our library10.1038/gt.2008.32

  84. 84.

    Nicoletti A, Kawase K, Thompson DA. Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific protein. Invest Ophthalmol Vis Sci. 1998;39(3):637-644.

    Not in our library

  85. 85.

    Esumi N, Oshima Y, Li Y, Campochiaro PA, Zack DJ. Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation. J Biol Chem. 2004;279(18):19064-19073.

    Not in our library10.1074/jbc.m309881200

  86. 86.

    Doroudchi MM, Greenberg KP, Liu J, Silka KA, Boyden ES, Lockridge JA, Arman AC, Janani R, Boye SE, Boye SL, Gordon GM, Matteo BC, Sampath AP, Hauswirth WW, Horsager A. Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness. Mol Ther. 2011;19(7):1220-1229.

    Not in our library10.1038/mt.2011.69

  87. 87.

    Macé E, Caplette R, Marre O, Sengupta A, Chaffiol A, Barbe P, Desrosiers M, Bamberg E, Sahel JA, Picaud S, Duebel J, Dalkara D. Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV restores ON and OFF visual responses in blind mice. Mol Ther. 2015;23(1):7-16.

    Not in our library10.1038/mt.2014.154

  88. 88.

    Aartsen WM, van Cleef KW, Pellissier LP, Hoek RM, Vos RM, Blits B, Ehlert EM, Balaggan KS, Ali RR, Verhaagen J, Wijnholds J. GFAP-driven GFP expression in activated mouse Muller glial cells aligning retinal blood vessels following intravitreal injection of AAV2/6 vectors. PLoS One. 2010;5(8):e12387.

    Not in our library10.1371/journal.pone.0012387

  89. 89.

    Ayuso E, Mingozzi F, Bosch F. Production, purification and characterization of adeno-associated vectors. Curr Gene Ther. 2010;10(6):423-436.

    Not in our library10.2174/156652310793797685

  90. 90.
    Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment · 2014
    No notice
  91. 91.

    Wright JF, Wellman J, High KA. Manufacturing and regulatory strategies for clinical AAV2-hRPE65. Curr Gene Ther. 2010;10(5):341-349.

    Not in our library10.2174/156652310793180715

  92. 92.

    Schnodt M, Büning H. Improving the quality of adeno-associated viral vector preparations: the challenge of product-related impurities. Hum Gene Ther Methods. 2017;28(3):101-108.

    Not in our library10.1089/hgtb.2016.188

  93. 93.

    Wright JF, Le T, Prado J, Bahr-Davidson J, Smith PH, Zhen Z, Sommer JM, Pierce GF, Qu G. Identification of factors that contribute to recombinant AAV2 particle aggregation and methods to prevent its occurrence during vector purification and formulation. Mol Ther. 2005;12(1):171-178.

    Not in our library10.1016/j.ymthe.2005.02.021

  94. 94.
    Manufacturing of recombinant adeno-associated viral vectors for clinical trials · 2016
    Not checked
  95. 95.

    Summerford C, Samulski RJ. Viral receptors and vector purification: new approaches for generating clinical-grade reagents. Nat Med. 1999;5(5):587-588.

    Not in our library10.1038/8470

  96. 96.

    Nass SA, Mattingly MA, Woodcock DA, Burnham BL, Ardinger JA, Osmond SE, Frederick AM, Scaria A, Cheng SH, O'Riordan CR. Universal method for the purification of recombinant AAV vectors of differing serotypes. Mol Ther Methods Clin Dev. 2018;9:33-46.

    Not in our library10.1016/j.omtm.2017.12.004

  97. 97.

    Qu G, Bahr-Davidson J, Prado J, Tai A, Cataniag F, McDonnell J, Zhou J, Hauck B, Luna J, Sommer JM, Smith P, Zhou S, Colosi P, High KA, Pierce GF, Wright JF. Separation of adeno-associated virus type 2 empty particles from genome containing vectors by anion-exchange column chromatography. J Virol Methods. 2007;140(1–2):183-192.

    Not in our library10.1016/j.jviromet.2006.11.019

  98. 98.

    Shalaev EY, Wang W, Gatlin LA, McNally EJ, Hastedt JE. Rational choice of excipients of use in lyophilized formulations. Protein formulation and delivery. 2008;197-217.

    Not in our library

  99. 99.

    Singh S, Kolhe P, Wang W, Nema S. Large-scale freezing of biologics. Bioprocess Int. 2009;7(9):32–44.

    Not in our library

  100. 100.

    Wu C, Shamblin S, Varshney D, Shalaev E, Varshney D, Singh M. Advance understanding of buffer behavior during lyophilization. Lyophilized biologics and vaccines: modality-based approaches. 2015;25-42.

    Not in our library

  101. 101.

    Croyle MA, Cheng X, Wilson JM. Development of formulations that enhance physical stability of viral vectors for gene therapy. Gene Ther. 2001;8(17):1281-1290.

    Not in our library10.1038/sj.gt.3301527

  102. 102.

    Venkatakrishnan B, Yarbrough J, Domsic J, Bennett A, Bothner B, Kozyreva OG, Samulski RJ, Muzyczka N, McKenna R, Agbandje-McKenna M. Structure and dynamics of adeno-associated virus serotype 1 VP1-unique N-terminal domain and its role in capsid trafficking. J Virol. 2013;87(9):4974-4984.

    Not in our library10.1128/jvi.02524-12

  103. 103.

    Xie Q, Hare J, Turnigan J, Chapman MS. Large-scale production, purification and crystallization of wild-type adeno-associated virus-2. J Virol Methods. 2004;122(1):17-27.

    Not in our library10.1016/j.jviromet.2004.07.007

  104. 104.

    Wang P, Li H, Yang HJ, Wang HB, Lu JH, Zhang Y, Hu J. Glycerol facilitates the disaggregation of recombinant adeno-associated virus serotype 2 on mica surface. Colloids Surf B: Biointerfaces. 2007;60(2):264-267.

    Not in our library10.1016/j.colsurfb.2007.06.027

  105. 105.

    Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z, Qu G, Zhou S, Zeiss C, Arruda VR, Acland GM, Dell'Osso LF, High KA, Maguire AM, Bennett J. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008;16(3):458-465.

    Not in our library10.1038/sj.mt.6300389

  106. 106.

    Sommer J, Sanftner L, Feng L, Suzuki B, Zhen Z, Powell S, Wright F, McClelland A, Cunningham J. Optimal recovery of AAV-AADC vector from Teflon catheters using Polysorbate 80 or Pluronic F68 (abstract 768). Mol Ther. 2002;5(Suppl):S251.

    Not in our library

  107. 107.

    Shalaev E, Franks F. Solid-liquid state diagrams in pharmaceutical lyophilisation: crystallization of solutes. In: Levine H, editor. Amorphous food and pharmaceutical systems. London: The Royal Society of Chemistry; 2002. p. 200–15.

    Not in our library

  108. 108.

    Anzo K, Harada M, Okada T. Enhanced kinetics of pseudo first-order hydrolysis in liquid phase coexistent with ice. J Phys Chem A. 2013;117(41):10619-10625.

    Not in our library10.1021/jp409126p

  109. 109.

    Bhatnagar BS, Bogner RH, Pikal MJ. Protein stability during freezing: separation of stresses and mechanisms of protein stabilization. Pharm Dev Technol. 2007;12(5):505-523.

    Not in our library10.1080/10837450701481157

  110. 110.

    Bhatnagar BS, Pikal MJ, Bogner RH. Study of the individual contributions of ice formation and freeze-concentration on isothermal stability of lactate dehydrogenase during freezing. J Pharm Sci. 2008;97(2):798-814.

    Not in our library10.1002/jps.21017

  111. 111.

    Franks F, Hatley RHM. Stability of proteins at subzero temperatures: thermodynamics and some ecological consequences. Pure Appl Chem. 1991;63(10):1367-1380.

    Not in our library10.1351/pac199163101367

  112. 112.

    Lund DB, Fennema OR, Powrie WD. Enzymic and acid hydrolysis of sucrose as influenced by freezing. J Food Sci. 1969;34:378-382.

    Not in our library10.1111/j.1365-2621.1969.tb10370.x

  113. 113.

    Pincock RE. Reactions in frozen systems. Acc Chem Res. 1969;2:97-103.

    Not in our library10.1021/ar50016a001

  114. 114.

    Pincock RE, Kiovsky TE. Kinetics of reactions in frozen solutions. J Chem Educ. 1966;43:358-360.

    Not in our library10.1021/ed043p358

  115. 115.

    Schwegman JJ, Carpenter JF, Nail SL. Evidence of partial unfolding of proteins at the ice/freeze-concentrate interface by infrared microscopy. J Pharm Sci. 2009;98(9):3239-3246.

    Not in our library10.1002/jps.21843

  116. 116.

    Singh SK, Kolhe P, Mehta AP, Chico SC, Lary AL, Huang M. Frozen state storage instability of a monoclonal antibody: aggregation as a consequence of trehalose crystallization and protein unfolding. Pharm Res. 2011;28(4):873-885.

    Not in our library10.1007/s11095-010-0343-z

  117. 117.

    Wright JF, Qu G, Tang C, Sommer JM. Recombinant adeno-associated virus: formulation challenges and strategies for a gene therapy vector. Curr Opin Drug Discov Devel. 2003;6(2):174-178.

    Not in our library

  118. 118.

    Howard DB, Harvey BK. Assaying the stability and inactivation of AAV serotype 1 vectors. Hum Gene Ther Methods. 2017;28(1):39-48.

    Not in our library10.1089/hgtb.2016.180

  119. 119.

    Guidance for FDA Reviewers and Sponsors, Content and Review of Chemistry, Manufacturing and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). Food and Drug Administration, Center for Biologics Evaluation and Research. 2008. Available from: https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm078694.pdf. Accessed 20 Nov 2018.

    Not in our library

  120. 120.
    Practical utilization of recombinant AAV vector reference standards: focus on vector genomes titration by free ITR qPCR · 2016
    Not checked
  121. 121.

    Neuberger EW, Perez I, Le Guiner C, Moser D, Ehlert T, Allais M, Moullier P, Simon P, Snyder RO. Establishment of two quantitative nested qPCR assays targeting the human EPO transgene. Gene Ther. 2016;23(4):330-339.

    Not in our library10.1038/gt.2016.2

  122. 122.

    Sommer JM, Smith PH, Parthasarathy S, Isaacs J, Vijay S, Kieran J, Powell SK, McClelland A, Wright JF. Quantification of adeno-associated virus particles and empty capsids by optical density measurement. Mol Ther. 2003;7(1):122-128.

    Not in our library10.1016/s1525-0016(02)00019-9

  123. 123.

    Joo KI, Fang Y, Liu Y, Xiao L, Gu Z, Tai A, Lee CL, Tang Y, Wang P. Enhanced real-time monitoring of adeno-associated virus trafficking by virus-quantum dot conjugates. ACS Nano. 2011;5(5):3523-3535.

    Not in our library10.1021/nn102651p

  124. 124.

    Bennett A, Patel S, Mietzsch M, Jose A, Lins-Austin B, Yu JC, Bothner B, McKenna R, Agbandje-McKenna M. Thermal stability as a determinant of AAV serotype identity. Mol Ther Methods Clin Dev. 2017;6:171-182.

    Not in our library10.1016/j.omtm.2017.07.003

  125. 125.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug applications (INDs): draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610795.pdf. Accessed 20 Nov 2018.

    Not in our library

  126. 126.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Human gene therapy for retinal disorders: draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610803.pdf. Accessed 20 Nov 2018.

    Not in our library

  127. 127.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up: draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610800.pdf. Accessed 20 Nov 2018.

    Not in our library

  128. 128.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Human gene therapy for hemophilia: draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610801.pdf. Accessed 20 Nov 2018.

    Not in our library

  129. 129.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Human gene therapy for rare diseases: draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610802.pdf. Accessed 20 Nov 2018.

    Not in our library

  130. 130.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Long term follow-up after administration of human gene therapy products: draft guidance for industry. 2018. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610797.pdf. Accessed 20 Nov 2018.

    Not in our library

  131. 131.

    European Medicines Agency. Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. 2018. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/07/WC500252056.pdf. Accessed 20 Nov 2018.

    Not in our library

  132. 132.

    U.S. Food and Drug Administration Center for Biologics Evaluation and Research. Design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products: guidance for industry. 2015. Available from: https://www.fda.gov/downloads/Guidances/UCM404087.pdf. Accessed 20 Nov 2018.

    Not in our library

  133. 133.

    European Medicines Agency. ICH considerations -- general principles to address virus and vector shedding. 2009. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002680.pdf. Accessed 20 Nov 2018.

    Not in our library

  134. 134.

    International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Guideline on virus and gene therapy vector shedding and transmission. 2009. Available from: http://www.ich.org/products/guidelines/multidisciplinary/multidisciplinary-single/article/virus-and-gene-therapy-vector-shedding-and-transmission.html. Accessed 20 Nov 2018.

    Not in our library

  135. 135.

    U.S. Food and Drug Administration. Summary basis for regulatory action -- LUXTURNA. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM592083.pdf. Accessed 20 Nov 2018.

    Not in our library

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