An analysis of retinal gene therapy clinical trials

Current Opinion in Molecular Therapeutics

Volumn 11, Issue 5, 2009, Pages 540-546

  MacLaren, R E ^a,b  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b MOORFIELDS EYE HOSPITAL   (United Kingdom)

Author keywords

Adeno associated viral; Clinical trial; Genetics; Leber's congenital amaurosis; Retinitis pigmentosa (RP); RPE65

Indexed keywords

11 CIS RETINAL; ADENOVIRUS VECTOR; CAPSID PROTEIN; GANCICLOVIR; HERPESVIRUS VECTOR; ISOMERASE; ISOTRETINOIN; LENTIVIRUS VECTOR; MESSENGER RNA; PARVOVIRUS VECTOR; PIGMENT EPITHELIUM DERIVED FACTOR; RETINAL PIGMENT EPITHELIUM SPECIFIC 65 PROTEIN; THYMIDINE KINASE; UNCLASSIFIED DRUG; VISUAL PROTEINS AND PIGMENTS;

ACNE; ADENO ASSOCIATED VIRUS; ADENO ASSOCIATED VIRUS SEROTYPE 2; DRUG EFFICACY; DRUG MECHANISM; DRUG TARGETING; DRUG TOLERABILITY; GENE EXPRESSION; GENE REPLACEMENT THERAPY; GENE THERAPY; HERPES SIMPLEX VIRUS; HUMAN; INVERTED TERMINAL REPEAT; LEBER CONGENITAL AMAUROSIS; MISSENSE MUTATION; NONHUMAN; PIGMENT EPITHELIUM; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN LOCALIZATION; RETINA MACULA AGE RELATED DEGENERATION; RETINITIS PIGMENTOSA; RETINOBLASTOMA; REVIEW; RPE 65 GENE; TRANSGENE; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT; VIRAL GENE DELIVERY SYSTEM;

ANIMALS; CARRIER PROTEINS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; EYE PROTEINS; GENE THERAPY; GENE TRANSFER TECHNIQUES; HUMANS; MUTATION; RETINAL DEGENERATION;

ANIMALIA;

EID: 70349900805     PISSN: 14648431     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (42)

1. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S et al: Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med (2008) 358(21):2231-2239. •• Describes the first clinical trial of a gene therapy for a retinal indication to use AAV with a cell-specific promoter.
2. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S et al: Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med (2008) 358(21):2240-2248. •• Describes the first clinical trial of a gene therapy for a retinal indication to use a vector purification method and a surfactant to increase the number of active AAV genomes delivered to the retina. (Pubitemid 351724453)
3. Hauswirth W, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon T, Boye SL, Flotte TR, Byrne B, 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. •• The third of the first three RPE65 retinal gene therapy trials. This trial was more in-depth than the other two with the analysis of visual improvement in the transduced areas, by correlating the expected levels of vision to the degree of retinal thinning as measured by optical coherence tomography (OCT) in treated patients.
4. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG et al: Gene therapy restores vision in a canine model of childhood blindness. Nat Genet (2001) 28(1):92-95. •• First proof-of-principle study using AAV2 gene therapy to treat a largeanimal model (dog) with RPE65 deficiency.
5. Pang JJ, Chang B, Kumar A, Nusinowitz S, Noorwez SM, Li J, Rani A, Foster TC, Chiodo VA, Doyle T, Li H et al: Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis. Mol Ther (2006) 13(3):565-572. (Pubitemid 43257624)
6. Chévez-Barrios P, Chintagumpala M, Mieler W, Paysse E, Boniuk M, Kozinetz C, Hurwitz MY, Hurwitz RL: Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol (2005) 23(31):7927-7935. (Pubitemid 46657392)
7. Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J, DiBartolomeo R et al: 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. • First gene therapy clinical trial to treat angiogenesis in age-related macular degeneration using adenoviral vectors.
8. Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S: Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA (2005) 102(38):13658-13663. (Pubitemid 41420904)
9. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang JJ, Sumaroka A, Windsor EA, Wilson JM, Flotte TR et al: Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA (2008) 105(39):15112-15117. • First detailed psychophysical analysis of retinal function following AAV-mediated RPE65 gene therapy.
10. Ali RR, Reichel MB, Thrasher AJ, Levinsky RJ, Kinnon C, Kanuga N, Hunt DM, Bhattacharya SS: Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum Mol Genet (1996) 5(5):591-594. • First application of AAV gene therapy to the retina, using LacZ in mice.
11. Jacobson SG, Acland GM, Aguirre GD, Aleman TS, Schwartz SB, Cideciyan AV, Zeiss CJ, Komaromy AM, Kaushal S, Roman AJ, Windsor EA et al: Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther (2006) 13(6):1074-1084. (Pubitemid 43796158)
12. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW et al: Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther (2005) 12(6):1072-1082. • Large-animal study demonstrating sustained and long-term RPE65 expression from an AAV2 vector during a period of several years.
13. Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY et al: Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther (2006) 17(8):845-858. (Pubitemid 44681454)
14. Le Meur G, Stieger K, Smith AJ, Weber M, Deschamps JY, Nivard D, Mendes-Madeira A, Provost N, Péréon Y, Cherel Y, Ali RR et al: Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther (2007) 14(4):292-303. • Demonstrated proof of efficiency of gene therapy using the human RPE65 promoter in dogs, providing essential background data for the subsequent Moorfields/UCL clinical trial.
15. 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. (Pubitemid 36790254)
16. Znoiko SL, Crouch RK, Moiseyev G, Ma JX: Identification of the RPE65 protein in mammalian cone photoreceptors. Invest Ophthalmol Vis Sci (2002) 43(5):1604-1609. (Pubitemid 34462664)
17. Jacobson SG, Aleman TS, Cideciyan AV, Heon E, Golczak M, Beltran WA, Sumaroka A, Schwartz SB, Roman AJ, Windsor EA, Wilson JM et al: Human cone photoreceptor dependence on RPE65 isomerase. Proc Natl Acad Sci USA (2007) 104(38):15123-15128. (Pubitemid 47619603)
18. Ablonczy Z, Crouch RK, Goletz PW, Redmond TM, Knapp DR, Ma JX, Rohrer B: 11-Cis-retinal reduces constitutive opsin phosphorylation and improves quantum catch in retinoid-deficient mouse rod photoreceptors. J Biol Chem (2002) 277(43):40491-40498.
19. -/- mice: A defect that can be corrected by 11-cis retinal. Invest Ophthalmol Vis Sci (2005) 46(10):3876-3882.
20. Bemelmans AP, Kostic C, Crippa SV, Hauswirth WW, Lem J, Munier FL, Seeliger MW, Wenzel A, Arsenijevic Y: Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis. PLoS Med (2006) 3(10):e347. (Pubitemid 44721828)
21. Bainbridge JW, Stephens C, Parsley K, Demaison C, Halfyard A, Thrasher AJ, Ali RR: In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium. Gene Ther (2001) 8(21):1665-1668.
22. Law WC, Rando RR: The molecular basis of retinoic acid induced night blindness. Biochem Biophys Res Commun (1989) 161(2): 825-829.
23. Van Hooser JP, Aleman TS, He YG, Cideciyan AV, Kuksa V, Pittler SJ, Stone EM, Jacobson SG, Palczewski K: Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc Natl Acad Sci USA (2000) 97(15): 8623-8628.
24. Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A: Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet (1997) 17(2):194-197.
25. Jin M, Li S, Moghrabi WN, Sun H, Travis GH: RPE65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell (2005) 122(3):449-459.
26. Batten ML, Imanishi Y, Tu DC, Doan T, Zhu L, Pang J, Glushakova L, Moise AR, Baehr W, Van Gelder RN, Hauswirth WW et al: Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. PLoS Med (2005) 2(11):e333. (Pubitemid 41735786)
27. Katz ML, Redmond TM: Effect of RPE65 knockout on accumulation of lipofuscin fluorophores in the retinal pigment epithelium. Invest Ophthalmol Vis Sci (2001) 42(12):3023-3030.
28. Schröder M, Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem (2005) 74:739-789.
29. Liu SY, Redmond TM: Role of the 3′-untranslated region of RPE65 mRNA in the translational regulation of the RPE65 gene: Identification of a specific translation inhibitory element. Arch Biochem Biophys (1998) 357(1):37-44.
30. Hamel CP, Tsilou E, Pfeffer BA, Hooks JJ, Detrick B, Redmond TM: Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. J Biol Chem (1993) 268(21):15751-15757.
31. Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z et al: Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther (2008) 16(3):458-465. • Provides a detailed analysis of how the use of surfactant prevents AAV2 from adhering to the inside of a plastic injection system to increase the yield of AAV2 delivered into the subretinal space.
32. Spear IS, Fife KH, Hauswirth WW, Jones CJ, Berns KI: Evidence for two nucleotide sequence orientations within the terminal repetition of adeno-associated virus DNA. J Virol (1977) 24(2):627-634.
33. Lusby E, Fife KH, Berns KI: Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J Virol (1980) 34(2):402-409. (Pubitemid 10104041)
34. Mingozzi F, High KA: Immune responses to AAV in clinical trials. Curr Gene Ther (2007) 7(5):316-324. (Pubitemid 47595774)
35. Herzog RW: Immune responses to AAV capsid: Are mice not humans after all? Mol Ther (2007) 15(4):649-650.
36. 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.
37. Xu L, Daly T, Gao C, Flotte TR, Song S, Byrne BJ, Sands MS, Parker-Ponder K: CMV-β-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 α promoter and results in therapeutic levels of human Factor X in mice. Hum Gene Ther (2001) 12(5):563-573. (Pubitemid 32511077)
38. Holz MK, Ballif BA, Gygi SP, Blenis J: mTOR and S6K1 mediate assembly of the translation pre-initiation complex through dynamic protein interchange and ordered phosphorylation events. Cell (2005) 123(4):569-580.
39. Pelletier J, Sonenberg N: Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature (1988) 334(6180):320-325. (Pubitemid 18177659)
40. Russell DW: AAV vectors, insertional mutagenesis, and cancer. Mol Ther (2007) 15(10):1740-1743.
41. Thompson DA, Gyürüs P, Fleischer LL, Bingham EL, McHenry CL, Apfelstedt-Sylla E, Zrenner E, Lorenz B, Richards JE, Jacobson SG, Sieving PA et al: Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci (2000) 41(13):4293-4299.
42. Felius J, Thompson DA, Khan NW, Bingham EL, Jamison JA, Kemp JA, Sieving PA: Clinical course and visual function in a family with mutations in the RPE65 gene. Arch Ophthalmol (2002) 120(1): 55-61. (Pubitemid 34721362)