Skip to main content

Advertisement

SpringerLink
Log in

Gene therapy for Leber congenital amaurosis: advances and future directions

  • Review Article
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.

Methods

A literature search of peer-reviewed and indexed publications from 1996–2011 using the PubMed search engine was performed. Key terms included “Leber congenital amaurosis”, LCA, RPE65, ”cone-rod dystrophy”, “gene therapy”, and “human trials” in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).

Results

Herein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.

Conclusions

Initial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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 (2008) Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med 358:2231–2239

    Article  PubMed  CAS  Google Scholar 

  2. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang JJ, Sumaroka A, Windsor EA, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW (2008) Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A 105:15112–15117

    Article  PubMed  CAS  Google Scholar 

  3. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG (2008) 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 19:979–990

    Article  PubMed  CAS  Google Scholar 

  4. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, 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 (2008) Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 358:2240–2248

    Article  PubMed  CAS  Google Scholar 

  5. 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 (2009) Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 20:999–1004

    Article  PubMed  CAS  Google Scholar 

  6. Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SG (2009) Vision 1 year after gene therapy for Leber's congenital amaurosis. N Engl J Med 361:725–727

    Article  PubMed  CAS  Google Scholar 

  7. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JI, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, McDonnell JW, Leroy BP, Simonelli F, Bennett J (2009) Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374:1597–1605

    Article  PubMed  CAS  Google Scholar 

  8. Banin E, Bandah-Rozenfeld D, Obolensky A, Cideciyan AV, Aleman TS, Marks-Ohana D, Sela M, Boye S, Sumaroka A, Roman AJ, Schwartz SB, Hauswirth WW, Jacobson SG, Hemo I, Sharon D (2010) Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel. Hum Gene Ther 21:1749–1757

    Article  PubMed  CAS  Google Scholar 

  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 (2010) Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18:643–650

    Article  PubMed  CAS  Google Scholar 

  10. 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 (2012) 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 130(1):9–24

    Article  PubMed  CAS  Google Scholar 

  11. Leber T (1869) Über Retinitis pigmentosa und angeborene Amaurose. Graefes Arch Clin Exp Ophthalmol 15:1–25

    Article  Google Scholar 

  12. Blum M, Hykin PG, Sanders M, Volcker HE (1992) Theodor Leber: a founder of ophthalmic research. Surv Ophthalmol 37:63–68

    Article  PubMed  CAS  Google Scholar 

  13. Franceschetti A, Dieterle P (1954) Importance diagnostique et prognostique de l'électrorétinogramme (ERG), dans les dégénérescences tapéto-rétiniennes avec rétrécissement du champ visuel et héméralopie. Confin Neurol 14:184–186

    Article  PubMed  CAS  Google Scholar 

  14. Stone EM (2007) Leber congenital amaurosis — a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol 144:791–811

    Article  PubMed  CAS  Google Scholar 

  15. Schappert-Kimmijser J, Henkes HE, Van Den Bosch J (1959) Amaurosis congenita (Leber). AMA Arch Ophthalmol 61:211–218

    Article  PubMed  CAS  Google Scholar 

  16. Lambert SR, Kriss A, Taylor D, Coffey R, Pembrey M (1989) Follow-up and diagnostic reappraisal of 75 patients with Leber's congenital amaurosis. Am J Ophthalmol 107:624–631

    PubMed  CAS  Google Scholar 

  17. Heher KL, Traboulsi EI, Maumenee IH (1992) The natural history of Leber's congenital amaurosis. Age-related findings in 35 patients. Ophthalmology 99:241–245

    PubMed  CAS  Google Scholar 

  18. Fulton AB, Hansen RM, Mayer DL (1996) Vision in Leber congenital amaurosis. Arch Ophthalmol 114:698–703

    Article  PubMed  CAS  Google Scholar 

  19. Walia S, Fishman GA, Jacobson SG, Aleman TS, Koenekoop RK, Traboulsi EI, Weleber RG, Pennesi ME, Heon E, Drack A, Lam BL, Allikmets R, Stone EM (2010) Visual acuity in patients with Leber's congenital amaurosis and early childhood-onset retinitis pigmentosa. Ophthalmology 117:1190–1198

    Article  PubMed  Google Scholar 

  20. Brecelj J, Stirn-Kranjc B (1999) ERG and VEP follow-up study in children with Leber's congenital amaurosis. Eye 13(Pt 1):47–54

    Article  PubMed  Google Scholar 

  21. Godel V, Regenbogen L (1977) Functional evaluation in central retinitis pigmentosa. Ophthalmologica 174:121–128

    Article  PubMed  CAS  Google Scholar 

  22. Birch DG, Peters AY, Locke KL, Spencer R, Megarity CF, Travis GH (2001) Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene. Exp Eye Res 73:877–886

    Article  PubMed  CAS  Google Scholar 

  23. Perrault I, Hanein S, Gerber S, Barbet F, Dufier JL, Munnich A, Rozet JM, Kaplan J (2003) Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele. J Med Genet 40:e90

    Article  PubMed  CAS  Google Scholar 

  24. Dharmaraj SR, Silva ER, Pina AL, Li YY, Yang JM, Carter CR, Loyer MK, El-Hilali HK, Traboulsi EK, Sundin OK, Zhu DK, Koenekoop RK, Maumenee IH (2000) Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet 21:135–150

    PubMed  CAS  Google Scholar 

  25. Simonelli F, Ziviello C, Testa F, Rossi S, Fazzi E, Bianchi PE, Fossarello M, Signorini S, Bertone C, Galantuomo S, Brancati F, Valente EM, Ciccodicola A, Rinaldi E, Auricchio A, Banfi S (2007) Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci 48:4284–4290

    Article  PubMed  Google Scholar 

  26. Perrault I, Rozet JM, Ghazi I, Leowski C, Bonnemaison M, Gerber S, Ducroq D, Cabot A, Souied E, Dufier JL, Munnich A, Kaplan J (1999) Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis. Am J Hum Genet 64:1225–1228

    Article  PubMed  CAS  Google Scholar 

  27. Porto FB, Perrault I, Hicks D, Rozet JM, Hanoteau N, Hanein S, Kaplan J, Sahel JA (2002) Prenatal human ocular degeneration occurs in Leber's congenital amaurosis (LCA2). J Gene Med 4:390–396

    Article  PubMed  Google Scholar 

  28. Pasadhika S, Fishman GA, Stone EM, Lindeman M, Zelkha R, Lopez I, Koenekoop RK, Shahidi M (2010) Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis. Invest Ophthalmol Vis Sci 51:2608–2614

    Article  PubMed  Google Scholar 

  29. Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A (1997) Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet 17:194–197

    Article  PubMed  CAS  Google Scholar 

  30. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A 95:3088–3093

    Article  PubMed  CAS  Google Scholar 

  31. Weleber RG, Michaelides M, Trzupek KM, Stover NB, Stone EM (2011) The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis. Invest Ophthalmol Vis Sci 52:292–302

    Article  PubMed  CAS  Google Scholar 

  32. Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K (1998) Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20:344–351

    Article  PubMed  CAS  Google Scholar 

  33. Lopes VS, Gibbs D, Libby RT, Aleman TS, Welch DL, Lillo C, Jacobson SG, Radu RA, Steel KP, Williams DS (2011) The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65. Hum Mol Genet 20:2560–2570

    Article  PubMed  CAS  Google Scholar 

  34. Znoiko SL, Rohrer B, Lu K, Lohr HR, Crouch RK, Ma JX (2005) Downregulation of cone-specific gene expression and degeneration of cone photoreceptors in the Rpe65−/− mouse at early ages. Invest Ophthalmol Vis Sci 46:1473–1479

    Article  PubMed  Google Scholar 

  35. Jacobson SG, Aleman TS, Cideciyan AV, Sumaroka A, Schwartz SB, Windsor EA, Traboulsi EI, Heon E, Pittler SJ, Milam AH, Maguire AM, Palczewski K, Stone EM, Bennett J (2005) Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc Natl Acad Sci U S A 102:6177–6182

    Article  PubMed  CAS  Google Scholar 

  36. Veske A, Nilsson SE, Narfstrom K, Gal A (1999) Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57:57–61

    Article  PubMed  CAS  Google Scholar 

  37. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95

    PubMed  CAS  Google Scholar 

  38. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG (2005) 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 12:1072–1082

    Article  PubMed  CAS  Google Scholar 

  39. Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y, Bote E, Grant RL, Golden JA, Narfstrom K, Syed NA, Orlin SE, High KA, Maguire AM, Bennett J (2010) Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med 2:21ra16. PMID:20374996

    Article  PubMed  Google Scholar 

  40. Barker SE, Broderick CA, Robbie SJ, Duran Y, Natkunarajah M, Buch P, Balaggan KS, MacLaren RE, Bainbridge JW, Smith AJ, Ali RR (2009) Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice. J Gene Med 11:486–497

    Article  PubMed  CAS  Google Scholar 

  41. Narfstrom K, Katz ML, Bragadottir R, Seeliger M, Boulanger A, Redmond TM, Caro L, Lai CM, Rakoczy PE (2003) Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 44:1663–1672

    Article  PubMed  Google Scholar 

  42. Jacobson SG, Acland GM, Aguirre GD, Aleman TS, Schwartz SB, Cideciyan AV, Zeiss CJ, Komaromy AM, Kaushal S, Roman AJ, Windsor EA, Sumaroka A, Pearce-Kelling SE, Conlon TJ, Chiodo VA, Boye SL, Flotte TR, Maguire AM, Bennett J, Hauswirth WW (2006) Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther 13:1074–1084

    Article  PubMed  CAS  Google Scholar 

  43. Dejneka NS, Surace EM, Aleman TS, Cideciyan AV, Lyubarsky A, Savchenko A, Redmond TM, Tang W, Wei Z, Rex TS, Glover E, Maguire AM, Pugh EN Jr, Jacobson SG, Bennett J (2004) In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9:182–188

    Article  PubMed  CAS  Google Scholar 

  44. Lai CM, Yu MJ, Brankov M, Barnett NL, Zhou X, Redmond TM, Narfstrom K, Rakoczy PE (2004) Recombinant adeno-associated virus type 2-mediated gene delivery into the Rpe65−/− knockout mouse eye results in limited rescue. Genet Vaccines Ther 2:3

    Article  PubMed  Google Scholar 

  45. Pang JJ, Chang B, Kumar A, Nusinowitz S, Noorwez SM, Li J, Rani A, Foster TC, Chiodo VA, Doyle T, Li H, Malhotra R, Teusner JT, McDowell JH, Min SH, Li Q, Kaushal S, Hauswirth WW (2006) Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis. Mol Ther 13:565–572

    Article  PubMed  CAS  Google Scholar 

  46. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D, Cherel Y, Chenuaud P, Samulski J, Moullier P, Rolling F (2003) 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 7:774–781

    Article  PubMed  CAS  Google Scholar 

  47. Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW (2006) Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther 17:845–858

    Article  PubMed  CAS  Google Scholar 

  48. Le Meur G, Weber M, Pereon Y, Mendes-Madeira A, Nivard D, Deschamps JY, Moullier P, Rolling F (2005) Postsurgical assessment and long-term safety of recombinant adeno-associated virus-mediated gene transfer into the retinas of dogs and primates. Arch Ophthalmol 123:500–506

    Article  PubMed  Google Scholar 

  49. Cideciyan AV (2010) Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29:398–427

    Article  PubMed  CAS  Google Scholar 

  50. Ashtari M, Cyckowski LL, Monroe JF, Marshall KA, Chung DC, Auricchio A, Simonelli F, Leroy BP, Maguire AM, Shindler KS, Bennett J (2011) The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest 121:2160–2168

    Article  PubMed  CAS  Google Scholar 

  51. 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 (2012) AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 4:120ra115

    Article  Google Scholar 

  52. Boye SL, Conlon T, Erger K, Ryals R, Neeley A, Cossette T, Pang J, Dyka FM, Hauswirth WW, Boye SE (2011) Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse. Invest Ophthalmol Vis Sci 52:7098–7108

    Article  PubMed  CAS  Google Scholar 

  53. 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 (2011) Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med 3:88ra54. PMID:21697530

    Article  PubMed  CAS  Google Scholar 

  54. Bemelmans AP, Kostic C, Crippa SV, Hauswirth WW, Lem J, Munier FL, Seeliger MW, Wenzel A, Arsenijevic Y (2006) Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis. PLoS Med 3:e347

    Article  PubMed  Google Scholar 

  55. Lheriteau E, Libeau L, Mendes-Madeira A, Deschamps JY, Weber M, Le Meur G, Provost N, Guihal C, Moullier P, Rolling F (2010) Regulation of retinal function but nonrescue of vision in RPE65-deficient dogs treated with doxycycline-regulatable AAV vectors. Mol Ther 18:1085–1093

    Article  PubMed  CAS  Google Scholar 

  56. Stieger K, Le Meur G, Lasne F, Weber M, Deschamps JY, Nivard D, Mendes-Madeira A, Provost N, Martin L, Moullier P, Rolling F (2006) Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors. Mol Ther 13:967–975

    Article  PubMed  CAS  Google Scholar 

  57. Bemelmans AP, Kostic C, Hornfeld D, Jaquet M, Crippa SV, Hauswirth WW, Lem J, Wang Z, Schorderet DE, Munier FL, Wenzel A, Arsenijevic Y (2006) Lentiviral vectors containing a retinal pigment epithelium specific promoter for leber congenital amaurosis gene therapy. Lentiviral gene therapy for LCA. Adv Exp Med Biol 572:247–253

    Article  PubMed  CAS  Google Scholar 

  58. Conley SM, Naash MI (2010) Nanoparticles for retinal gene therapy. Prog Retin Eye Res 29:376–397

    Article  PubMed  CAS  Google Scholar 

  59. Johnson CJ, Berglin L, Chrenek MA, Redmond TM, Boatright JH, Nickerson JM (2008) Technical brief: subretinal injection and electroporation into adult mouse eyes. Mol Vis 14:2211–2226

    PubMed  CAS  Google Scholar 

  60. Jo DH, Lee TG, Kim JH (2011) Nanotechnology and nanotoxicology in retinopathy. Int J Mol Sci 12:8288–8301

    Article  PubMed  CAS  Google Scholar 

  61. Fradot M, Busskamp V, Forster V, Cronin T, Leveillard T, Bennett J, Sahel JA, Roska B, Picaud S (2011) Gene therapy in ophthalmology: validation on cultured retinal cells and explants from postmortem human eyes. Hum Gene Ther 22:587–593

    Article  PubMed  CAS  Google Scholar 

  62. Sun X, Pawlyk B, Xu X, Liu X, Bulgakov OV, Adamian M, Sandberg MA, Khani SC, Tan MH, Smith AJ, Ali RR, Li T (2010) Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Ther 17:117–131

    Article  PubMed  CAS  Google Scholar 

  63. Tan MH, Smith AJ, Pawlyk B, Xu X, Liu X, Bainbridge JB, Basche M, McIntosh J, Tran HV, Nathwani A, Li T, Ali RR (2009) Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum Mol Genet 18:2099–2114

    Article  PubMed  CAS  Google Scholar 

  64. Boye SE, Boye SL, Pang J, Ryals R, Everhart D, Umino Y, Neeley AW, Besharse J, Barlow R, Hauswirth WW (2010) Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 (GC1) knockout mouse. PLoS One 5:e11306

    Article  PubMed  Google Scholar 

  65. Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Roman AJ, Swider M, Schwartz SB, Banin E, Stone EM (2011) Human retinal disease from AIPL1 gene mutations: foveal cone loss with minimal macular photoreceptors and rod function remaining. Invest Ophthalmol Vis Sci 52:70–79

    Article  PubMed  CAS  Google Scholar 

  66. Pennesi ME, Stover NB, Stone EM, Chiang PW, Weleber RG (2011) Residual Residual electroretinograms in young Leber congenital amaurosis patients with mutations of AIPL1. Invest Ophthalmol Vis Sci 52:8166–8173

    Article  PubMed  CAS  Google Scholar 

  67. Testa F, Surace EM, Rossi S, Marrocco E, Gargiulo A, Di Iorio V, Ziviello C, Nesti A, Fecarotta S, Bacci ML, Giunti M, Della Corte M, Banfi S, Auricchio A, Simonelli F (2011) Evaluation of Italian patients with Leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. Invest Ophthalmol Vis Sci 52:5618–5624

    Article  PubMed  CAS  Google Scholar 

  68. Bonnet C, Augustin S, Ellouze S, Benit P, Bouaita A, Rustin P, Sahel JA, Corral-Debrinski M (2008) The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim Biophys Acta 1783:1707–1717

    Article  PubMed  CAS  Google Scholar 

  69. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M (2008) Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 83:373–387

    Article  PubMed  CAS  Google Scholar 

  70. Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J (2010) Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Arch Ophthalmol 128:1129–1135

    Article  PubMed  CAS  Google Scholar 

  71. Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frezal J, Dufier JL, Pittler S, Munnich A, Kaplan J (1996) Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nat Genet 14:461–464

    Article  PubMed  CAS  Google Scholar 

  72. Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP (1997) Mutations in RPE65 cause Leber's congenital amaurosis. Nat Genet 17:139–141

    Article  PubMed  CAS  Google Scholar 

  73. Dharmaraj S, Leroy BP, Sohocki MM, Koenekoop RK, Perrault I, Anwar K, Khaliq S, Devi RS, Birch DG, De Pool E, Izquierdo N, Van Maldergem L, Ismail M, Payne AM, Holder GE, Bhattacharya SS, Bird AC, Kaplan J, Maumenee IH (2004) The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol 122:1029–1037

    Article  PubMed  CAS  Google Scholar 

  74. Dryja TP, Adams SM, Grimsby JL, McGee TL, Hong DH, Li T, Andreasson S, Berson EL (2001) Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet 68:1295–1298

    Article  PubMed  CAS  Google Scholar 

  75. Lotery AJ, Jacobson SG, Fishman GA, Weleber RG, Fulton AB, Namperumalsamy P, Heon E, Levin AV, Grover S, Rosenow JR, Kopp KK, Sheffield VC, Stone EM (2001) Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol 119:415–420

    PubMed  CAS  Google Scholar 

  76. Le Meur G, Stieger K, Smith AJ, Weber M, Deschamps JY, Nivard D, Mendes-Madeira A, Provost N, Pereon Y, Cherel Y, Ali RR, Hamel C, Moullier P, Rolling F (2007) Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther 14:292–303

    Article  PubMed  Google Scholar 

  77. 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 (2008) Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther 16:458–465

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Marcus Blum (Helios Klinikum Erfurt) for his generous gift of English translations of the original German descriptions of LCA by Theodor Leber, and Michael Gorin for his comments on this manuscript. We especially thank the patients and families of all LCA patients who have contributed and will contribute to human gene therapy trials. This work was partially supported by the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (R00-DC009287-03), and a Career Development Award from Research to Prevent Blindness (Z.A.).

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Ophthalmology, University of Cincinnati and Cincinnati Children’s Hospital, College of Medicine, 3333 Burnet Ave, ML 7003, Cincinnati, OH, 45229, USA

    Robert B. Hufnagel

  2. Cincinnati Children’s Hospital, Cincinnati, OH, 45229, USA

    Zubair M. Ahmed

  3. University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Zélia M. Corrêa

  4. Cincinnati Eye Institute, Cincinnati, OH, 45242, USA

    Robert A. Sisk

Authors
  1. Robert B. Hufnagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zubair M. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zélia M. Corrêa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert A. Sisk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert B. Hufnagel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hufnagel, R.B., Ahmed, Z.M., Corrêa, Z.M. et al. Gene therapy for Leber congenital amaurosis: advances and future directions. Graefes Arch Clin Exp Ophthalmol 250, 1117–1128 (2012). https://doi.org/10.1007/s00417-012-2028-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-012-2028-2

Keywords

Search

Navigation