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Gene Augmentation Trials Using the Rpe65-Deficient Dog: Contributions Towards Development and Refinement of Human Clinical Trials

  • Simon M. Petersen-JonesEmail author
  • Matthew J. Annear
  • Joshua T. Bartoe
  • Freya M. Mowat
  • Susie E. Barker
  • Alexander J. Smith
  • James W. Bainbridge
  • Robin R. Ali
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Dogs with a spontaneous mutation in Rpe65 have been key in the testing of gene augmentation therapy using viral vectors to introduce a normal copy of the Rpe65 gene. These ground-breaking experiments have led to Phase I/II human clinical trials for treatment of Leber congenital amaurosis type II (LCAII).

The Rpe65-deficient dog remains a useful model for studies to refine this treatment approach. A recent question it has been used to answer is whether or not immune response resulting from the gene augmentation treatment of one eye interferes with the success of the same treatment in the second eye. Fortunately, it was shown that treatment of the second eye had a similar success to that of the first eye, clearly demonstrating potential for gene augmentation therapy in the second eye of LCAII patients.

Keywords

Leber congenital amaurosis RPE65 Canine model Briard Gene therapy Gene augmentation AAV2 Immune response Repeated injection Subretinal injection 

Notes

Acknowledgments

This work was supported by the British Retinitis Pigmentosa Society, The Midwest Eye Banks and Transplantation Center Research Program and Michigan State University College of Veterinary Medicine Purebred Dog Endowment Fund. JWB is a Welcome Trust Advanced Fellow. RRA and JWB are investigators at The NIHR Centre for Ophthalmology at UCl and Moorfields Eye Hospital.

References

  1. Acland GM, Aguirre GD, Bennett J et al (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 12:1072–1082PubMedCrossRefGoogle Scholar
  2. Acland GM, Aguirre GD, Ray J et al (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95PubMedGoogle Scholar
  3. Aguirre GD, Baldwin V, Pearce-Kelling S et al (1998) Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol Vis 4:23PubMedGoogle Scholar
  4. Aguirre GK, Komaromy AM, Cideciyan AV et al (2007) Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation. PLoS Med 4:e230PubMedCrossRefGoogle Scholar
  5. Amado D, Mingozzi F, Hui D et al (2010) Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med 2:21ra16Google Scholar
  6. Annear MJ, Bartoe JT, Barker SE et al (2011) Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Ther 18(1):53–61PubMedCrossRefGoogle Scholar
  7. Bainbridge JW, Smith AJ, Barker SS et al (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358:2231–2239PubMedCrossRefGoogle Scholar
  8. Barker SE, Broderick CA, Robbie SJ et al (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 11:486–497PubMedCrossRefGoogle Scholar
  9. Bennicelli J, Wright JF, Komaromy A et al (2008) Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther 16:458-465PubMedCrossRefGoogle Scholar
  10. Cideciyan AV (2010) Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29:398–427PubMedCrossRefGoogle Scholar
  11. den Hollander AI, Roepman R, Koenekoop RK et al (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27:391–419CrossRefGoogle Scholar
  12. Ford M, Bragadottir R, Rakoczy PE et al (2003) Gene transfer in the RPE65 null mutation dog: relationship between construct volume, visual behavior and electroretinographic (ERG) results. Doc Ophthalmol 107:79–86PubMedCrossRefGoogle Scholar
  13. Gearhart PM, Gearhart CC, Petersen-Jones SM (2008) A novel method for objective vision testing in canine models of inherited retinal disease. Invest Ophthalmol Vis Sci 49:3568–3576PubMedCrossRefGoogle Scholar
  14. Halbert CL, Rutledge EA, Allen JM et al (2000) Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 74:1524–1532PubMedCrossRefGoogle Scholar
  15. Halbert CL, Standaert TA, Aitken ML et al (1997) Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration. J Virol 71:5932–5941PubMedGoogle Scholar
  16. Halbert CL, Standaert TA, Wilson CB et al (1998) Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J Virol 72:9795–9805PubMedGoogle Scholar
  17. Hauswirth WW, Aleman TS, Kaushal S et al (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 19:979–990PubMedCrossRefGoogle Scholar
  18. Jacobson SG, Aleman TS, Cideciyan AV et al (2009) Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 50:2368–2375PubMedCrossRefGoogle Scholar
  19. Jacobson SG, Aleman TS, Cideciyan AV et al (2005) Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc Natl Acad Sci U S A 102:6177–6182PubMedCrossRefGoogle Scholar
  20. Le Meur G, Stieger K, Smith AJ et al (2007) Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther 14:292–303PubMedCrossRefGoogle Scholar
  21. Li Q, Miller R, Han PY et al (2008) Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis 14:1760–1769PubMedGoogle Scholar
  22. Li W, Kong F, Li X et al (2009) Gene therapy following subretinal AAV5 vector delivery is not affected by a previous intravitreal AAV5 vector administration in the partner eye. Mol Vis 15:267–275PubMedGoogle Scholar
  23. Maguire AM, Simonelli F, Pierce EA et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248PubMedCrossRefGoogle Scholar
  24. Narfström K, Bragadottir R, Redmond TM et al (2003a) Functional and structural evaluation after AAV.RPE65 gene transfer in the canine model of Leber’s congenital amaurosis. Adv Exp Med Biol 533:423–430PubMedCrossRefGoogle Scholar
  25. Narfström K, Katz ML, Bragadottir R et al (2003b) Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 44:1663–1672PubMedCrossRefGoogle Scholar
  26. Narfström K, Vaegan, Katz M et al (2005) Assessment of structure and function over a 3-year period after gene transfer in RPE65−/− dogs. Doc Ophthalmol 111:39–48PubMedCrossRefGoogle Scholar
  27. Narfström K, Wrigstad A, Nilsson SE (1989) The Briard dog: a new animal model of congenital stationary night blindness. Br J Ophthalmol 73:750–756PubMedCrossRefGoogle Scholar
  28. Pang J, Boye SE, Lei B et al (2010) Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency. Gene Ther 17:815–826PubMedCrossRefGoogle Scholar
  29. Pang JJ, Chang B, Hawes NL et al (2005) Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol Vis 11:152–162PubMedGoogle Scholar
  30. Redmond TM, Yu S, Lee E et al (1998) Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20:344–351PubMedCrossRefGoogle Scholar
  31. Stone EM (2007) Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol 144:791–811PubMedCrossRefGoogle Scholar
  32. Thompson DA, Gyurus P, Fleischer LL et al (2000) Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci 41:4293–4299PubMedGoogle Scholar
  33. Veske A, Nilsson SE, Narfström K et al (1999) Retinal dystrophy of swedish Briard/Briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57:57–61PubMedCrossRefGoogle Scholar
  34. Wang Z, Allen JM, Riddell SR et al (2007) Immunity to adeno-associated virus-mediated gene transfer in a random-bred canine model of Duchenne muscular dystrophy. Hum Gene Ther 18:18–26PubMedCrossRefGoogle Scholar
  35. Wrigstad A, Narfström K, Nilsson SE (1994) Slowly progressive changes of the retina and retinal pigment epithelium in Briard dogs with hereditary retinal dystrophy. A morphological study. Doc Ophthalmol 87:337–354PubMedCrossRefGoogle Scholar
  36. Znoiko SL, Rohrer B, Lu K et al (2005) Downregulation of cone-specific gene expression and degeneration of cone photoreceptors in the Rpe65−/− mouse at early ages. Invest Ophthalmol Vis Sci 46:1473–1479PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Simon M. Petersen-Jones
    • 1
    Email author
  • Matthew J. Annear
    • 1
  • Joshua T. Bartoe
    • 1
  • Freya M. Mowat
    • 1
  • Susie E. Barker
    • 2
  • Alexander J. Smith
    • 2
  • James W. Bainbridge
    • 2
  • Robin R. Ali
    • 2
  1. 1.Department of Small Animal Clinical SciencesMichigan State UniversityEast LansingUSA
  2. 2.Department of GeneticsUCL Institute of OphthalmologyLondonUK

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