Gene Therapy for Stargardt Disease Associated with ABCA4 Gene

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 801)

Abstract

Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt’s disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8 kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4-/- murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt’s disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach.

Keywords

ABCA4 Gene therapy Nanoparticles Lentivirus STGD1 Viral Non-viral 

References

  1. 1.
    Illing M, Molday LL, Molday RS (1997) The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily. J Biol Chem 272(15):10303–10310PubMedCrossRefGoogle Scholar
  2. 2.
    Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 98(1):13–23PubMedCrossRefGoogle Scholar
  3. 3.
    Molday RS (2007) ATP-binding cassette transporter ABCA4: molecular properties and role in vision and macular degeneration. J Bioenerg Biomembr 39(5-6):507–517PubMedCrossRefGoogle Scholar
  4. 4.
    Conley SM, Cai X, Makkia R, Wu Y, Sparrow JR, Naash MI (2012) Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt’s dystrophy. Biochim Biophys Acta 1822(7):1169–1179PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Han Z, Conley SM, Makkia RS, Cooper MJ, Naash MI (2012) DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice. J Clin Invest 122(9):3221–3226PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Mata NL, Weng J, Travis GH (2000) Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA 97(13):7154–7159PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH (2003) Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration. Proc Natl Acad Sci USA 100(8):4742–4747PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Azarian SM, Megarity CF, Weng J, Horvath DH, Travis GH (1998) The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis. Hum Genet 102(6):699–705PubMedCrossRefGoogle Scholar
  9. 9.
    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 (2008) Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther 15(19):1311–1320PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lai Y, Yue Y, Duan D (2010) Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or = 8.2 kb. Mol Ther 18(1):75–79PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Di Vicino U, Cutillo L, Sparrow JR, Williams DS, Bennett J, Auricchio A (2008) Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest 118(5):1955–1964PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    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(21):2231–2239PubMedCrossRefGoogle Scholar
  13. 13.
    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(7):725–727PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    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(21):2240–2248PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hirsch ML, Agbandje-McKenna M, Samulski RJ (2010) Little vector, big gene transduction: fragmented genome reassembly of adeno-associated virus. Mol Ther 18(1):6–8PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18(1):80–86PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Balaggan KS, Binley K, Esapa M, Iqball S, Askham Z, Kan O, Tschernutter M, Bainbridge JW, Naylor S, Ali RR (2006) Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors. J Gene Med 8(3):275–285PubMedCrossRefGoogle Scholar
  18. 18.
    Miyoshi H, Takahashi M, Gage FH, Verma IM (1997) Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. Proc Natl Acad Sci USA 94(19):10319–10323PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Greenberg KP, Geller SF, Schaffer DV, Flannery JG (2007) Targeted transgene expression in muller glia of normal and diseased retinas using lentiviral vectors. Invest Ophthalmol Vis Sci 48(4):1844–1852PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4(5):346–358PubMedCrossRefGoogle Scholar
  21. 21.
    Sarkis C, Philippe S, Mallet J, Serguera C (2008) Non-integrating lentiviral vectors. Curr Gene Ther 8(6):430–437PubMedCrossRefGoogle Scholar
  22. 22.
    Farjo R, Skaggs J, Quiambao AB, Cooper MJ, Naash MI (2006) Efficient non-viral ocular gene transfer with compacted DNA nanoparticles. PLoS One 1:e38PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Han Z, Koirala A, Makkia R, Cooper MJ, Naash MI (2012) Direct gene transfer with compacted DNA nanoparticles in retinal pigment epithelial cells: expression, repeat delivery and lack of toxicity. Nanomedicine (Lond) 7(4):521–539CrossRefGoogle Scholar
  24. 24.
    Koirala A, Makkia RS, Cooper MJ, Naash MI (2011) Nanoparticle-mediated gene transfer specific to retinal pigment epithelial cells. Biomaterials 32(35):9483–9493PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Fink TL, Klepcyk PJ, Oette SM, Gedeon CR, Hyatt SL, Kowalczyk TH, Moen RC, Cooper MJ (2006) Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles. Gene Ther 13(13):1048–1051PubMedCrossRefGoogle Scholar
  26. 26.
    Konstan MW, Davis PB, Wagener JS, Hilliard KA, Stern RC, Milgram LJ, Kowalczyk TH, Hyatt SL, Fink TL, Gedeon CR, Oette SM, Payne JM, Muhammad O, Ziady AG, Moen RC, Cooper MJ (2004) Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum Gene Ther 15(12):1255–1269PubMedCrossRefGoogle Scholar
  27. 27.
    Padegimas L, Kowalczyk TH, Adams S, Gedeon CR, Oette SM, Dines K, Hyatt SL, Sesenoglu-Laird O, Tyr O, Moen RC, Cooper MJ (2012) Optimization of hCFTR Lung Expression in Mice Using DNA Nanoparticles. Mol Ther 20(1):63–72PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Yurek DM, Fletcher AM, Smith GM, Seroogy KB, Ziady AG, Molter J, Kowalczyk TH, Padegimas L, Cooper MJ (2009) Long-term transgene expression in the central nervous system using DNA nanoparticles. Mol Ther 17(4):641–650PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Cai X, Conley SM, Nash Z, Fliesler SJ, Cooper MJ, Naash MI (2010) Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB J 24(4):1178–1191PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Koirala A, Makkia RS, Conley SM, Cooper MJ, Naash MI (2013) S/MAR-containing DNA nanoparticles promote persistent RPE gene expression and improvement in RPE65-associated LCA. Hum Mol Genet 22(8):1632–1642PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Han Z, Conley SM, Makkia R, Guo J, Cooper MJ, Naash MI (2012) Comparative Analysis of DNA Nanoparticles and AAVs for Ocular Gene Delivery. PLoS One 7(12):e52189PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2014

Authors and Affiliations

  • Zongchao Han
    • 1
  • Shannon M. Conley
    • 1
  • Muna I. Naash
    • 1
  1. 1.Department of Cell BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

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