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Gene Therapy Strategies for Usher Syndrome Type 1B

  • David S. WilliamsEmail author
  • Vanda S. Lopes
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Usher syndrome type 1B (Usher 1B) is an inherited deaf-blindness disorder, caused by mutations in the MYO7A gene. Newborns with Usher 1 are readily identified due to their congenital profound deafness. Thus, they are prime candidates for gene therapy to treat their ensuing progressive blindness. MYO7A functions in both the retinal pigment epithelium (RPE) and photoreceptor cells, and Myo7a-null mice demonstrate mutant phenotypes in both cell types. Preclinical studies have tested the efficacy of correcting these mutant phenotypes by delivering MYO7A cDNA with different lentiviral and adeno-associated viral vectors, following subretinal injections. Lentiviruses successfully delivered functional MYO7A to both RPE and photoreceptor cells, although the integrating viruses resulted in some variation in expression level, and thus efficacy, from cell to cell. The size of MYO7A cDNA is too large to be packaged by adeno-associated virus (AAV) without fragmentation; however, AAV delivery was nevertheless found to correct the mutant phenotypes. Therefore, although each viral approach has its own limitation, both vectors work to restore functional MYO7A in the mouse retina, and are realistic candidates for use in preventing blindness in Usher 1B patients.

Keywords

Adeno-associated virus Gene therapy Lentivirus Melanosome MYO7A Photoreceptor Opsin Retinal pigment epithelium Usher syndrome 

Notes

Acknowledgments

We are grateful to Drs. Samuel Jacobson, Bill Hauswirth, Katie Binley, Xian-Jie Yang, and their respective laboratories for discussions and collaborative research. We are supported by grants from the NIH and NNRI. DSW is a Jules and Doris Stein RPB Professor.

References

  1. Allocca M, Doria M, Petrillo M et al (2008) Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest 118: 1955–64PubMedCrossRefGoogle Scholar
  2. Astuto LM, Weston MD, Carney CA et al (2000) Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I. Am J Hum Genet 67: 1569–74PubMedCrossRefGoogle Scholar
  3. 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: 2231–9PubMedCrossRefGoogle Scholar
  4. Bharadwaj AK, Kasztejna JP, Huq S et al (2000) Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. Exp Eye Res 71: 173–81PubMedCrossRefGoogle Scholar
  5. Blanchet C, Roux AF, Hamel C et al (2007) [Usher type I syndrome in children: genotype/phenotype correlation and cochlear implant benefits]. Rev Laryngol Otol Rhinol (Bord) 128: 137–43Google Scholar
  6. Bushman F D (2003) Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 115: 135–8PubMedCrossRefGoogle Scholar
  7. Chen ZY, Hasson T, Kelley PM et al (1996) Molecular cloning and domain structure of human myosin-VIIa, the gene product defective in Usher syndrome 1B. Genomics 36: 440–448PubMedCrossRefGoogle Scholar
  8. Cideciyan AV, Aleman TS, Boye SL et al (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: 15112–7PubMedCrossRefGoogle Scholar
  9. Cuevas JM, Espin SC, Millan JM et al (1999) Identification of three novel mutations in the MYO7A gene. Hum Mutat 14: 181CrossRefGoogle Scholar
  10. Dong B, Nakai H, Xiao W (2010) Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther 18: 87–92PubMedCrossRefGoogle Scholar
  11. El-Amraoui A, Sahly I, Picaud S et al (1996) Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells. Hum Mol Genet 5: 1171–8PubMedCrossRefGoogle Scholar
  12. Gibbs D, Azarian SM, Lillo C et al (2004) Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes. J Cell Sci 117: 6473–83PubMedCrossRefGoogle Scholar
  13. Gibbs D, Kitamoto J, Williams DS (2003) Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proc Natl Acad Sci U S A 100: 6481–86PubMedCrossRefGoogle Scholar
  14. Gibson F, Walsh J, Mburu P et al (1995) A type VII myosin encoded by mouse deafness gene shaker-1. Nature 374: 62–64PubMedCrossRefGoogle Scholar
  15. Grieger JC, Samulski RJ (2005) Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. J Virol 79: 9933–44PubMedCrossRefGoogle Scholar
  16. Gruter O, Kostic C, Crippa SV et al (2005) Lentiviral vector-mediated gene transfer in adult mouse photoreceptors is impaired by the presence of a physical barrier. Gene Ther 12: 942–7PubMedCrossRefGoogle Scholar
  17. Hashimoto T, Gibbs D, Lillo C et al (2007) Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Ther 14: 584–94PubMedCrossRefGoogle Scholar
  18. Hasson T, Heintzelman MB, Santos-Sacchi J et al (1995) Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc. Natl. Acad. Sci. USA 92: 9815–19PubMedCrossRefGoogle Scholar
  19. Hasson T, Walsh J, Cable J et al (1997) Effects of shaker-1 mutations on myosin-VIIa protein and mRNA expression. Cell Motility and the Cytoskeleton 37: 127–38PubMedCrossRefGoogle Scholar
  20. 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: 979–90PubMedCrossRefGoogle Scholar
  21. Holme RH and Steel KP (2002) Stereocilia defects in waltzer (Cdh23), shaker1 (Myo7a) and double waltzer/shaker1 mutant mice. Hear Res 169: 13–23PubMedCrossRefGoogle Scholar
  22. Jacobson SG, Aleman TS, Sumaroka A et al (2009) Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations. Invest Ophthalmol Vis Sci 50: 1886–94PubMedCrossRefGoogle Scholar
  23. Jacobson SG, Cideciyan AV, Aleman TS et al (2008) Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Hum Mol Genet 17: 2405–15PubMedCrossRefGoogle Scholar
  24. Janecke AR, Meins M, Sadeghi M et al (1999) Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. Hum Mutat 13: 133–40PubMedCrossRefGoogle Scholar
  25. Jones, BW and Marc RE (2005) Retinal remodeling during retinal degeneration. Exp Eye Res 81: 123–37PubMedCrossRefGoogle Scholar
  26. Kelley PM, Weston MD, Chen ZY et al (1997) The genomic structure of the gene defective in Usher syndrome type Ib (MYO7A). Genomics 40: 73–9PubMedCrossRefGoogle Scholar
  27. Kostic C, Chiodini F, Salmon P et al (2003) Activity analysis of housekeeping promoters using self-inactivating lentiviral vector delivery into the mouse retina. Gene Ther 10: 818–21PubMedCrossRefGoogle Scholar
  28. Lai Y, Yue Y, Duan D (2010) Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome ≥ 8.2 kb. Mol Ther 18: 75–9PubMedCrossRefGoogle Scholar
  29. Levy G, Levi-Acobas F, Blanchard S et al (1997) Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. Hum Mol Genet 6: 111–6PubMedCrossRefGoogle Scholar
  30. Lillo C, Kitamoto J, Liu X et al (2003) Mouse models for Usher syndrome 1B. Adv Exp Med Biol 533: 143–150PubMedCrossRefGoogle Scholar
  31. Liu X, Ondek B, Williams DS (1998) Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice. Nat. Genet. 19: 117–118PubMedCrossRefGoogle Scholar
  32. Liu X, Udovichenko IP, Brown SDM et al (1999) Myosin VIIa participates in opsin transport through the photoreceptor cilium. J. Neurosci. 19: 6267–6274PubMedGoogle Scholar
  33. Liu X, Vansant G, Udovichenko IP et al (1997) Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells. Cell Motil. Cytoskel. 37: 240–252CrossRefGoogle Scholar
  34. Liu XZ, Angeli SI, Rajput K et al (2008) Cochlear implantation in individuals with Usher type 1 syndrome. Int J Pediatr Otorhinolaryngol 72: 841–7PubMedCrossRefGoogle Scholar
  35. Lopes VS, Ramalho JS, Owen DM et al (2007) The ternary Rab27a-Myrip-Myosin VIIa complex regulates melanosome motility in the retinal pigment epithelium. Traffic 8: 486–99PubMedCrossRefGoogle Scholar
  36. 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: 2240–8PubMedCrossRefGoogle Scholar
  37. Mitchell RS, Beitzel BF, Schroder AR et al (2004) Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2: E234PubMedCrossRefGoogle Scholar
  38. Ouyang XM, Yan D, Du LL et al (2005) Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum Genet 116: 292–9PubMedCrossRefGoogle Scholar
  39. Udovichenko IP, Gibbs D, Williams DS (2002) Actin-based motor properties of native myosin VIIa. J Cell Sci 115: 445–450PubMedGoogle Scholar
  40. Weil D, Blanchard S, Kaplan J et al (1995) Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374: 60–61PubMedCrossRefGoogle Scholar
  41. Weil D, Levy G, Sahly I et al (1996) Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. Proc Natl Acad Sci U S A 93: 3232–3237.PubMedCrossRefGoogle Scholar
  42. Weston MD, Kelley PM, Overbeck LD et al (1996) Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. Am J Hum Genet 59: 1074–83PubMedGoogle Scholar
  43. Williams DS (2008) Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res 48: 433–41PubMedCrossRefGoogle Scholar
  44. Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18: 80–6PubMedCrossRefGoogle Scholar
  45. Yanez-Munoz RJ, Balaggan KS, MacNeil A et al (2006) Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 12: 348–53PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Departments of Ophthalmology and NeurobiologyUCLA School of MedicineLos AngelesUSA

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