Abstract
MERTK-associated retinal degenerations are thought to have defects in phagocytosis of shed outer segment membranes by the retinal pigment epithelium (RPE), as do the rodent models of these diseases. We have subretinally injected an RPE-specific AAV2 vector, AAV2-VMD2-hMERTK, to determine whether this would provide long-term photoreceptor rescue in the RCS rat, which it did for up to 6.5 months, the longest time point examined. Moreover, we found phagosomes in the RPE in the rescued regions of RCS retinas soon after the onset of light. The same vector also had a major protective effect in Mertk-null mice, with a concomitant increase in ERG response amplitudes in the vector-injected eyes. These findings suggest that planned clinical trials with this vector will have a favorable outcome.
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References
Alexander JJ, Hauswirth WW (2008) Adeno-associated viral vectors and the retina. Adv Exp Med Biol 613:121–128
Bainbridge JW, Smith AJ, Barker SS et al (2008) Effect of gene therapy on visual function in Leber’ congenital amaurosis. N Engl J Med 358:2231–2239
Bok D, Hall MO (1971) The role of the pigment epithelium in the etiology of inherited retinal dystrophy in the rat. J Cell Biol 49:664–682
Boye SE, Boye SL, Lewin AS et al (2013) A comprehensive review of retinal gene therapy. Mol Ther 21:509–519
Charbel Issa P, Bolz HJ, Ebermann I et al (2009) Characterisation of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene. Br J Ophthalmol 93:920–925
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 105:15112–15117
Conlon TJ, Deng WT, Erger K et al (2013) Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa. Hum Gene Ther Clin Devt 24:23–28
D’Cruz PM, Yasumura D, Weir J et al (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–651
Deng WT, Dinculescu A, Li Q et al (2012) Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats. Invest Ophthalmol Vis Sci 53:1895–1904
Dowling JE, Sidman RL (1962) Inherited retinal dystrophy in the rat. J Cell Biol 14:73–109
Duncan JL, LaVail MM, Yasumura D et al (2003) An RCS-like retinal dystrophy phenotype in Mer knockout mice. Invest Ophthalmol Vis Sci 44:826–838
Faktorovich EG, Steinberg RH, Yasumura D et al (1992) Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat. J Neurosci 12:3554–3567
Gal A, Li Y, Thompson DA et al (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26:270–271
Jacobson SG, Boye SL, Aleman TS et al (2006) Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther 17:845–858
LaVail MM (1976) Rod outer segment disc shedding in rat retina: relationship to cyclic lighting. Science 194:1071–1074
LaVail MM (1980) Circadian nature of rod outer segment disc shedding in the rat. Invest Ophthalmol Vis Sci 19:407–411
LaVail MM, Battelle BA (1975) Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat. Exp Eye Res 21:167–192
LaVail MM, Gorrin GM, Repaci MA et al (1987) Genetic regulation of light damage to photoreceptors. Invest Ophthalmol Vis Sci 28:1043–1048
Lewin AS, Drenser KA, Hauswirth WW et al (1998) Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat Med 4:967–971
Mackay DS, Henderson RH, Sergouniotis PI et al (2010) Novel mutations in MERTK associated with childhood onset rod-cone dystrophy. Mol Vis 16:369–377
Maguire AM, Simonelli F, Pierce EA et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248
Mullen RJ, LaVail MM (1976) Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. Science 192:799–801
Ostergaard E, Duno M, Batbayli M et al (2011) A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases. Mol Vis 17:1485–1492
Shahzadi A, Riazuddin SA, Ali S et al (2010) Nonsense mutation in MERTK causes autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family. Br J Ophthalmol 94:1094–1099
Smith AJ, Schlichtenbrede FC, Tschernutter M et al (2003) AAV-mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther 8:188–195
Strick DJ, Vollrath D (2010) Focus on molecules: MERTK. Exp Eye Res 91:786–787
Thompson DA, McHenry CL, Li Y et al (2002) Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. Am J Hum Genet 70:224–229
Tschernutter M, Schlichtenbrede FC, Howe S et al (2005) Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy. Gene Ther 12:694–701
Tschernutter M, Jenkins SA, Waseem NH et al (2006) Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene. Br J Ophthalmol 90:718–723
Vollrath D, Feng W, Duncan JL et al (2001) Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A 98:12584–12589
Acknowledgements
This study was supported by NIH grants EY001919, EY006842 and EY002162 (MML), The Foundation Fighting Blindness (MML, DV, WWH) and Unrestricted Awards to UCSF and the University of Florida from Research to Prevent Blindness.
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LaVail, M. et al. (2016). Gene Therapy for MERTK-Associated Retinal Degenerations. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_65
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DOI: https://doi.org/10.1007/978-3-319-17121-0_65
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