Current clinical trials and progress of gene therapy for the treatment of inherited retinal degenerations_Chinese Journal of Ocular Fundus Diseases

Authors：

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China (Fan Guoping, special-term professor, Department of Human Genetics, Daivd Geffen School of Medicine, University of California Los Angeles;

Corresponding author：

Keywords：

Retinal degeneration/genetics; Gene therapy; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.06.025

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Inherited retinal degenerations (IRD) are a group of diseases with high genetic heterogeneity and differences in inheritance patterns, age of onset and severity of visual dysfunction. It is one of the leading causes of blindness. In recent years, gene therapy becomes a popular research area in the treatment of genetic diseases due to the rapid development of gene diagnosis technology. Several clinical trials worldwide have proved the safety and effectiveness of gene therapies in IRD. Clinical application of adeno-associated virus -mediated gene therapies for Leber congenital amaurosis and choroideremia clinical trials indicate that patients' retinal functions were improved at different levels after treatment. There are a number of other IRD clinical trials ongoing currently, which bring new possibilities to treat IRD. This article reviews the pathogenesis of IRD, gene vectors and clinical trials in IRD.

Citation： SongQinglu, LiuQinghuai, FanGuoping. Current clinical trials and progress of gene therapy for the treatment of inherited retinal degenerations. Chinese Journal of Ocular Fundus Diseases, 2016, 32(6): 650-653. doi: 10.3760/cma.j.issn.1005-1015.2016.06.025 Copy

1.	Dalkara D, Sahel JA.Gene therapy for inherited retinal degenerations[J].C R Biol, 2014, 337(3):185-192. DOI:10.1016/j.crvi.2014.01.002.
2.	Mendes HF, van der Spuy J, Chapple JP, et al. Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy[J]. Trends Mol Med, 2005, 11(4): 177-185.
3.	Lewis RA, Allikmets R, Lupski JR. Inherited macular dystrophies and susceptibility to degeneration[M]// Valle D, Beaudet AL, Vogelstein B, et al. The online metabolic and molecular bases of inherited disease. New York:McGraw-Hill Companies, 2016:243:1-35.
4.	Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies[J].Prog Retin Eye Res, 2014, 43:108-128. DOI: 10.1016/j.preteyeres. 2014.08.001.
5.	Dalkara D, Duebel J, Sahel JA. Gene therapy for the eye focus on mutation-independent approaches[J]. Curr Opin Neurol, 2015, 28(1): 51-60. DOI: 10.1097/WCO.0000000000000168.
6.	Tamboli V, Mishra GP, Mitrat AK. Polymeric vectors for ocular gene delivery[J]. Ther Deliv, 2011, 2(4):523-536. DOI: 10.4155/tde.11.20.
7.	Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors[J]. Gene Ther, 2012, 19(6):649-658. DOI: 10.1038/ gt.2012.6.
8.	Khabou H, Desrosiers M, Winckler C, et al. Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant‐7m8[J/OL].Biotechnol Bioeng, 2016[2016-06-04].https://www.ncbi.nlm.nih.gov/pubmed/27259396.DOI:10.1002/bit.26031.[published online ahead of print].
9.	Bennett J, Wilson J, Sun D, et al. Adenovirus vector-mediated in vivo gene transfer into adult murine retina[J].Invest Ophthalmol Vis Sci, 1994, 35(5): 2535-2542.
10.	Puppo A, Cesi G, Marrocco E, et al. Retinal transduction profiles by high-capacity viral vectors[J]. Gene Ther, 2014, 21(10):855-865. DOI: 10.1038/ gt.2014.57.
11.	Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease[J]. Invest Ophthalmol Vis Sci, 2013, 54(6):4061-4071. DOI: 10.1167/iovs.13-11871.
12.	Balaggan KS, Binley K, Esapa M, et al. Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors[J].J Gene Med, 2006, 8(3):275-285. DOI: 10.1002/jgm.845.
13.	Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis[J].World J Clin Cases, 2015, 3(2):112-124. DOI: 10.12998/ wjcc. v3.i2.112.
14.	Littink KW, den Hollander AI, Cremers FP, et al. The power of homozygosity mapping: discovery of new genetic defects in patients with retinal dystrophy[J]. Adv Exp Med Biol, 2012, 723:345-351. DOI: 10.1007/978-1-4614-0631-0_45.
15.	Smith J, Ward D, Michaelides M, et al. New and emerging technologies for the treatment of inherited retinal diseases: a horizon scanning review[J].Eye (Lond), 2015, 29(9):1131-1140. DOI: 10.1038/eye.2015.115.
16.	Jacobson SG, Aleman TS, Cideciyan AV, et al. Human cone photoreceptor dependence on RPE65 isomerase[J].Proc Natl Acad Sci USA, 2007, 104(38):15123-15128. DOI: 10.1073/pnas.0706367104.
17.	Annear MJ, Bartoe JT, Barker SE, et al. Gene therapy in the second eye of RPE65-deficient dogs improves retinal function[J].Gene Ther, 2011, 18(1):53-61. DOI: 10.1038/gt.2010.111.
18.	Bainbridge JW, Smith AJ, Barker SS, et al.Effect of gene therapy on visual function in Leber's congenital amaurosis[J].N Engl J Med, 2008, 358(21):2231-2239. DOI: 10.1056/NEJMoa0802268.
19.	Cideciyan AV, Jacobson SG, Beltran WA, et al.Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement[J].Proc Natl Acad Sci USA, 2013, 110(6):517-525. DOI: 10.1073/ pnas.1218933110.
20.	Hauswirth WW, Aleman TS, Kaushal S, et al.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 Ⅰtrial[J].Hum Gene Ther, 2008, 19(10):979-990. DOI: 10.1089/hum.2008.107.
21.	Jacobson SG, Cideciyan AV, Ratnakaram R, et al.Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years[J].Arch Ophthalmol, 2012, 130(1):9-24. DOI: 10.1001/ archophthalmol.2011.298.
22.	Maguire AM, High KA, Auricchio A, et al.Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial[J].Lancet, 2009, 374(9701):1597-1605. DOI: 10.1016/S0140-6736(09)61836-5.
23.	Simonelli F, Maguire AM, Testa F, et al.Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18(3):643-650. DOI: 10.1038/mt.2009.277.
24.	Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis[J].N Engl J Med, 2015, 372(20):1887-1897. DOI: 10.1056/NEJMoa1414221.
25.	Schimmer J, Breazzano S. Investor outlook: focus on upcoming LCA2 gene therapy phase Ⅲ results[J].Hum Gene Ther Clin Dev, 2015, 26(3):144-149. DOI: 10.1089/humc. 2015.29001.sch.
26.	Schimmer J, Breazzano S. Investor outlook: significance of the positive LCA2 gene therapy phase Ⅲ results[J]. Hum Gene Ther Clin Dev, 2015, 26(4):208-210. DOI: 10.1089/humc.2015.29004.sch.
27.	Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase[J].Science, 1993, 259(5093):377-381.
28.	MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial[J]. Lancet, 2014, 383(9923): 1129-1137. DOI: 10.1016/S0140-6736(13)62117-0.
29.	Carvalho LS, Vandenberghe LH. Promising and delivering gene therapies for vision loss[J]. Vision Res, 2015, 111(Pt B):124-133. DOI: 10.1016/j.visres.2014.07. 013.
30.	Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy[J].Gene Ther, 2008, 15(19):1311-1320. DOI: 10.1038/gt.2008.78.
31.	Zallocchi M, Binley K, Lad Y, et al. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat[J/OL].PLoS One, 2014, 9(4):94272[2014-04-04].http://www.doc88.com/p-7738295378677.html. DOI: 10.1371/journal.pone.0094272.
32.	Henriksen BS, Marc RE, Bernstein PS. Optogenetics for retinal disorders[J]. J AAPOS, 2014, 18(4):374-377. DOI: 10.1016/j.jaapos.2014.04.002.
33.	Koilkonda RD, Yu H, Chou TH, et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial[J].JAMA Ophthalmol, 2014, 132(4):409-420. DOI: 10.1001/jamaophthalmol.2013.7630.
34.	Cwerman-Thibault H, Augustin S, Ellouze S, et al. Gene therapy for mitochondrial diseases: Leber hereditary optic neuropathy as the first candidate for a clinical trial[J].C R Biol, 2014, 337(3):193-206. DOI: 10.1016/j.crvi.2013.11.011.
35.	O'Reilly M, Kohn DB, Bartlett J, et al. Gene therapy for rare diseases: Summary of a National Institutes of Health workshop, September 13, 2012[J].Hum Gene Ther, 2013, 24(4):355-362. DOI: 10.1089/hum.2013.064.

1. Dalkara D, Sahel JA.Gene therapy for inherited retinal degenerations[J].C R Biol, 2014, 337(3):185-192. DOI:10.1016/j.crvi.2014.01.002.
2. Mendes HF, van der Spuy J, Chapple JP, et al. Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy[J]. Trends Mol Med, 2005, 11(4): 177-185.
3. Lewis RA, Allikmets R, Lupski JR. Inherited macular dystrophies and susceptibility to degeneration[M]// Valle D, Beaudet AL, Vogelstein B, et al. The online metabolic and molecular bases of inherited disease. New York:McGraw-Hill Companies, 2016:243:1-35.
4. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies[J].Prog Retin Eye Res, 2014, 43:108-128. DOI: 10.1016/j.preteyeres. 2014.08.001.
5. Dalkara D, Duebel J, Sahel JA. Gene therapy for the eye focus on mutation-independent approaches[J]. Curr Opin Neurol, 2015, 28(1): 51-60. DOI: 10.1097/WCO.0000000000000168.
6. Tamboli V, Mishra GP, Mitrat AK. Polymeric vectors for ocular gene delivery[J]. Ther Deliv, 2011, 2(4):523-536. DOI: 10.4155/tde.11.20.
7. Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors[J]. Gene Ther, 2012, 19(6):649-658. DOI: 10.1038/ gt.2012.6.
8. Khabou H, Desrosiers M, Winckler C, et al. Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant‐7m8[J/OL].Biotechnol Bioeng, 2016[2016-06-04].https://www.ncbi.nlm.nih.gov/pubmed/27259396.DOI:10.1002/bit.26031.[published online ahead of print].
9. Bennett J, Wilson J, Sun D, et al. Adenovirus vector-mediated in vivo gene transfer into adult murine retina[J].Invest Ophthalmol Vis Sci, 1994, 35(5): 2535-2542.
10. Puppo A, Cesi G, Marrocco E, et al. Retinal transduction profiles by high-capacity viral vectors[J]. Gene Ther, 2014, 21(10):855-865. DOI: 10.1038/ gt.2014.57.
11. Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease[J]. Invest Ophthalmol Vis Sci, 2013, 54(6):4061-4071. DOI: 10.1167/iovs.13-11871.
12. Balaggan KS, Binley K, Esapa M, et al. Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors[J].J Gene Med, 2006, 8(3):275-285. DOI: 10.1002/jgm.845.
13. Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis[J].World J Clin Cases, 2015, 3(2):112-124. DOI: 10.12998/ wjcc. v3.i2.112.
14. Littink KW, den Hollander AI, Cremers FP, et al. The power of homozygosity mapping: discovery of new genetic defects in patients with retinal dystrophy[J]. Adv Exp Med Biol, 2012, 723:345-351. DOI: 10.1007/978-1-4614-0631-0_45.
15. Smith J, Ward D, Michaelides M, et al. New and emerging technologies for the treatment of inherited retinal diseases: a horizon scanning review[J].Eye (Lond), 2015, 29(9):1131-1140. DOI: 10.1038/eye.2015.115.
16. Jacobson SG, Aleman TS, Cideciyan AV, et al. Human cone photoreceptor dependence on RPE65 isomerase[J].Proc Natl Acad Sci USA, 2007, 104(38):15123-15128. DOI: 10.1073/pnas.0706367104.
17. Annear MJ, Bartoe JT, Barker SE, et al. Gene therapy in the second eye of RPE65-deficient dogs improves retinal function[J].Gene Ther, 2011, 18(1):53-61. DOI: 10.1038/gt.2010.111.
18. Bainbridge JW, Smith AJ, Barker SS, et al.Effect of gene therapy on visual function in Leber's congenital amaurosis[J].N Engl J Med, 2008, 358(21):2231-2239. DOI: 10.1056/NEJMoa0802268.
19. Cideciyan AV, Jacobson SG, Beltran WA, et al.Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement[J].Proc Natl Acad Sci USA, 2013, 110(6):517-525. DOI: 10.1073/ pnas.1218933110.
20. Hauswirth WW, Aleman TS, Kaushal S, et al.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 Ⅰtrial[J].Hum Gene Ther, 2008, 19(10):979-990. DOI: 10.1089/hum.2008.107.
21. Jacobson SG, Cideciyan AV, Ratnakaram R, et al.Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years[J].Arch Ophthalmol, 2012, 130(1):9-24. DOI: 10.1001/ archophthalmol.2011.298.
22. Maguire AM, High KA, Auricchio A, et al.Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial[J].Lancet, 2009, 374(9701):1597-1605. DOI: 10.1016/S0140-6736(09)61836-5.
23. Simonelli F, Maguire AM, Testa F, et al.Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18(3):643-650. DOI: 10.1038/mt.2009.277.
24. Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis[J].N Engl J Med, 2015, 372(20):1887-1897. DOI: 10.1056/NEJMoa1414221.
25. Schimmer J, Breazzano S. Investor outlook: focus on upcoming LCA2 gene therapy phase Ⅲ results[J].Hum Gene Ther Clin Dev, 2015, 26(3):144-149. DOI: 10.1089/humc. 2015.29001.sch.
26. Schimmer J, Breazzano S. Investor outlook: significance of the positive LCA2 gene therapy phase Ⅲ results[J]. Hum Gene Ther Clin Dev, 2015, 26(4):208-210. DOI: 10.1089/humc.2015.29004.sch.
27. Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase[J].Science, 1993, 259(5093):377-381.
28. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial[J]. Lancet, 2014, 383(9923): 1129-1137. DOI: 10.1016/S0140-6736(13)62117-0.
29. Carvalho LS, Vandenberghe LH. Promising and delivering gene therapies for vision loss[J]. Vision Res, 2015, 111(Pt B):124-133. DOI: 10.1016/j.visres.2014.07. 013.
30. Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy[J].Gene Ther, 2008, 15(19):1311-1320. DOI: 10.1038/gt.2008.78.
31. Zallocchi M, Binley K, Lad Y, et al. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat[J/OL].PLoS One, 2014, 9(4):94272[2014-04-04].http://www.doc88.com/p-7738295378677.html. DOI: 10.1371/journal.pone.0094272.
32. Henriksen BS, Marc RE, Bernstein PS. Optogenetics for retinal disorders[J]. J AAPOS, 2014, 18(4):374-377. DOI: 10.1016/j.jaapos.2014.04.002.
33. Koilkonda RD, Yu H, Chou TH, et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial[J].JAMA Ophthalmol, 2014, 132(4):409-420. DOI: 10.1001/jamaophthalmol.2013.7630.
34. Cwerman-Thibault H, Augustin S, Ellouze S, et al. Gene therapy for mitochondrial diseases: Leber hereditary optic neuropathy as the first candidate for a clinical trial[J].C R Biol, 2014, 337(3):193-206. DOI: 10.1016/j.crvi.2013.11.011.
35. O'Reilly M, Kohn DB, Bartlett J, et al. Gene therapy for rare diseases: Summary of a National Institutes of Health workshop, September 13, 2012[J].Hum Gene Ther, 2013, 24(4):355-362. DOI: 10.1089/hum.2013.064.

Chinese Journal of Ocular Fundus Diseases

Current clinical trials and progress of gene therapy for the treatment of inherited retinal degenerations

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