Current work on genetic and molecular biomarkers for treatment response in age-related macular degeneration (AMD) is still exploratory, and precision medicine for AMD is not yet ready for implementation in the clinic. |
Several genetic and molecular biomarkers that associate with response to anti- vascular endothelial growth factor therapy have been identified, but these associations have not been consistently replicated. |
Studies on complement system biomarkers may be useful to identify patients for complement-inhibiting therapies that are currently under development. |
1 Introduction
2 Current Therapeutic Interventions for Age-Related Macular Degeneration Management
2.1 Dietary Supplements for Slowing Disease Progression
2.2 Anti-VEGF Antibodies for Choroidal Neovascularization Treatment
References |
N
a
| Ethnicity/country of origin | Design | Anti-VEGF | Treatment regimen | Treatment outcome definition(s) | Gene: SNPs | Conclusion |
---|---|---|---|---|---|---|---|---|
Brantley et al. [50] | 86 | Caucasian | R | BVZ | 6-weekly inj. until no active CNV | VA after at least 6 months of treatment | CFH: rs1061170 ARMS2: rs10490924 CFH + ARMS2: rs1061170 + rs10490924 | CFH rs1061170 CC → worse response |
Lee et al.[51] | 156 | Caucasian | R | RNZ | PRN | VA after 6, 9 months N of inj. after 9 months Interval between required inj. after 9 months Interval between follow-up appointments after 9 months | CFH: rs1061170 | CFH rs1061170 CC → worse response |
Teper et al. [64] | 90 | Caucasian | P | RNZ | 3 monthly inj. + SUSTAIN criteria | Change in VA after 12 months Change in CSRT after 12 months N of inj. after 12 months | CFH: rs1061170 ARMS2: rs10490924 | ARMS2 rs10490924 TT → worse response |
Imai et al.[52] | 83 | Japanese | R | BVZ | 1 inj. + retreatment after recurrence of AMD | Responders vs. non-responders: responders if improvement in VA after 1, 3 months Change in CRT after 1, 3 months CNV recurrence after 1, 3 months | CFH: rs800292, rs1061170, rs1410996 HTRA1: rs11200638 VEGFA: rs699947, rs1570360, rs2010963 PEDF: rs12150053, rs12948385, rs9913583, rs1136287 | CFH rs1061170 CT → worse response than TT VEGFA rs699947 C → worse response PEDF rs1136287 → not described |
Nakata et al. [152] | 94 | NI (Japan) | R | BVZ | 1–3 inj., when remnant exudative changes 2nd and or 3rd inj. monthly | VA after 12 months Change in VA after 12 months N of inj. after 12 months N of recurrences after 12 months Periods until recurrence after 12 months | VEGFA: rs699946, rs699947 | VEGFA rs69946 A → worse response |
Nischler et al. [53] | 197 | NI (Austria) | P | BVZ | 1 inj. + 6-weekly until no active CNV | N of treatments CMT after treatment VA after treatment Reading VA after treatment Gain or loss of ≥ 3 lines in distance VA Gain or loss of ≥ 3 lines in reading VA | CFH: rs1061170 | CFH rs1061170 CC → worse response |
Wickremasinghe et al. [92] | 168 | Caucasian | R | RNZ or BVZ and RNZ | No specific retreatment strategies (75% 3 monthly inj.) | Improved: 2-line gained in VA; stable: VA within 2 lines of baseline; or decreased: reduction in VA of 2 lines or more | APOE: ε2, ε3 and ε4 | APOE ε4 allele → better response |
Francis et al. [95] | 44 | Caucasian | P | RNZ | Monthly “as needed” | Change in letters after 12 months | GWAS: Illumina 660-Quad SNP array: > 480,000 SNPs | Candidate gene analysis: CFH rs1065489 AA → worse response |
Kloeckener-Gruissem et al. [54] | 243 eyes, 215 individuals | NI (Switzerland) | R | RNZ | PRN | Change in VA after 12 months, poor responders: ≤ 25th percentile; good responders: ≥ 75th percentile | CFH: rs1061170 FZD4: rs10898563 | CFH rs1061170 CC → worse response CFH rs1061170 CT and FZD4 rs10898563 AG → better response |
Wang et al. [153] | 106 | Caucasian | NI | BVZ/RNZ | 1 inj. + PRN for 12 months | Poor responder (based on VA, and OCT parameters) | 21 SNPs in IL23, PLA2G12A, HIF1A, STAT3, VEGF, KDR | No associations found (after correction for multiple testing) |
McKibbin et al. [65] | 104 | Caucasian | R | RNZ | 3 monthly inj. + PRN | Gain of > 5 letters vs. rest after 6 months Change in VA after 6 months | CFH: rs1061170 HTRA1: rs11200638 VEGFA: rs1413711 | No association found (after correction for multiple testing) |
Orlin et al. [66] | 150 | NI (USA) | R | BVZ/RNZ | 3 monthly inj. + TE | After last visit, positive responders: improvement or no change in VA; negative responders: loss of VA or final VA 20/200 | CFH: rs1061170 ARMS2: rs10490924, rs3750848, del443ins54 HTRA1: rs3793917, rs11200638, rs932275 | No associations found |
Smailhodzic et al. [55] | 420 eyes, 397 individuals | NI (the Netherlands, Germany, Canada) | R | RNZ | 3 monthly inj. + PRN | Change in VA after 3 months | CFH: rs1061170 ARMS2: rs10490924 VEGFA: rs699947, rs833069 KDR: rs2071559, rs7671745 LPR5: rs3736228 FZD4: rs10898563 CFH + ARMS2: rs1061170 + rs10490924 CFH + ARMS2 + VEGFA: rs1061170 + rs10490924 + rs699947 | CFH rs1061170 TT → better response CFH + ARMS2 0 risk alleles → better response CFH + ARMS2 1 or 2 risk alleles → older age at first inj. CFH + ARMS2 + VEGFA less risk alleles → better response |
Boltz et al. [154] | 185 eyes, 141 individuals | NI (Germany) | P | BVZ | PRN for 42–182 days | Mean change in VA after treatment N of treatments after treatment Duration of the treatment | VEGFA: rs1413711, rs3025039, rs2010963, rs833061, rs699947, rs3024997, rs1005230 | No associations found |
Menghini et al. [56] | 204 eyes, 194 individuals | NI (Switzerland) | R | RNZ | 3 monthly inj. + PRN or PRN | After 12, 24 months, good responders: ≥ 5-letter improvement; poor responders: ≥ 5-letter loss | CFH: rs1061170 | CFH rs1061170 CT → better response CFH rs1061170 CT/TT → better response |
Tian et al. [67] | 144 | Chinese | P | BVZ | 6-weekly inj. | Change in letters after 3 months Change in CRT after 3 months Maximum lesion thickness after 3 months | CFH: rs800292, rs1061170, rs10801555, rs1410996 ARMS2: rs10490924 HTRA1: rs11200638 VEGFA: rs833069, rs3025039 SERPING1: rs1005510, rs2511989 C3: rs2230205, rs2250656 | CFH rs800292 CC → worse response ARMS2 rs10490924 TT → worse response HTRA1 rs11200638 AA → worse response |
Kang et al. [57] | 75 | Korean | R | BVZ | 3 monthly inj. + PRN for 6 months/12 months | Change in VA after 3, 6, 12 months Change in CRT after 3, 6, 12 months N of additional inj. after loading dose | CFH: rs1061170 ARMS2: rs10490924 HTRA1: rs11200638 | ARMS2: rs10490924 G → worse response CFH rs1061170 TC → worse response than TT |
Lazzeri et al. (2013) | 64 | Italian | P | RNZ | 3 monthly inj. | Change in letters after 3 months | VEGFA: rs699947, rs1570360 | VEGFA rs699947 C → better response |
Dikmetas et al. [58] | 193 | Turkish | R | RNZ | PRN | At final examination, good response: ≥ 5 letters; bad response: decrease of ≥ 5 letters; very good response: ≥ 15 letters; very bad response: decrease in VA of ≥ 15 letters | CFH: rs1061170 | CFH rs1061170 C → worse response |
Chang et al. [68] | 102 | Korean | R | RNZ | 3 monthly inj. + PRN | Change in VA after 3, 6 months Change in CSMT after 3, 6 months | CFH: rs1061170 ARMS2: rs10490924 HTRA1: rs11200638 VEGFA: rs833069 KDR: rs2071559 | VEGFA rs833069 G → better response |
Kitchens et al. [69] | 101 | NI (USA) | R | BVZ/RNZ | 3 monthly inj. + PRN for 6 months/12 months | Based on OCT, responder: no fluid after inj. for after least 1 month; non-responder: fluid present 1 month after the 3rd inj. Based on VA, responder: gained ≥ 3 lines after month 9; non-responder: no gain of ≥ 3 lines after month 9 | CFH: rs1061170 ARMS2: rs10490924 VEGFA: rs699947, rs1570360, rs833060, rs36208049, rs833061, rs25648, rs59260042, rs2010963 | ARMS2 rs10490924 TT → worse response |
Abedi et al. [70] | 224 | Caucasian | P | BVZ/RNZ | 3 monthly inj. + PRN | Change in VA after 12 months | CFH: rs800292, rs3766404, rs1061170, rs2274700, rs393955 HTRA1: rs11200638 CFHR1–5: rs10922153, rs16840639, rs6667243, rs1853883 ARMS2: rs3793917, rs10490924 C3: rs2230199, rs1047286 C2: rs547154 CFB: rs641153 F13B: rs6003 | HTRA1 rs11200638 AA → worse response ARMS2 rs10490924 TT → worse response |
Hagstrom et al. [71] | 834 | CATT (98% Caucasian), NI | P | BVZ/RNZ | PRN/monthly | VA after 12 months Change in VA after 12 months Proportion of patients with ≥ 15-letter increased after 12 months Proportion of patients with a thin (< 120 µm), normal (120–212 µm) and thick (> 212 µm) retina after 12 months Change in TFT after 12 months N of inj. after 12 months | CFH: rs1061170 ARMS2: rs10490924 HTRA1: rs11200638 C3: rs2230199 | No associations found |
Abedi et al. [155] | 201 | Caucasian | P | BVZ/RNZ | 3 monthly inj. + PRN for 12 months | Change in VA after 3, 6, 12 months Responder vs. non-responder or stable for VEGFA rs3025000 at 12 months | VEGFA: rs3024994, rs3025000, rs3025042, rs3025047, rs3025035, rs3025030, rs3025010 | VEGFA rs3025000 T → better response |
Lotery et al. [72] | 509 | IVAN, NI | P | BVZ/RNZ | 3 monthly inj. + PRN/monthly | Change in TRT after 12 months or the preceding measurement nearest to this time point; responders ≥ 75th percentile; non-responders ≤ 25th percentile | CFH: rs1061170 FZD4: rs10898563 ARMS2: rs10490924 482 additional SNPs in candidate genes | No associations found (after correction for multiple testing) |
Hautamäki et al. [73] | 96 | NI (Finland) | R (59), from a P study (37) | BVZ | 3 inj. within 5 months | Responder, partial responder or non-responder based on neuroepithelial detachment, cystic changes and area of cysts | IL8: rs4073 CFH: rs1061170 ARMS2: rs10490924 C3: rs2230199 VEGFA: rs699947, rs2146323, rs3025033 EPO: rs1617640 | IL8 rs4073 A → worse response |
Habibi et al. [74] | 70 | Tunisian | P | BVZ | 6-weekly inj. until non-active CNV | Improvement in VA: 2-line gain after 6 months; stable vision: VA within 2 lines of baseline; decrease: reduction in VA of 2 lines or more | CFH: rs1061170 | No association found |
Zhao et al. [156] | 223 eyes, individuals NI | Caucasian | P | BVZ/RNZ | 4 monthly inj. + PRN | Responders: ≥ 5 letters and resolution of intraretinal or subretinal fluid after 12 months; non-responders: rest of the patients | VEGFA: rs943080 | VEGFA rs943080 T → worse response |
Yuan et al. [75] | 168 | Han Chinese | P | RNZ | 3 monthly inj. + PRN | Change in VA after 6 months Change in CRT after 6 months Change in maximum lesion thickness after 6 months | CFH: rs1061170 HTRA1: rs11200638 VEGFA: rs1413711 | HTRA rs11200638 A → worse response |
Hagstrom et al. [157] | 831 | CATT (98% Caucasian), NI | P | BVZ/RNZ | PRN/monthly | Change in TRT after the latest time point for which data were available through 1 year; responders: ≥ 75th percentile; non-responders: ≤ 25th percentile | EPAS1: rs6726454, rs7589621, rs9679290, rs12712973 | No associations found |
Hermann et al. [158] | 366 | NI (the Netherlands, Germany, Canada) | NI | RNZ | 3 monthly inj. + PRN | Change in VA after 3, 12 months | 126 SNPs in VEGFA, VEGFB, VEGFC, VEGFD, PGF, VEGR1, VEGFR2, VEGFR3, PEDF | KDR rs4576072 C → better response KDR rs4576072 (C) and rs6828477 (C) 3 alleles → better response |
Hagstrom et al. [159] | 835 | CATT (98% Caucasian), NI | P | BVZ/RNZ | 3 monthly inj. + PRN/monthly | VA after 12 months Change in VA after 12 months TRT after 12 months Change in TFT after 12 months Presence of fluid on OCT Presence of leakage on FA after 12 months Change in lesion size after 12 months N of inj. after 12 months | VEGFA: rs699947, rs699946, rs833069, rs833070, rs1413711, rs2010963, rs2146323 KDR: rs2071559 N of risk alleles | No associations found |
Cruz-Gonzalez et al. [160] | 94 | Caucasian | P | RNZ | 3 monthly inj. + SUSTAIN criteria | Subjective improvement: patients measure their improvement after each inj. on a scale from 1 to 10, Subjective improvement ≥ 6 VA improvement: gain ≥ 5 letters OCT improvement: improvement > 100 μmin in central subfield retinal thickness | VEGFA: rs699947, rs833061 KDR: rs2071559 | VEGFA rs8330611 CC → better response VEGFA rs699947 AA → better response |
Matsumiya et al. [84] | 120 | Japanese | R | RNZ | 3 monthly inj. | Anatomical resolution of the lesions after 3 months Dry lesion in OCT/no exudative lesion Change in VA after 3 months Change in CRT after 3 months | CFH: rs1061170, rs800292 HTRA1: rs10490924 CFH: rs1061170 + rs800292 | CFH rs1061170 TT + rs800292 GG → worse response |
Park et al. [78] | 273 | Korean | P | RNZ | 5 monthly inj. | Good response after month 5: visual improvement of ≥ 8 letters | 23 SNPs in 12 AMD genes | No associations found (after correction for multiple testing) |
Veloso et al. [161] | 92 | Brazilian | P | RNZ | 3 monthly inj. + PRN | Change in VA after 1, 3, 6 and 12 months Change in CRT after 1, 3, 6 and 12 months | VEGFA: rs1413711 | VEGFA rs1413711 CC → worse response |
Hautamäki et al. [59] | 50 | Caucasian | P | BVZ | PRN | Change in CS after 24 months Presence of intra/subretinal fluid in OCT after 24 months N of inj. after 24 months | IL8: rs4073 VEGFA: rs699947, rs2146323, rs3025033 CFH: rs1061170 ARMS2: rs10490924 C3: rs2230199 IL8 rs4073 + VEGF rs699947 + CFH rs1061170 | VEGFA rs699947 AA → worse response ARMS2: rs10490924 TT → worse response IL8: rs4073 AA → worse response CFH rs1061170 CC → worse response IL8 rs4073 A + VEGF rs699947 A + CFH rs1061170 C 3–6 risk alleles → worse response |
Piermarocchi et al. [60] | 94 | Caucasian | P | RNZ | 3 monthly inj. + PRN | Change in VA after 12 months | CFH: rs1061170 ARMS2: rs10490924 C3: rs2230199 | CFH rs1061170 C → worse response |
Medina et al. [61] | 25 | Brazilian | P | BVZ | 1 inj. | Improvement in VA and CRT is evaluated separately per genotype. Results are compared | CFH: rs1061170 | CFH rs1061170 CC → worse response |
Hagstrom et al. [162] | 1347 | CATT and IVAN, NI | P | BVZ/RNZ | PRN/monthly | Change in VA after 12 months | KDR: rs4576072, rs6828477 N of risk alleles in KDR rs4576072 + rs6828477 | No associations found |
Kuroda et al. [85] | 343 eyes, 326 individuals | Japanese | R | RNZ | 3 monthly inj. + PRN | Recurrence after 12 months Change in VA after 12 months | CFH: rs1410996 ARMS2: rs10490923 | No associations found |
Lorés-Motta et al. [91] | 377 | NI (the Netherlands, Germany, Canada) | R | RNZ | 3 monthly inj. + PRN/TE | Change in VA after 3, 6 and 12 months | NRP1: rs2070296 N of risk alleles in KDR rs4576072 + NRP1 rs2070296 | NRP1 rs2070296 GA and AA → worse response 3, 4, 5 risk alleles in KDR rs4576072 + NRP1 rs2070296 → worse response |
Bakbak et al. [93] | 109 | Turkish | P | RNZ | 3 monthly inj. + PRN | After 6 months, loss > 5 letters, loss or gain of VA between 5 letters or gain > 5 letters | APOE: ε2, ε3 and ε4 | APOE ε4 allele → better response |
Lazzeri et al. [94] | 64 | NI (Italy) | P | RNZ | 3 monthly inj. + PRN | VA after 3, 12 months Retinal sensitivity after 3, 12 months TFT after 3, 12 months N of inj. in the follow-up phase | KDR: rs2071559 IL8: rs4073 | IL8 rs4073 AA → worse response KDR rs20715559 CC → better response |
Cruz-Gonzalez et al. [86] | 100 | Caucasian | P | RNZ | 3 monthly inj. + PRN | VA improvement: gain ≥ 5 letters OCT improvement: gain > 100 µm in CSRT | CFH: rs1410996 ARMS2: rs10490923 HTRA1: rs11200638 | No associations found |
Riaz et al. [96] | 661 (discovery: 285, replication: 376) | NI (Australia, the Netherlands, Germany, Canada) | R | RNZ | 3 monthly inj. + PRN/TE | Change in VA in after 3, 6 months; non-responder: lose ≥ 5 letters; responder: rest | GWAS: Illumina 4.3 M SNP array: > 1,000,000 SNPs | OR52B4 rs4910623 G → worse response |
Habibi et al. [76] | 90 | Tunisian | R | BVZ | 3 monthly inj. + PRN | After 12 months, good responder: reduction of < 2 lines; poor responder: reduction of ≥ 2 lines | CFH: rs1061170 C3: rs2230199 VEGFA: rs2010963, rs3025039, rs699947 N of risk alleles in CFH, C3 and VEGFA VEGFA haplotypes | VEGFA haplotype rs2010963 G, rs3025039 T, rs699947 A → worse response |
Chaudhary et al. [87] | 70 | Caucasian (68), Asian (2) | P | RNZ | 3 monthly inj. + PRN | Moderate vision gain: gain of ≥ 15 letters after 6 months Change in CMT after 6 months Change in VA after 6 months | CFH: rs1048663, rs3766405, rs412852, rs11582939, rs1066420 C3: rs2230199 ARMS2: rs10490924 mtDNA: A2917G CFH haplotypes | CFH haplotype that reduces risk to AMD leads to better response |
Kepez Yildiz et al. [99] | 109 | Turkish | R | NI | 3 monthly inj. | Good responder group and non-responder group based on VA and OCT parameters after 3 months | CFH: rs1061170 VEGFA: rs2146323, rs699947 | No associations found |
Shah et al. [62] | 72 | NI (USA) | R | BVZ/RNZ | PRN | Change in VA after 6, 12 months Change in central foveal thickness after 6, 12 months | 20 SNPs in AMD genes N of risk alleles in CFH rs1061170 and rs1410996 Number of risk alleles for CFI rs10033900 and CFI rare variants | CFH rs1061170 TT → better response 0–2 risk alleles in CFH rs1061170 and rs1410996 → better response |
Bardak et al. [163] | 39 | NI (Turkey) | R | RNZ | 3 monthly inj. | Responders: absence of intraretinal or subretinal fluid; non-responder: presence. Comparisons for each genotype | ARMS2: rs10490923 | ARMS2 rs10490924 TT shows differences in response |
Valverde-Megías et al. [77] | 103 | Caucasian | P | RNZ | 3 monthly inj. + PRN | N of inj. after 4 years | CFH: rs1061170 ARMS2: rs10490924 | ARMS2 rs10490924 TT → worse response |
Yamashiro et al. [83] | 461 (discovery: 256, replication: 205) | NI (Japan) | P | RNZ | 3 monthly inj. + PRN | Dry macula after treatment Requirement for an additional treatment VA changes after 12 months | GWAS: Illumina HumanOmni2.5–8 BeadChip Kit. Imputation followed: > 8,400,000 SNPs | No genome-wide level significant associations No associations with P < 5 × 10−6 replicated 9 candidate SNPs: ARMS2: rs10490924 G → better response |
Medina et al. [63] | 46 | Brazilian | R | BVZ/RNZ | PRN | Baseline and 12 months VA and CRT compared for each genotype separately | CFH: rs1061170 | CFH rs1061170 C → worse response |
3 Therapies in Clinical Trials
3.1 Complement-Inhibiting Therapies
Gene | SNP | Study | Allele/genotype tested | Complement activation measurement(s) | Direction of the effect | P value |
---|---|---|---|---|---|---|
CFH
| rs12144939 | Ristau et al. [120] | T | C3d/C3 | − | 4.6 × 10−6 |
rs1410996 | Ristau et al. [120] | T | C3d/C3 | − | 10−4 | |
Reynolds et al. [109] | TT, CT and TT | Bb, C3a, C5a, FH | NA | |||
rs800292 | Hecker et al. [111] | G | Ba | + | 7.1 × 10−6 | |
Hecker et al. [111] | G | C3d | + | 0.0013 | ||
Ristau et al. [120] | A | C3d/C3 | − | 0.003 | ||
Paun et al. [121] | A | C3d/C3 | − | 0.002 | ||
Hecker et al. [111] | G | FB, FD, FH/FHR-1 | NA | |||
CHFR4
| rs6685931 | Lores-Motta et al. [122] | C | C3d/C3 | + | 6.32 × 10−8 |
CFB
| rs4151667 | Hecker et al. [111] | T | Ba | + | 3.9 × 10−6 |
Ristau et al. [120] | A | C3d/C3 | − | 1.0 × 10−5 | ||
Paun et al. [121] | A | C3d/C3 | − | 4.1 × 10−6 | ||
Hecker et al. [111] | T | FB, FD, FH/FHR-1, C5a, C3d | NA | |||
Smailhodzic et al. [113] | TA | FB | − | <0.001 | ||
rs641153 | Paun et al. [121] | A | C3d/C3 | − | 0.048 | |
Reynolds et al. [109] | CT/TT | Bb, C3a, C5a, FH | NA | |||
C2
| rs9332739 | Hecker et al. [111] | G | Ba | + | 2 × 10−6 |
Hecker et al. [111] | G | FB, FD, FH/FHR-1, C5a, C3d | NA | |||
Reynolds et al. [109] | CG/CC | Bb, C3a, C5a, FH | NA | |||
C3
| rs6795735 | Ristau et al. [120] | A | C3d/C3 | + | 0.04 |
rs2230199 | Reynolds et al. [109] | CG/GG | C5a | + | 0.04 | |
Ristau et al. [120] | G | C3d/C3 | + | 0.04 | ||
Paun et al. [121] | G | C3d/C3 | + | 0.035 | ||
Hecker et al. [111] | C | C3d | + | 0.039 | ||
Hecker et al. [111] | C | FB, FD, FH/FHR-1, C5a, Ba | NA | |||
Reynolds et al. [109] | CG/GG | Bb, C3a, FH | NA | |||
ARMS2
| rs10490924 | Reynolds et al. [109] | GT/TT | C5a | + | 0.02 |
Reynolds et al. [109] | GT/TT | Bb, C3a, FH | NA | |||
Hecker et al. [111] | NS | FB, FD, FH/FHR-1, C5a, Ba, C3d | NA |
3.2 Gene- and Cell-Based Therapies
3.2.1 Gene Therapy
Drug | Gene expressed | Target | Clinical phase | Results | References | Clinicaltrials.gov identifier | Funding (clinicaltrials.gov) |
---|---|---|---|---|---|---|---|
Gene therapy | |||||||
AdGVPEDF.11D | PEDF | NV AMD | Phase I | Completed: No serious adverse events and no dose-limiting toxicities; transient intraocular inflammation occurred in 25% of patients | Campochiaro et al. [132] | NCT00109499 | GenVec |
AAV2-sFLT01 | sFLT101 (domain 2 of Flt-1 linked to human IgG1-Fc) | NV AMD | Phase I | Completed: safe and well-tolerated at all doses; potential effect of baseline anti-AAV2 serum antibodies and transgene expression | Heier et al. [134] | NCT01024998 | Genzyme, a Sanofi Company |
OXB-201 (RetinoStat) | Angiostatin and endostatin | NV AMD | Phase I | Completed: well-tolerated with no dose-limiting toxicities; reduction in leakage for 71% of participants; reduction in fluid in 1 patient | Campochiaro et al. [138] | NCT01301443 | Oxford BioMedica |
Phase I | Ongoing (long-term safety—15 years) | NCT01678872 | Oxford BioMedica | ||||
RGX-314 | sAnti-VEGF protein | NV AMD | Phase I | Ongoing | NCT03066258 | Regenxbio Inc. | |
AAVCAGsCD59 or HMR59 | CD59 | GA AMD | Phase I | Ongoing | NCT03144999 | Hemera Biosciences | |
rAAV.sFLT-1 | sFLT1 | NV AMD | Phase I | Completed: safe and well-tolerated after 36 months | NCT01494805 | Lions Eye Institute, Perth, Western Australia | |
Phase II | Phase IIa completed: smaller improvement than ranibizumab alone | Constable et al. [135] | NCT01494805 | Lions Eye Institute, Perth, Western Australia |
Type of therapy | Target | Clinical phase | Results | Reference | Clinicaltrials.gov identifier/UMIN_CTR identifier | Funding (clinicaltrials.gov) |
---|---|---|---|---|---|---|
Stem cell therapy | ||||||
Autologous BMSCs | GA AMD | Phase I/II | Unknown (estimated completion date 2015) | NCT02016508 | Al-Azhar University | |
Autologous BMSCs | NV and GA AMD | Phase I/II | Completed | NCT01518127 | University of Sao Paulo | |
hCNSSC | GA AMD | Phase I/II | Completed: long-term safety assessment terminated | NCT01632527 | StemCells, Inc. | |
hESC-RPE | GA AMD | Phase I/II | Completed: safe and possible activity of the cells | NCT01344993 | Astellas Institute of Regenerative Medicine | |
Human umbilical tissue-derived cells (Palucorcel, CNTO-2476) | GA AMD | Phase I/IIa | Completed: subretinal delivery associated with perforations and detachment; well-tolerated; may lead to VA improvements | Ho et al. [166] | NCT01226628 | Janssen Research & Development, LLC |
Autologous BMSCs | GA AMD | Phase I | Completed: well-tolerated | Park et al. [78] | NCT01736059 | University of California, Davis |
hESC-RPE (OpRegen) | GA AMD | Phase I/II | Ongoing | NCT02286089 | Cell Cure Neurosciences Ltd. | |
Somatic cell nuclear transfer hESC-RPE | GA AMD | Phase I | Ongoing | NCT03305029 | CHA University | |
hESC-RPE | GA AMD | Early phase I | Ongoing | NCT03046407 | Chinese Academy of Sciences | |
hESC-RPE | GA AMD | Early phase I | Ongoing | NCT02755428 | Chinese Academy of Sciences | |
hESC-RPE in suspension and seeded on a substrate | NV and GA AMD | Phase I/II | Ongoing | NCT02903576 | Federal University of Sao Paulo | |
Autologous BMSCs | AMD | Not specified | Ongoing | NCT03011541 | MD Stem Cells | |
Autologous iPSC-RPE | GA AMD | Production of the cells | Ongoing | NCT02464956 | Moorfields Eye Hospital NHS Foundation Trust | |
hESC-RPE (Pf-05206388) | NV AMD | Phase I | Ongoing (long-term safety, 4-year follow-up) | NCT03102138 | Pfizer | |
hESC-RPE on a parylene membrane (CPCB-RPE) | GA AMD | Phase I/II | Ongoing | NCT02590692 | Regenerative Patch Technologies, LLC | |
Autologous BMSCs | AMD | Not specified | Ongoing | NCT01920867 | Retina Associates of South Florida | |
hESC-RPE | AMD | Phase I | Ongoing | NCT02749734 | Southwest Hospital, China | |
hESC-RPE | GA AMD | Phase I/II | Ongoing (long-term safety and tolerability) | NCT02463344 | Astellas Institute for Regenerative Medicine | |
Somatic cell nuclear transfer hESC-RPE | GA AMD | Phase I/IIa | Ongoing (preliminary results: safe and tolerated; 2 patients included; 1 patient gained VA and the other maintained VA) | Song et al. [142] | NCT01674829 | CHA Biotech CO., Ltd |
hESC-RPE (ASP7317) | GA AMD | Phase Ib/II | Not open yet | NCT03178149 | Astellas Institute for Regenerative Medicine | |
hESC-RPE | GA AMD | Phase I/II | Not open yet (evaluation of long-term safety) | NCT03167203 | Astellas Institute for Regenerative Medicine | |
Autologous fibroblast iPSC-RPE sheet | NV AMD | Phase I/II | Completed: patient 1 after 1 year the cell sheet appears to be safe and remains intact, VA maintained. Patient 2 did not receive therapy due to concerns about genetic changes in the iPSCs and iPSC-derived RPE | Mandai et al. [143] | UMIN000011929 | RIKEN |
Allogenic HLA-matched iPSC-RPE | NV AMD | Phase I | Ongoing | Unknown | RIKEN |