PMID- 30878487 OWN - NLM STAT- MEDLINE DCOM- 20200305 LR - 20200305 IS - 1879-1891 (Electronic) IS - 0002-9394 (Linking) VI - 204 DP - 2019 Aug TI - Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. PG - 113-123 LID - S0002-9394(19)30104-7 [pii] LID - 10.1016/j.ajo.2019.03.006 [doi] AB - PURPOSE: To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. DESIGN: Phase 1/2a clinical trial. METHODS: Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X10(11)vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti-vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring <2, and HD-2 (n = 10), requiring >2 retreatments. RESULTS: Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44% of HD-2 patients, and 51% of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34%) maintained significant visual improvement at 3 years. None of these observations were statistically significant. CONCLUSIONS: Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly. CI - Copyright (c) 2019. Published by Elsevier Inc. FAU - Rakoczy, Elizabeth P AU - Rakoczy EP AD - Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia. Electronic address: elizabeth.rakoczy@uwa.edu.au. FAU - Magno, Aaron L AU - Magno AL AD - Lions Eye Institute, Nedlands, Western Australia, Australia. FAU - Lai, Chooi-May AU - Lai CM AD - Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia. FAU - Pierce, Cora M AU - Pierce CM AD - Lions Eye Institute, Nedlands, Western Australia, Australia. FAU - Degli-Esposti, Mariapia A AU - Degli-Esposti MA AD - Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia. FAU - Blumenkranz, Mark S AU - Blumenkranz MS AD - Byers Eye Institute at Stanford, Palo Alto, CA, USA. FAU - Constable, Ian J AU - Constable IJ AD - Lions Eye Institute, Nedlands, Western Australia, Australia; Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190313 PL - United States TA - Am J Ophthalmol JT - American journal of ophthalmology JID - 0370500 RN - EC 2.7.10.1 (FLT1 protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1) SB - IM MH - Aged MH - Aged, 80 and over MH - Female MH - Follow-Up Studies MH - Genetic Therapy/methods MH - Genetic Vectors/*administration & dosage MH - Humans MH - Intravitreal Injections MH - Macula Lutea/*pathology MH - Male MH - Middle Aged MH - Retrospective Studies MH - Time Factors MH - Tomography, Optical Coherence MH - Treatment Outcome MH - Vascular Endothelial Growth Factor Receptor-1/*genetics MH - *Visual Acuity MH - Wet Macular Degeneration/diagnosis/*therapy EDAT- 2019/03/18 06:00 MHDA- 2020/03/07 06:00 CRDT- 2019/03/18 06:00 PHST- 2018/06/21 00:00 [received] PHST- 2019/02/26 00:00 [revised] PHST- 2019/03/06 00:00 [accepted] PHST- 2019/03/18 06:00 [pubmed] PHST- 2020/03/07 06:00 [medline] PHST- 2019/03/18 06:00 [entrez] AID - S0002-9394(19)30104-7 [pii] AID - 10.1016/j.ajo.2019.03.006 [doi] PST - ppublish SO - Am J Ophthalmol. 2019 Aug;204:113-123. doi: 10.1016/j.ajo.2019.03.006. Epub 2019 Mar 13.