title: Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial.
abstract: OBJECTIVE
  To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 months.
  
  
  METHODS
  Phase 1 dose escalation trial.
  
  
  METHODS
  Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-corrected visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 1010vector genomes) and 3 high-dose (1 × 1011vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months 18 and 36. All subjects received intravitreal ranibizumab at baseline and at week 4, and retreatment injections at subsequent visits based on prespecified criteria for active wet AMD. The primary endpoint was ocular and systemic safety, but exploratory data including BCVA, retinal center point thickness, and the number of ranibizumab retreatments at and between study visits were also analyzed.
  
  
  RESULTS
  Six of the 8 subjects completed the 36-month study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were observed during the long-term follow-up period. Exploratory data analysis suggests stability of wet AMD over the 36-month period.
  
  
  CONCLUSIONS
  Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favourable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.
authors.affiliation: Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia; Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Constable
authors.affiliation: Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Chooi-May
authors.initials: CM
authors.lastname: Lai
authors.affiliation: Lions Eye Institute, Nedlands, Western Australia, Australia.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Magno
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia; Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia.
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.affiliation: Adverum Biotechnologies, Inc, Menlo Park, California.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Barone
authors.affiliation: Jules Stein Eye Institute, UCLA, Los Angeles, California.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.affiliation: Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Blumenkranz
authors.affiliation: Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia. Electronic address: Elizabeth.rakoczy@uwa.edu.au.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Rakoczy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020256:Choroidal Neovascularization / Q000150:complications / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007267:Injections; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000008:administration & dosage*; D008297:Male; D017472:Receptors, Interleukin-1; D012160:Retina; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy; D057135:Wet Macular Degeneration / Q000503:physiopathology / Q000628:therapy*
chemical_list: C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D017472:Receptors, Interleukin-1