One year after gene therapy, the three young adults with RPE65
-LCA (P1, age 25; P2, age 24; and P3, age 22) (Cideciyan et al.
; Hauswirth et al.
) remained healthy and without vector-related serious adverse events. Humoral immune response was monitored by measuring levels of circulating antibody to AAV serotype 2 capsid. Antibody titers at the 12-month time point (P1, 4860; P2, 12,583; P3, 59,141
mU/ml) were well below the population mean titer (1,042,089
mU/ml) and within the range of measurements obtained in each patient between baseline and 3 months posttreatment (). The AAV2 capsid antigen-specific lymphocyte proliferation response at 12 months showed no significant rise in stimulation index (). Physical examinations remained normal and there were no clinically significant abnormalities in routine blood and urine tests in all subjects through 12 months.
FIG. 1. Immunological assays before surgery (baseline) and at 14-, 90-, and 365-day time points after retinal gene therapy. (A) Humoral immune response to AAV serotype 2 (AAV2) assayed by circulating serum antibody titers against AAV2 capsid in P1, P2, and P3 (more ...)
Clinical ocular examinations of study and control eyes were unchanged from 3 months. Visual acuities, central retinal structure by optical coherence tomography (), and standard kinetic visual fields at the 6-, 9-, and 12-month time points were not different from those measured at the 3-month time point.
FIG. 2. Central vision and retinal structure in RPE65-LCA during the 12 months after gene therapy. (A) Visual acuity as a function of time before and after the day of surgery (0) in the study eyes of P1, P2, and P3. Gray symbols, data previously reported (Hauswirth (more ...)
Statistically significant increases in light sensitivity were previously found in study eyes 1–3 months after treatment (Cideciyan et al.
). Between 3 and 12 months, there were no further changes in the magnitude or retinal extent of the visual sensitivity increase (). Chromatic stimuli and light adaptation conditions were used to determine the rod and cone photoreceptor contributions to the visual sensitivity. For P1, visual sensitivity in the treated retinal region was mediated by rods. For P2 and P3, there were both rod and cone contributions depending on the testing conditions. Remarkable improvements of rod- and cone-based vision measured within the first 3 months after treatment were unchanged between 3 months and 1 year (). The unexpected finding of slowed retinoid cycle kinetics (Cideciyan et al.
) in treated retina also remained. There were increases in rod photoreceptor sensitivity with extended dark adaptation at 1 year and these increases were comparable to those documented within the first few months after treatment ().
FIG. 3. Visual function improvement due to gene therapy is stable up to 12 months after treatment. (A) Light sensitivity to achromatic stimuli in study eyes along vertical (P1 and P2) and horizontal (P3) meridians after allowing for an extended (3–8hr) (more ...)
Would maintained visual improvement have been expected 1 year after this gene therapy? Treated murine Rpe65 models have not been monitored for relatively long time periods, but durability of the human visual gains is consistent with electrophysiological data in long-term studies of treated RPE65
-mutant dogs (Acland et al.
; Aguirre et al.
). A major difference between human and canine RPE65 disease, however, is the significant retinal cell death in humans at all ages (Jacobson et al.
). Treated retinal areas in RPE65
-LCA are not normal with a full complement of retinal cells and it is uncertain what the rate of further cell loss will be in this already degenerate, albeit better functioning, tissue. Spreading negative influences from nearby untreated degenerate retina by non–cell-autonomous mechanisms may also be a potential threat to longevity of the restored visual islands (Cronin et al.
Further reports of early and later visual consequences of ocular gene therapy in this human congenital retinal blindness will undoubtedly emerge. There will be variation in the magnitude of efficacious effect as was evident in the earliest reports (Bainbridge et al.
; Cideciyan et al.
; Hauswirth et al.
; Maguire et al.
). The considerable interindividual differences in severity of photoreceptor loss in the first three decades of life in RPE65
-LCA patients (Jacobson et al.
), taken together with details of injection site, vector dose and volume, and genotype should permit estimates of the basis of the variation in response and lead to refined treatment strategies in subsequent cohorts of patients in these early-phase trials.