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Gene therapy yields ‘modest’ impact on retinal sensitivity in Leber’s congenital amaurosis
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Gene therapy resulted in a modest and temporary improvement in retinal sensitivity among patients with Leber’s congenital amaurosis, according to a study.
In a phase 1/2 open-label trial, 12 patients with early-onset, severe retinal dystrophy caused by mutations in RPE65 underwent gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector, rAAV2/2.hRPE65p.hRPE65, carrying RPE65 complementary DNA.
Four patients received a lower dose (1 × 1011 vector genomes) and eight patients received a higher dose (1 × 1012 vector genomes).
Eyes with worse visual acuity were studied; a control group comprised untreated contralateral eyes. Patient age ranged from 6 to 23 years.
Visual function, contrast sensitivity, color vision and spectral sensitivities were evaluated at baseline and over a 3-year period.
Microperimetry, Goldmann kinetic perimetry and dark-adapted automated static perimetry were used to evaluate visual fields. Investigators also assessed vision-guided ambulatory navigation and performed color fundus photography, autofluorescence imaging, optical coherence tomography and electroretinography.
The primary safety outcome was the incidence of a grade 3 adverse event at 3 years, defined as a 15-letter loss in ETDRS visual acuity or severe refractory intraocular inflammation.
No intraoperative adverse events were reported.
Six patients had improved retinal sensitivity on dark-adapted perimetry; five of those patients showed improvement on microperimetry.
Improvements in retinal sensitivity peaked at 6 to 12 months after treatment, then declined.
Significant improvements in spectral sensitivity were seen in two patients; the improvements peaked at 12 months after treatment and declined thereafter.
Visual acuity decreased by more than 15 letters in two patients.
Intraocular inflammation or immune responses occurred in five of eight patients who received the higher dose and in none of the four patients who received the lower dose.
“In trials involving humans to date, although RPE65 gene supplementation can improve retinal function and there is some evidence of a dose response, neither the magnitude of improvement nor its durability has matched that observed in animal models,” the authors wrote.
The authors further stated, “In humans, the improvements in retinal sensitivity were modest even in participants with relatively mild retinal degeneration and failed to protect against ongoing degeneration. We conclude that gene therapy with an rAAV2/2 vector carrying the RPE65 cDNA led to temporary, variable, and incomplete restoration of retinal function in humans, which partly reflects a persistent unmet demand for RPE65.” - by Matt Hasson
Disclosure: See the study for a full list of all authors’ relevant financial disclosures.
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