Gene Therapy Shows Promise for Blindness Reversal

By Charles Bankhead
PHILADELPHIA, 29 April 2008 -- Gene therapy for blindness caused by Leber's congenital amaurosis led to improved vision for four of the first six patients treated, including all three at a hospital here.
None of the patients had restoration of normal vision, but the results provide impetus for continued evaluation of gene therapy for the inherited blinding disease, Joan E. Bennett, M.D., Ph.D., of the University of Pennsylvania, and colleagues reported online in the New England Journal of Medicine.
Noting that the three patients were young adults, the authors speculated that earlier treatment might lead to greater vision improvement.
"It is possible that efficacy will be improved if treatment is applied before amblyopia and retinal degeneration are established . . . ," the authors concluded. "Our study provides the foundation for gene-therapy approaches to the treatment of [Leber's congenital amaurosis] and possibly other forms of retinal degeneration."
In the same issue of the NEJM, British investigators reported significant vision improvement in one of three patients with Leber's treated with gene therapy.
The published reports coincided with a presentation at the Association for Research in Vision and Ophthalmology meeting in Fort Lauderdale, Fla.
Leber's congenital amaurosis comprises a group of recessively inherited severe rod-cone dystrophies that have an onset in infancy. Mutation of the RPE65 gene causes a form of the disease that involves impaired vision at birth, progressing to blindness by the third decade of life in most cases, Dr. Bennett and coauthors noted.
RPE65 is expressed in the retinal pigment epithelium and encodes a protein that is integral to the visual cycle, a biochemical pathway that regenerates visual pigment after exposure to light. The encoded enzyme catalyzes the conversion of all-trans-retinyl esters to 11-cis-retinal. The latter is the precursor of rhodopsin, which is required for phototransduction and vision. Lack of a functional RPE65 renders rod photoreceptor cells unable to respond to light. Mutations in RPE65 account for approximately of cases.
The presence of visual function in childhood and evidence that photoreceptor-cell death occurs late in the disease process suggest that Leber's might be amenable to gene therapy. Dr. Bennett and colleagues previously reported use of gene-replacement therapy to restore vision in an animal model of Leber's.
In the current study, investigators administered subretinal injections of a recombinant adeno-associated viral vector carrying RPE65 complementary DNA to three patients ages 19 to 26. All three patients had modest improvement in measures of retinal function and on subjective tests of visual acuity.
"Patients' vision improved from detecting hand movements to reading lines on an eye chart," said co-author Albert M. Maguire, M.D., also of the University of Pennsylvania.
However, the patients have been followed for only five months, the authors noted.
In one patient, an asymptomatic macular hole developed, which was considered an adverse event. However, the patient subsequently regained some retinal function.
The British study involved three patients ages 17 to 23 with early-onset, severe retinal dystrophy caused by mutations in RPE65. All had visual acuity worse than 20/120 on the Snellen visual acuity scale, reported Robin R. Ali, Ph.D., of University College London, and colleagues.
None of the patients had clinically significant improvement in visual acuity or in peripheral visual fields or change in retinal responses. During follow-up for as long as 12 months, one patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry, as well as improvement in a subjective test of visual mobility.
"Our findings provide support for the development of further clinical studies in children with RPE65 deficiency," Dr. Ali and colleagues concluded. "These children are more likely to benefit than adults."
In an accompanying editorial, Joan W. Miller, M.D., of Harvard, offered a cautious assessment of the two studies. Noting the brief follow-up in both studies, she said the data "suggest that in the short term, the procedure is safe. Moreover, the data are suggestive of efficacy."
The reproducibility and persistence of improved retinal function remain to be demonstrated, as does the therapy's ability to delay or prevent retinal degeneration. Additionally, systemic or ocular complications could arise with treatment of more patients, use of higher doses, or longer follow-up.
Given those limitations, Dr. Miller agreed with the authors of the two studies that "treatment of younger patients with less advanced retinal degeneration might allow greater improvement of visual function."
Drs. Bennett and Maguire identified themselves as co-inventors of a technique for preventing blindness which has one or more patents pending (but with no financial interest). Several co-authors acknowledged commercial relationships relevant to the study. Dr. Ali and several co-authors reported interests in patent and intellectual property rights related to the study, and one co-author is an employee of Targeted Genetics and has received consulting fees from Sangamo Biosciences. Dr. Miller acknowledged consulting fees and grant support from Genzyme, which has a gene-therapy program.

Primary source: The New England Journal of MedicineSource reference:Maguire AM, et al "Safety and efficacy of gene transfer for Leber's congenital amaurosis" N Engl J Med 2008; 358: DOI: 10.1056/NEJMoa0802315. Additional source: The New England Journal of MedicineSource reference: Bainbridge JWB, et al "Effect of gene therapy on visual function in Leber's congenital amaurosis" N Engl J Med 2008; 358: DOI: 10.1056/NEJMoa0802268. Additional source: The New England Journal of MedicineSource reference: Miller JW "Preliminary results of gene therapy for retinal degeneration"N Engl J Med 2008; 358: DOI: 10.1056/NEJMe0803081.