An article published Online First and in a future edition of The Lancet reports that gene therapy can improve the eyesight of people, especially children, who have particularly poor vision or are nearly blind due to a genetically-inherited sight disorder. The reported improvement remained stable during two-years of monitoring. The article is the work of Professor Jean Bennett, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, and colleagues from the Children’s Hospital of Philadelphia, PA, USA. The findings of this phase 1 trial are being presented at the 2009 joint meeting of the American Academy of Ophthalmology and Pan-American Association of Ophthalmology (AAO-PAAO), San Francisco, CA (USA).

Leber congenital amaurosis (LCA) is one of the most severe forms of inherited retinal degeneration, which is a group of diseases that are caused by mutations in any one of at least thirteen genes. In early infancy and during early childhood, patients with LCA have severe loss of vision and abnormal eye movements. There is no treatment for LCA. Severe visual impairment during childhood usually progresses to total blindness by the third or fourth decade of life. In this study the type of LCA is rare. Each year, there are around five babies born in the USA with the condition. This disease was selected for study because proof-of-concept of gene therapy had been recognized in animal models. In addition, the gene had been cloned and the cellular degeneration in this disease is somewhat slow thereby providing a reasonably large window of time in which to intervene. Also, success in treatment of this disease could lead the way for development of gene-based treatments for other more common retinal degenerative diseases.

Gene therapy is the insertion of genes into an individual’s cells and tissues to treat a disease. The authors evaluated in this study the effect of gene therapy on retinal and visual function in children and adults with LCA. The study involved twelve patients aged 8 to 44 years. Every one of them received genetic material essential for correction of LCA by injection. The injection was made in the eye which had the worst vision. The genetic material was carried by the adeno-associated virus (AAV) which delivered the genetic material to the diseased cells in the eye. In other words, the AAV transported the DNA into the cell.

All patients tolerated the treatment. It resulted in an improvement in both subjective and objective measurements of vision. Patients had an increase of least 100-fold in pupillary light response which is the constriction of the pupil when it is exposed to light. An 8-year-old child developed almost the same level of light sensitivity as that in normal-sighted individuals. The best improvement was noted in children aged 8, 9, 10, and 11. They all gained ambulatory vision which allows them to walk without help.

The authors explain: “All 12 patients given gene therapy in one eye showed improvement in retinal function. The effect was stable during follow-up. The results support our hypothesis that the response to subretinal gene therapy depends on the extent of retinal degeneration and, therefore, the age of the patient.”

They note: “The most noteworthy result was the ability of children to navigate an obstacle course independently and accurately, even in dim light…The visual recovery noted in the children confirms the hypothesis that efficacy will be improved if treatment is applied before retinal degeneration has progressed. Assessment of whether the treatment alters the natural progression of the retinal degeneration will be possible in follow-up studies.”

They write in conclusion: “The success of this gene therapy study in children provides the foundation for gene therapy approaches to the treatment of other forms of LCA and of additional early onset retinal diseases.”

In an associated note, Drs Frans P M Cremers and Rob W J Collin, Radboud University Nijmegen Medical Centre, Netherlands, remark: “The study by Bennett and coworkers will further boost gene therapy trials and provide hope for patients with inherited blindness and other genetic disorders. As novel therapeutic strategies are being developed for each of the separate genetic defects, ascertaining and genotyping the corresponding patients will be the real challenge in the coming decade.”

“Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial”
Albert M Maguire, Katherine A High, Alberto Auricchio, J Fraser Wright, Eric A Pierce, Francesco Testa, Federico Mingozzi, Jeannette L Bennicelli, Gui-shuang Ying, Settimio Rossi, Ann Fulton, Kathleen A Marshall, Sandro Banfi, Daniel C Chung, Jessica I W Morgan, Bernd Hauck, Olga Zelenaia, Xiaosong Zhu, Leslie Raffini, Frauke Coppieters, Elfride De Baere, Kenneth S Shindler, Nicholas J Volpe, Enrico M Surace, Carmela Acerra, Arkady Lyubarsky, T Michael Redmond, Edwin Stone, Junwei Sun, Jennifer Wellman McDonnell, Bart P Leroy, Francesca Simonelli, Jean Bennett
DOI: 10.1016/S0140-6736(09)61836-5
The Lancet

Written by Stephanie Brunner (B.A.)