Gene therapy can improve the eyesight of people, especially children, who have extremely poor vision or are virtually blind due to a genetically-inherited sight disorder. Furthermore, the improvement remained stable during two-years of follow-up. The findings of this phase 1 trial are reported in an Article Online First and in an upcoming edition of the Lancet, written by 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 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).
One of the most severe forms of inherited retinal degeneration is Leber congenital amaurosis (LCA), which is a group of diseases that are caused by mutations in any one of at least 13 genes. Patients with LCA have severe loss of vision and abnormal eye movements in early infancy and during early childhood. There is no treatment for LCA and severe visual impairment during childhood usually progresses to total blindness by the third or fourth decade of life. The form of LCA in this study is rare, with around 5 babies born in the USA each year with the condition. This disease was selected for study because proof-of-concept of gene therapy had been established in animal models, the gene had been cloned, the cellular degeneration in this disease is fairly slow thereby providing a reasonably large window of time in which to intervene, and success in this disease could pave 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. In this study, the authors assessed the effect of gene therapy on retinal and visual function in children and adults with LCA. The study looked at 12 patients aged 8—44 years, each of whom had genetic material essential for correction of LCA injected into the eye which had the worst vision. The genetic material was carried by a virus (adeno-associated virus [AAV]) which delivered the genetic material to the diseased cells in the eye. Put another way, the AAV 'piggy-backed' the DNA into the cell.
The treatment was well tolerated by all the patients and resulted in an improvement in both subjective and objective measurements of vision. Patients had an increase of least 100-fold in pupillary light response (constriction of the pupil when it is exposed to light) and an 8-year-old child developed nearly the same level of light sensitivity as that in normal-sighted individuals, The greatest improvement was noted in children (aged 8, 9, 10, and 11), all of whom gained ambulatory vision (vision which allows them to walk unaided).
The authors say: "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 add: "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 conclude: "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 accompanying Comment, Drs Frans P M Cremers and Rob W J Collin, Radboud University Nijmegen Medical Centre, Netherlands, say: "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."
For interviews with Professor Jean Bennett and other researchers, please contact:
Karen Kreeger, University of Pennsylvania School of Medicine. T) +1 215.459.0544 E) karen.kreeger@uphs.upenn.edu
Joey McCool Ryan, The Children's Hospital of Philadelphia T) +1 267.258.6735 E) mccool@email.chop.edu
Dr Frans P M Cremers, Radboud University Nijmegen Medical Centre, Netherlands. T) +31-24-3614017 / +31-24-3559223 / +31-6-18404164 E) F.Cremers@antrg.umcn.nl
For full Article and Comment, see: http://press.thelancet.com/genetherapy.pdf
For links to video footage of a child patient negotiating an obstacle course, before and after gene therapy improved/restored his sight, see:
https://lilkatia.sharefile.com/?cmd=d&id=be10adf8b6e549dc (video 1)
https://lilkatia.sharefile.com/?cmd=d&id=616cd5c91ca648b0 (video 2)
Video notes: Results of mobility course testing in subject CH09 (8yo) 3 months after injection of the left eye. Video 1 shows the subject traversing the obstacle course with his left (injected) eye patched. He has difficulty seeing the course and it takes him a long time to complete the test. Video 2, captured within 10 minutes of Video 1, shows the same subject traversing a reconfigured obstacle course with his contralateral (right, uninjected) eye patched (he is using his injected eye for navigation). He has no difficulty completing the test accurately. Room light for both tests is 10 lux. (Movies have been colour corrected)
Journal
The Lancet