RPE65 Gene Therapy to Cure a Type of Blindness

Leber's congenital amaurosis (LCA) - A rare genetic eye disease (disorder): Characterized by severe visual deficiency, total or nearly total blindness, occurs at birth or within the first few years of life. Children with LCA account 10 - 18 percent of all cases of congenital blindness. When first examined retina may appear normal. Vitreo - retinal specialist or neuro-ophthalmologist use diagnostic electroentinogrphy (ERG) tests, measure visual function, detecting little if any activity in the retina (neural cells that line the back of the eyeball). A low level of retinal activity, measured by ERG, indicates very little visual function, surmises the diagnosis of LCA. Symptoms are characterized or include crossed eyes (strabismus), involuntary or rapid eye movement (nystagmus), clouding of the lenses of the eyes (cataracts), unusual sensitivity to light (photophobia), and / or abnormal protrusion of the front (anterior), and sunken eyeballs. Frequently as a result of LCA, central nervous system complications develop or motor impairments, mental retardation, epileptic seizures, and hearing disorders. The cause of Leber's congenital amaurosis linked to a mutation in specific gene and eleven types genes are currently known. One of these specific genes is a defect in the retinal pigment epithelium 65 (RPE65) gene. Dr. Maguire associate professor, Scheie Eye Institute, University of Pennsylvania and research investigator, Kirby Center for Molecular Ophthalmology, Philadelphia said: "The presence of the defect results in a lack of retinol accumulation in the intact photoreceptors (Back part of the eyeball composed of many cells responsible for detecting light, enabling to see) which cannot receive light and initiate photoransduction."

Genetically Leber's congenital amaurosis inherited both parents, carriers of the defective gene (RPE65). This is referred to as an autosomal recessive pattern of inheritance. If only one parent has the disease gene, child will be a carrier but have no symptoms.

Early diagnosis of Leber's congenital amaurosis, occasionally confused with other retinal eye problems, such as retinitis, pigmentosa, congenital and hereditary optic atrophy, Usher syndrome (hearing and vision problems) and other eye diseases. Advisable wait until symptoms of LCA are confirmed before pursuing treatment.

In May 2007, Targeted Genetics Corporation (public traded company -- symbol TGEN), Seattle USA biotech firm, reported the start of clinical trials (one and two) in the United Kingdom, gene therapy (Over 70 percent to date have been for the treatment of cancer) for the treatment of Leber's congenital amaurosis, by inserting a normal copy of RPE65 gene. Currently no effective treatment is available. Delivery of normal copy RPE65 genes successfully treated blind dogs, proceeding 15 years of laboratory and animal experiments. Dr. Maguire and colleagues from the University of Pennsylvania, University of Florida and Cornell University treated several Briard dogs by subretinal injecting (Injecting fluids or drugs into the subrentinal space by the use of a flexible micro - cannula device) healthy copies of RPE65 gene, diagnosed having LCA.
Dr. Maguire said: "After one injection, we have seen the treatment effect last for more than 13 months in our treated dogs, with no statistically significant diminution in response". The electroetinographic (ERG) test confirmed an increase of thirty percent restored light vision. Also, dogs demonstrated visual behavior in the treated eyes; they avoided obstacles when ambulating and maintained fixation on objects. Furthermore, Dr. Maguire said: "To bring this treatment to human clinical trials, toxicity studies must be carried out." The process by which RPE65 gene is delivered, using a harmless virus or "vector" to carry the gene into the cells. The vector has been manufactured for upcoming human trial by Targeted Genetics.

In February 2007, Surgeons at the Moorfields Eye Hospital in London, performed for the first time (first of eleven planned), injecting donated copies of healthy RPE65 gene into the back of a patient's eye, born with inherited eye disorder, stops his retina detecting light properly. The procedure requires pinpoint accuracy avoid tearing the retina. Following this surgery, begins human Phase One / Two clinical trial (adults and children), new type of gene therapy: Inserting healthy RPE65 genes, conducted by a team from UCL Institute of Ophthalmology and Moorfields Eye Hospital is led by Professor Robin and includes leading eye surgeon Mr. James Bainbridge and leading specialist Professor Tony Moore. Britain's Department of Health gave two million dollars to fund the clinical trial. Professor Moore said: "Some indications of the results of the trial may be available within several months. However, the subjects will need to be followed-up to assess the long term effect of the treatment. It will be many months before we have the full picture. We anticipate the best outcome in younger patients, as well will be treating the disease in the early stages of its development." Also, Professor Moore commented human gene therapy potentially could lead to effective treatment for other debilitating diseases. In the future, treating retinal degeneration require specific individualized gene therapy, prior to be approved, must be tested in a clinical trial for that disease.