Gene therapy of age-related blindness
The results of a small preliminary clinical study conducted by Johns Hopkins University specialists working under the guidance of Professor Peter A Campochiaro demonstrated the safety and effectiveness of gene therapy, the purpose of which is to preserve the vision of patients with a "wet" form of age-related macular degeneration.
Age-related macular degeneration is the leading cause of blindness in the elderly. This disease is characterized by the growth of abnormal blood vessels, through the pores in the walls of which the fluid sweats into the central area of the retina, known as the yellow spot and providing the ability to read, drive a car and recognize faces.
Abnormal vascular growth in this disease is caused by increased production of vascular epithelial growth factor in the retina. Modern methods of treatment consist in the periodic introduction directly into the eye tissue of therapeutic proteins that bind and inactivate vascular epithelial growth factor, which helps to reduce the amount of fluid in the retina and improve vision. However, therapeutic proteins are removed from the eye tissues within a month, so patients have to have repeated injections every 6-8 weeks. Doctors note that many patients cannot withstand such a regime, and irregular administration of the drug does not provide effective prevention of vision loss.
The authors developed a gene therapy approach to the treatment of age-related macular degeneration and analyzed its safety and efficacy in a phase 1 clinical trial involving 19 men and 50 women aged 50 years and older with severe forms of wet macular degeneration.
As a therapeutic agent, they used the AAV2 virus vector, harmless to humans, which embeds a gene encoding the therapeutic protein sFLT01 neutralizing vascular epithelial growth factor into the DNA of cells.
The study participants were divided into 5 cohorts who received injections of an experimental drug into the vitreous body. Dosages of the therapeutic vector diluted in 0.05 ml of liquid increased from 2x10 8 to 2x10 10 viral particles. Patients of each cohort were carefully examined to identify possible undesirable side effects for at least 4 weeks before the administration of a higher dosage of the drug to patients of the next group.
After embedding the therapeutic virus into the genome, retinal cells began to secrete the protein sFLT01, which binds vascular endothelial growth factor, thus preventing the growth of abnormal blood vessels and the effusion of fluid into the tissue. The purpose of this intervention was to permanently stop the progression of macular degeneration.
For safety and ethical reasons, the study included patients whose vision could not be restored using standard treatments, while only 11 out of 19 had the potential to reduce the amount of fluid in the retinal tissue. After the procedure, 4 of these 11 patients had significant improvements. Their retina is almost completely cleared of fluid, which corresponds to the results of standard therapy when it is carried out under optimal conditions. Two more patients had a partial decrease in the amount of fluid in the retina.
In the remaining five patients, there was no decrease in the amount of fluid in the retina, while pre-existing antibodies to the AAV2 virus were detected in their blood.
Based on the results obtained, the researchers concluded that if further studies confirm the safety and effectiveness of gene therapy, its clinical use may have significant limitations. This is due to the fact that approximately 60% of the US population is infected with adenoassociated viruses, to which the AAV2 virus belongs. The authors believe that the immune response formed in this case destroys therapeutic vectors before they have time to embed the therapeutic gene into the DNA of target cells. The data available to date are insufficient to draw unambiguous conclusions and only additional clinical studies will allow us to confirm this assumption.
Article by Jeffrey S Heier et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial published in The Lancet.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Johns Hopkins Medicine: New Gene Therapy for Vision Loss Proven Safe in Humans.
19.05.2017