The effect of gene therapy for blindness may be temporary
Gene therapy for blindness has produced contradictory results
Three different research groups completed clinical trials of their methods and reported receiving contradictory results: in some, the effect of therapy turned out to be "long-lasting", while other scientists registered a gradual deterioration in the condition of patients who voluntarily agreed to innovative treatment.
As part of this work, biomedics have tried to cure their patients of a rare form of hereditary blindness known as Leber's amaurosis. This disease leads to complete loss of vision at about the age of forty. Approximately 10% of all reported cases of this disease are caused by mutations in a specific gene called RPE65, which encodes an enzyme that promotes the creation of rhodopsin by retinal pigment epithelial cells. A mutation in RPE65 leads to the death of photoreceptor cells and, accordingly, to the development of blindness.
The first attempt to cure patients of this disease was made by researchers from the UK and the USA in 2007. Then a team of volunteers was injected by surgeons into one eye with a solution containing a neutralized virus that delivered a healthy copy of the RPE65 gene to retinal cells.
Just a few days after the procedure, the volunteers demonstrated more pronounced photosensitivity, as well as the ability to navigate the maze, in particular, in low-light conditions. Patients shared their inspiring stories on the Internet, which convinced the public and even the scientific community that such gene therapy can become a one-time and long-lasting salvation from a rare form of blindness.
However, in 2013, a team led by Samuel Jacobson from the University of Pennsylvania, who conducted clinical trials in the United States, reported disappointing news. The results of the new tests showed that although 15 patients from the American group actually began to see better compared to the indicators before the start of the tests, photoreceptor cells continue to die.
One of Dr. Jacobson's patients who had
significant improvement of the condition after gene therapy
(photo by Foundation Fighting Blindness).
A new study, the results of which are presented in an article in The New England Journal of Medicine (Jacobson et al., Improvement and Decline in Vision with Gene Therapy in Childhood Blindness), explains the effects observed over the past two years. Jacobson's group reports that in three patients with long-term therapy results, the retinal region reached a maximum of increased visual sensitivity in the period between one and three years after the treatment. After this period, the effect of therapy began to gradually decrease, although at the time of the final tests, the condition of the patients' photoreceptors was still better than before the start of clinical trials.
The head of clinical trials in the UK, Robin Ali from University College London, notes that the improvement in vision in his patients was significantly different from what was observed in preclinical studies on dogs that underwent the same treatment. Dr. Ali attributes the short-lived effect of therapy in humans to the fact that the human retina, unlike the dog's, does not receive enough healthy RPE65 genes.
"In order to develop a truly effective therapy, it is necessary to restore the normal function of photoreceptors. At the moment, we are planning to conduct a new stage of clinical trials with a much more powerful viral gene delivery system. It should lead to a higher expression of RPE65," says Ali.
However, both Ali and his American colleague Jacobson agree that the new more powerful therapy has a significant disadvantage – increased toxicity compared to the previous analogue. Therefore, scientists are also considering the possibility of introducing an additional drug that will slow down the degeneration of photoreceptors in the long term.
However, another research group, led by geneticist Jean Bennett from the University of Pennsylvania Medical School, reports much more encouraging results of clinical trials of gene therapy for Leber's amaurosis. These scientists claim that the effect persists in their patients for 7.5 years, and there are no signs of deterioration in the volunteers.
"It would be naive to say that photoreceptors will remain healthy in the future, but so far we have not observed signs of degeneration of retinal neurons," says Dr. Bennett. She also explained that the reason for the gradual deterioration of the condition of colleagues' patients may be sparing therapy, which is used by British scientists.
The difference between gentle and more powerful therapy lies in how exactly the treatment is carried out. In the second case, on which great hopes are pinned, surgeons use a surfactant that provokes deep and targeted penetration of gene-carrying viruses to the cells of the retina of the eye. Thus, more healthy RPE65 genes are delivered to the tissue, and the effectiveness of therapy increases, and the duration of the effect increases.
All three clinical trial managers agree that there is no reason to stop the research. They are sure that the effectiveness of therapy is obvious, but they have yet to adjust the delivery system of healthy genes and identify all possible side effects of this treatment technique.
At the same time, another research group published a new article in the journal Stem Cell Reports with the results of a study of stem cell therapy aimed at treating another form of blindness – macular degeneration, or dystrophy, of the retina (Song et al., Treatment of Macular Degeneration Using Embryonic Stem Cell-Derived Retinal Pigment Epithelium: Preliminary Results in Asian Patients).
Scientists from the research center at the American company Ocata Therapeutics, led by the world-famous Robert Lanza, demonstrated the safety of using stem cells to treat macular dystrophy and replace them with "collapsing" retinal cells.
This study was solely a safety assessment and did not involve the use of control groups. After a year after the operation, all four volunteers were able to read 9-19 letters more from the vision check table compared to the indicators before the start of therapy.
"This bodes well, but I think we should not rush to conclusions until we have conducted full–fledged clinical trials with the control group," says Dr. Lanza.
Unlike a group of Japanese researchers who used induced pluripotent stem cells in their therapy against macular degeneration of the retina, Dr. Lanza's team used embryonic stem cells. These cells are effectively transformed into retinal pigment epithelium and prevents the deterioration of the eye neurons. In people with macular dystrophy, this layer is gradually depleted, and photoreceptors, as well as other cells important for light perception, are gradually destroyed.
Instead of provoking the formation of layers of photoreceptor cells, as most researchers do in similar experiments, Lanza's team injected individual stem cells directly into the eyes of volunteers.
At the moment, Lanza and his colleagues have started collaborating with Korean researchers to expand the capabilities of this technique. The joint work of scientists from the west and the east will help to develop a universal method of treating macular degeneration of the retina: Caucasians and Asians have various genetic risk factors contributing to the development of macular degeneration.
Whether the effect will be temporary or long-lasting in this case is still difficult to say. However, the researchers expect, if not at all to prevent the subsequent deterioration of the patient's retina, then to prolong the effect for as long as possible.
Portal "Eternal youth" http://vechnayamolodost.ru05.05.2015