Gene therapy of Leber's amaurosis
Maxim Rousseau, Polit.roo
Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended to approve the method of genetic therapy of Leber's amaurosis – a congenital pathology of the retina, which inevitably leads to complete blindness.
The disease in question was described by the German ophthalmologist Theodor von Leber in 1869. In people with Leber's amaurosis, both the organs of vision, and the nerve pathways leading from the eye to the brain, and the neurons of the brain responsible for vision are in perfect order. However, their vision is lost because light-sensitive cells die in their retina and are not restored. The reason for this lies in the mutation of the gene responsible for the proper development of these cells, most often the RPE65 gene. There are 189 different variants of mutations leading to Leber's amaurosis. However, 146 of them met in practice only once, and only eight types of mutations are responsible for 70% of cases of the disease. Depending on the specific mutation, a person may already be born blind, lose sight in the first months of life, and there are cases when retinal cells die slowly, and then blindness occurs by about 30 years. Leber's amaurosis is quite rare. This disorder occurs, according to various sources, in one newborn per 40 thousand or even 81 thousand. Before the advent of gene therapy, Leber's amaurosis was completely incurable.
The goal of gene therapy is to replace a defective copy of a gene in a patient with a functional one, or at least deliver a sufficient number of normal copies of the gene to his body so that they work instead of his own. Previously, we have repeatedly talked about the experiences of using gene therapy for the treatment of leukemia, sickle cell anemia, adrenoleukodystrophy, cystic fibrosis, hereditary deafness, beta-thalassemia, hemophilia and other diseases. Experiments on the treatment of Leber's amaurosis began in the mid-2000s. At first, they were carried out on animals that had similar mutations that disrupt the restoration of retinal cells. In 2006, Sue Semple-Rowland from the University of Florida and her colleagues were able to restore vision to six experimental chickens out of seven. The necessary genetic design was introduced to them in the embryonic period with the help of a specially designed virus. French scientists in the same year conducted a successful experiment on dogs.
In 2008, employees of the Moorfields Eye Hospital and the Institute of Ophthalmology at University College London (Institute of Ophthalmology) told about their experiment on the use of gene therapy for Leber's amaurosis in humans. The experiment was led by gene therapy specialist Professor Robin Ali and ophthalmologist James W.B. Bainbridge, the results of which were described in an article published by The New England Journal of Medicine. The team of scientists worked with patients who had a type of Leber's amaurosis, which manifested itself not immediately after birth, but gradually. They had three patients aged 17 to 23 years with a mutation in the RPE65 gene and increasing vision loss. They were injected with a virus containing a corrected version of the gene under the retina of the eye (the so-called "subretinal injection"). A few months later, the check showed that there was no improvement in vision in two patients, but no progress of the disease was observed. But the third, 17-year-old Stephen Howarth, has significantly improved his eyesight. Before therapy, Stephen had particular difficulties with twilight vision. At night in the city, he could only see bright spots of light: street lights and car headlights. In a dimly lit room, he moved only by touch, and did not go outside at night at all. After gene therapy, he began to easily overcome a special darkened maze, in which he had previously passed only a meter per minute. On a city street at night, Stephen began to distinguish the sidewalk, road markings, house walls, road signs, even cracks in the asphalt. He became so emboldened that he decided to take night walks around his hometown.
For gene therapy of Leber's amaurosis, a modified adenoassociated virus is used, which is grown in HEK 293 cell culture. The virus is supplied with complementary DNA containing a working version of the RPE65 gene. In 2009, the results of the first phase of clinical trials of this therapy method conducted by the University of Pennsylvania and the Children's Hospital of Philadelphia were published. The work was led by Jean E. Bennett, Albert Maguire, Katherine High and J. Fraser Wright. 12 patients aged from 8 to 44 years participated. As a precaution, the viral drug was injected only into one of the eyes. As a result, vision improvement was observed in all twelve patients, and in children the progress was greater than in adults.
After the successful results of subsequent experiments, Spark therapeutics was established at the University of Pennsylvania in 2013 to bring this method of therapy to real use. The method was called Voretigene neparvovec (now the word Luxturna is taken as the commercial name). In parallel, in Florida, Samuel Jacobson and William Hauswirth conducted an independent trial on twelve patients with the support of the US National Institute of Vision. Unlike the Pennsylvania experiments, the injection of the drug was not made into the central fossa of the retina, which normally is its most sensitive area to light and provides a central field of vision (yellow spot), but just below. As a result, the patients' vision improved, but the area of the clearest vision turned out to be shifted to the place where the drug was injected.
In August of this year Spark therapeutics published the results of the third phase of clinical trials. They were successful again. According to scientists, the modified virus can persist in the retina area and ensure the correct operation of the gene for a long time, for at least several years. Now the company's application for the official registration of its method has been reviewed by the sixteen-person advisory committee on cellular, tissue and gene therapy at the FDA. This is an independent body and its decisions serve only as a recommendation for FDA employees, but the weight of these recommendations is very high. The committee members voted unanimously for the approval of gene therapy for Leber's amaurosis. Now, by January 12, 2018, the FDA must make an official decision whether or not to approve the use of this method in clinical practice in the United States. If the answer is positive, Luxturna will become the first gene therapy method approved in the United States that uses a viral carrier.
It should be remembered that Luxturna does not cure Leber's amaurosis completely and does not restore lost retinal cells. Patients' vision is limited by the capabilities of those viable cells that they have preserved at the time of injection. That is why therapy gives more improvement in children than in adults. It is not completely clear how long the effect will last. Will an additional injection be needed in ten years? Or in twenty?
It is also unclear how much the treatment will cost. Executive director of Spark therapeutics Jeff Marrazzo has not yet named specific numbers, but, according to external experts, such therapy will cost at least 475 thousand dollars.
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