Gene therapy is a treatment method that uses normal genes to fill or replace certain diseases or missing genes in genetic diseases. In recent years, researchers in Oxford, England, and Philadelphia, USA, have announced that they have treated patients with vision-affected diseases with rare genetic diseases that have improved their vision. Italian scientists have also announced that they have reduced the condition of patients with two other genetic diseases. The results of these studies, as well as citation statistics recorded on the Web of Science website, focus on one category of gene therapy – and it has been hampered since its inception.
In 1980, Martin J. Cline, a researcher at the University of California, Los Angeles (UCLA), was condemned by American research organizations because he tried to use gene therapy to treat thalassemia. At the time it seemed to be a violation of morality. Klein was originally allowed to use two separate genes in the therapy, but in the experiment, he used two genes linked to the same plasmid vector. In other words, he became the first person to apply recombinant DNA to the human body. However, this therapy did not play any role, and the subsequent public commotion made him unable to investigate the reasons for the failure. In the early 1990s, with full approval, some attempts were made to treat children's severe immunodeficiency syndrome in children in the same way. One of the treatments was mentioned above. The Italian research team launched. Then, in 1999, a patient died of a series of adverse reactions during the trial. This incident caused public doubts, and some common problems in other trials were immediately revealed. As a result, scientists and related institutions have once again been condemned and fined.
However, the researchers did not feel discouraged, but continued the research. Their achievements in recent years have also shown that it takes a long time to make breakthroughs and progress in gene therapy, and it must be tested on the human body. The latest development in this area may be attributed to Albert Maguire and Jean Bennett of the University of Pennsylvania, who led a team and research results. Published in the "Lancet" magazine in 2009 (for details, please see the paper 3. The papers mentioned in this article are attached to the table in the text, sorted by citation count). Their team treated 12 patients, ranging in age from 8 to 44 years old, all suffering from Lebers congenital amaurosis. The disease is caused by a genetic defect called RPE65, which causes retinal degeneration and blindness in the patient. McGuire and Bennett injected an adenovirus into the patient's eye, which contained the intact RPE65 gene. As a result, the visual acuity of all patients was improved, and the 8-year-old patient had the best visual acuity recovery, almost reaching the normal human vision level.
How did their team do this? In 1989, several Swedish researchers pointed out in a paper that a dog named Bree hound would also have a similar condition, affecting their sensitivity to light. degree. (See paper 6 for details). Ten years later, they published a paper detailing the genetic mutations in RPE65, which has long been considered a genetic defect (see paper 4 for details). In 2007, after successfully demonstrating that gene therapy can effectively treat animal genetic diseases, a French research team tested the improved viral gene delivery system, which is specifically designed to replace defective RPE65 genes. Evaluation. They injected the modified virus into the eyes of the sick Breeder, and the visual acuity of the younger hounds was significantly improved (see paper 5 for details). The results of McGuire and Bennett's research show that similar treatments are equally safe and effective in the treatment of human Lyber's congenital sputum (see paper 2 for details). Their second year of research also confirmed another point, that is, the younger the patient, the more effective the treatment.
Modified retrovirus
Robert MacLaren, a professor at Oxford University, also announced in January this year a similar study with McGuire and Bennett. He used a virus that is harmless to the human body and carries a healthy gene. It is injected into the patient to treat another congenital retinal disease: hereditary primary choroideremia (see paper 9 for details). At San Raffaele Telethon in Milan, researchers in Italy use a virus modified by the human immunodeficiency virus (HIV). They use retroviruses like HIV because these viruses add their genetic information to the DNA of human cells when they are infected. In order to replace defective genes with healthy genes, this retrovirus will be an ideal "messenger".
In 1996, the Italian team led by Professor Rich Nadini published a report that these HIV-positive viruses successfully introduced health genes into human and animal cell lines. This paper was later cited many times ( See paper 1). As of August 2013, this method has effectively treated several patients with metachromatic leukodystrophy (see paper 8 for details), and several patients with Viscot-Orr. Patients with Wiskott-Aldrich syndrome (see paper 7 for details). These are extremely rare conditions. Among them, the susceptible white matter lesion is caused by the deficiency of arylsulfatase A, which leads to the degradation of fatty myelin, which hinders nerve development. Viscote-Aldrich syndrome is a disease of the human immune system and coagulation system, which is usually fatal.
In the treatment of these two diseases, this team from Italy used hematopoietic stem cell transplantation. That is, they take hematopoietic stem cells from the patient's bone marrow, and then combine these stem cells with a lentivirus containing a healthy gene and then inject them back into the patient. These stem cells are gradually diminished by replication and differentiation, which spread from the inside of the bone marrow to various parts of the body. The first group of patients treated were divided into two groups of three, and the team's recently published findings are still in their infancy. "For the expected age of onset of leukopenic lesions, the three patients enrolled in the trial had been older than 7 months to 21 months, but showed no signs of seizures or worsening." In the treatment of Viscot Aldrich syndrome, "three patients ... showed an increase in the number of platelets, improved immune function, and increased medical scores." In the course of treatment with gene therapy, two groups of patients There has been no change in the genes that are known to cause cancer, and this was one of the public concerns about the introduction of the "messenger" tool.
It seems that gene therapy seems to have gone out of the ice, began to undergo extensive tests, and even began to be adopted. In recent years, research has focused on rare genetic diseases, which is undoubtedly a great boon for those suffering from it. For most people, gene therapy also needs to be further improved to repair cancer-related genes to treat cancer. Research on the use of gene therapy for cancer has been carried out for many years, but it is still in chaos. If this type of research can be successful, countless people will benefit greatly. (Mimi)
Paper sorted paper name citations
1) et al., "In vivo delivery and stable transduction of nondividing cells by a lentiviral vector," Science, 272 (5259): 263-7, 1996. [Salk Inst., La Jolla, CA; Whitehead Inst., Cambridge , MA]
2,744
2) et al., “Safety and efficacy of gene transfer for Leber's congenital amaurosis,†New Engl. J. Med., 358(21): 2240-8, 2008. [12 US and Italian institutions]
674
3) et al., “Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis,†Lancet, 374 (9701): 1597-1605, 2009. [9 US and Italian institutions]
220
4) et al., “Retinal dystrophy of Swedish briard Briard-beagle dogs is due to 4-bp deletion in RPE65,†Genomics, 57(1): 57-61, 1999 [U. Klinikum Hamburg Eppendorf, Germany; Linkoping U . Sweden; Swedish U. Agr. Sci. Fac. Vet. Med., Uppsala]
101
5) et al., "Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector using an AAV that specifically targets the retinal pigmented epithelium," Gene Therapy, 14(4): 292-303, 2007. [CHU Nantes, France; Ecole Natl. Vet., Nantes, France; UCL, London, UK; Hop. St. Eloi, Montpelier, France] Web of Science
78
6) et al., “The Briard dog: A new animal model of congenital stationary night blindness,†British J. Ophthalmology, 73(9): 750-6, 1989. [Swedish U. Agr. Sci. Fac. Vet. , Uppsala; Linkoping U., Sweden]
55
7) et al., "Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich Syndrome," Science, 341(6148): 865, 2013. [15 institutions worldwide]
14
8) et al., “Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy,†Science, 341(6148): 864, 2013. [Ist. Sci. San Raffaele, Milan, Italy]
11
9) et al., “Retinal gene therapy in patients with choroideremia: Initial findings from a phase ? trial,†Lancet, 383 (9923): 1129-37, 29 March 2014. [12 institutions worldwide]
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