In the mid-1990s, scientists made a strange and important discovery: a painter named Steve Crohn seemed to be immune to HIV.
A few years before this discovery was revealed, Crohn's boyfriend and many friends around him died of AIDS. However, although Crohn has positive sexual relations with other HIV carriers, it seems that he has never been infected with HIV.
According to the researchers' findings, the reason behind this is that there is a mutant gene called CCR5 in the gene of Crohn's disease, which can effectively prevent HIV from invading immune cells in the body.
In the following decades, researchers who studied HIV carried out special research on this Delta 32 mutant gene. This mutant gene is also a gene that China scientist He Jiankui tried to replicate. Last year, he used CRISPR gene editing technology to edit the case of human embryos, which also shocked the whole scientific community. Then a pair of twin girls were born, which is also the first baby born through gene editing in the world.
Nowadays, some research teams are trying to reconstruct rare protective mutant genes for HIV-infected people in order to successfully cure the virus as soon as possible.
Among them, Genentech, a biotechnology company from Maryland, plans to start clinical trials before the end of this year. Some scientists believe that the treatment scheme with the help of genetic materials such as DNA or RNA is the most effective one-off long-term solution to cure HIV at present. More than 32 million people worldwide have died of HIV infection. However, these so-called gene editing technologies face many challenges.
So far, there are only two cases of successful cure of HIV in the world. One of them is Timothy Ray Brown, known as the "Berlin Patient", and the other is an anonymous patient from London, which was only recently known.
In both cases, patients received bone marrow transplantation to treat hematological tumors, and their bone marrow donors also carried CCR5 mutant gene. In the process of bone marrow transplantation, the healthy hematopoietic stem cells of the donor will replace the unhealthy hematopoietic stem cells of the recipient, making them continue to differentiate and form a series of immune cells.
In short, through bone marrow transplantation, the whole immune system of two patients can be "reset" and HIV virus can be cured in the process.
However, it is unrealistic that not all HIV-infected people can receive bone marrow transplantation.
First of all, it is not easy to find a matching bone marrow donor, not to mention that the genes in bone marrow donors also have their own CCR5 mutant genes.
It is understood that only about 1% of people of European descent carry two mutant genes. In order to resist HIV, people must obtain two kinds of mutant genes through heredity.
In addition, bone marrow transplantation also has certain risks, after all, it may cause damage to recipient cells from donor cells.
Gene editing therapy can avoid this series of problems.
Scientists from Genentech Company in the United States edited this harmless virus to carry an RNA molecule that can "resist" CCR5 mutant gene. This experimental treatment needs to draw 400 ml of blood from patients infected with HIV.
T cells are immune cells in the blood that can resist infection and can be isolated by some techniques. Later, scientists will cultivate and proliferate more T cells in the laboratory and use them to treat the edited virus. About two weeks later, these edited cells were injected into the patient. And this process is a one-time treatment of HIV.
"We believe that in this way, the patient's immune system can return to normal," said Jeff galvin, CEO of Genentech.
Scientists of the company tested and verified the treatment scheme in their laboratory by extracting T cells from the blood of 13 HIV-infected people.
According to galvin, after the treatment plan is verified, these cured cells are no longer infected with HIV. Since then, the company has reached a cooperative relationship with the National Institute of Infectious Diseases under the organization of the National Institutes of Health. The agency is also testing gene therapy for these human cells.
Galvin said that he hopes to recruit 15 to 18 patients to participate in his clinical trial before the end of this year. The University of Maryland in Baltimore will be one of its clinical trial bases.
For its recruitment criteria, first of all, patients must have enough T cells for treatment. There are some problems with this standard, because if the patient's HIV is not cured, the number of T cells in his body is very small. However, with the help of antiretroviral drugs that can prevent and treat HIV, there is still a chance to restore some of these immune cells.
In addition, although antiretroviral drugs are also effective, they usually produce a series of serious side effects, such as anorexia, fatigue, vomiting and even unpredictable emotions.
According to galvin, it is for this reason that his company is so interested in gene therapy. "We also urgently need to bring hope to these HIV-infected people and let them feel the meaning of life again." Galvin said.
Dr Hans-Peter Kim is the director of the stem cell and gene therapy program at the Hutchinson Fred Cancer Research Center in Seattle, USA. He is also one of many scientists who are interested in studying how to cure AIDS through gene therapy.
Dr Kim's team used CCR5 mutant gene in monkeys through CRISPR gene editing tool. At first, they extracted bone marrow stem cells from macaques infected with HIV-like virus, then edited CCR5 gene with CRISPR, and finally transplanted the cells back into macaques.
The edited gene will continue to proliferate and begin to differentiate into healthy new cells that can resist the virus. The whole process is similar to bone marrow transplantation, except that stem cells are taken from the same animal, not the donor, thus reducing the risk of mismatch.
However, with the passage of time, the number of editing cells in macaques will continue to decrease, so macaques will not fully recover. Dr. Jin's team is also working hard to study and improve this technology. "What we can't confirm at present is whether CCR5 gene editing alone is enough to cure the virus." Jin said.
Sangamo Therapeutics, a biopharmaceutical company from California, also tried CCR5 gene editing method.
10 years ago, the company started a clinical experiment to extract and edit T cells from HIV-infected people. At that time, an old gene editing tool called zinc finger nuclease was used. However, the company's approach is mixed.
A research report of 20 14 showed that the HIV virus load in the blood of 4 patients decreased. Among them, 1 patients can't even detect HIV. The results showed that there was a mutation in CCR5 gene of this patient. However, among the 100 patients who have accepted the company's clinical trials, most of them still need to take medicine every day to fight HIV.
Ironically, however, the success of antiretroviral drugs in treating HIV can only mean that any method of treating HIV through gene technology will face higher standards if it is approved by the US Food and Drug Administration.
"If patients infected with HIV insist on taking one or two tablets a day, generally speaking, this situation can be alleviated." Dr. Paul Sachs, an infectious disease doctor at Brigham and Women's Hospital affiliated to Harvard Medical School, said. "Therefore, any improvement based on this therapy must be fully guaranteed."
According to a recent research report in Nature Medicine, if a patient carries the double CCR5 mutation gene, his life span may be shorter.
After consulting the death records of about 400,000 people, the researchers found that the possibility of such patients dying before the age of 76 is 2 1% higher than that of people with a single CCR5 mutation gene.
Dr. Sachs believes that one possible reason for the findings of this study is that people who carry these mutant genes are more likely to be infected with influenza and other viruses, and if the elderly are infected with these viruses, they will easily die.
Therefore, Dr. Sachs also warned that for patients infected with HIV, if the treatment of CCR5 mutant gene is not handled properly, it may also lead to unexpected results. "Whether it will cause harmful health consequences? This answer is still unknown. "
Even so, if a gene therapy can really cure HIV and get the approval of FDA, another problem that worries Dr. Sachs is how to solve the high treatment cost for about 37 million patients infected with HIV around the world.
The cost of many gene therapies is staggering, even as high as $373,000 to $2,654,380+.
In view of these challenges at present, Dr. Sachs and relevant people think that gene therapy may be the best development direction for long-term treatment of HIV. He said, "Gene therapy may be the best treatment at present."
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