//
Gut bacteria can mediate CRB1 mutation-related blinding eye disease, but blind use of antibiotics is not advisable, and the key is to repair the barrier through gene therapy.
On March 14, 2024, a research team from Zhongshan Eye Center and Guangzhou Medical University led by Professor Wei Lai revealed for the first time that intestinal bacteria can mediate CRB1 mutation-related blindness after eight years of scientific research. The breakthrough discovery was published in the journal Cell.
Source: Cell's official website
This has led many people to think that simple antibiotics can treat CRB1-associated retinitis pigmentosa, a blinding eye disease. In this regard, the developer interviewed Wei Lai, the head of the study, who proposed that the treatment of such diseases should focus on the use of gene therapy to repair the barrier, rather than the blind use of antibiotics.
In the past, Wei Lai rarely publicized his scientific research results, but this time he responded, "The core is that I don't want anyone to go the wrong way." ”
Why is antibiotic therapy not recommended?
Back in 2015, Wei Lai and his team noticed an anomaly: although genetic mutations persist throughout life, hereditary retinal degenerative diseases do not occur in the embryonic stage, but generally begin in childhood or adolescence, manifesting as progressive vision loss and even blindness. Previous studies have shown that mutations in the CRB1 gene are one of the common causes, but the pathogenesis is not yet clear.
Wei Lai
Out of curiosity, the researchers found in a mouse model with a natural CRB1 gene mutation that mice need to be stimulated by an external environmental factor - bacteria to develop the disease. Genome sequencing of the bacteria showed that the bacteria came from the colonic part of the intestine.
In-depth exploration has found that CRB1 has important functions in the retina and intestine, and its expression and loss of function will lead to damage to the colonic epithelial barrier and blood-extraretinal barrier, allowing intestinal bacteria to enter the blood circulation system and migrate to the retina, and ultimately induce retinitis pigmentosa-like disease progression.
The researchers also used antibiotics and gene therapy to repair the intestinal barrier in mice, respectively. The results showed that both of these ways of blocking the entry of gut bacteria into the blood/retina were able to treat fundus diseases associated with mutations in the CRB1 gene.
CRB1-associated retinal degeneration relies on intestinal bacterial translocation
Source: Cell
"This study suggests that bacteria are important," Wei said, "but even more important is the compromised barrier that allows bacteria to get in and out." ”
In his opinion, according to the current findings, it is not advisable to simply understand that antibiotic treatment is not advisable for three reasons: first, there are many types of antibiotics, and it is not clear which ones are effective for the disease; Second, bactericidal treatment should be combined with barrier repair, otherwise the patient needs to take antibiotics for life; Third, long-term treatment with a large number of antibiotics can easily cause dysbiosis, and cause a series of side effects such as metabolism and immunity.
In contrast, barrier-repairing gene therapy is much more feasible. Theoretically, by supplementing the target gene to correct the expression of CRB1 protein in patients, the purpose of repairing the barrier and blocking bacterial invasion can be achieved. Among them, intestinal gene therapy has more advantages and is more important than fundus gene therapy.
Because fundus gene therapy repairs the second barrier, gut bacteria can still enter the bloodstream and affect other tissues such as blood vessels and the brain. Intestinal gene therapy repairs the first barrier, which can keep bacteria out of the blood circulatory system. Moreover, the latter is simple to operate, and can be administered locally to the intestinal mucosal epithelial cells, with few side effects, and can be treated repeatedly until the intestinal barrier is completely repaired.
Currently, researchers have observed in patients with mutations in the CRB1 gene, consistent with animal experiments, that is, intestinal barrier damage and migration of intestinal bacteria in peripheral blood. In the next step, they will continue to explore safe and effective gene therapy methods.
"I believe that after we have completed the first step of opening the door, many people in the scientific community will begin to use different experiences and expertise to quickly and effectively complete the follow-up exploration work, so as to benefit patients as soon as possible." Wei said.
It is important to note that neither antibiotics nor gene therapy can block the cause of the disease, but cannot reverse blindness.
Bacteria entering the bloodstream are not cleared by the immune system?
Some people may wonder why intestinal bacteria can still migrate all the way to the retina when they enter the bloodstream and are not detected and eliminated by the immune system.
In response, Wei Lai responded that in fact, the human body has its own tolerance mechanism, and for foreign substances such as bacteria and viruses, only when they are regarded as a threat by the immune system above a certain dose of "gate" will they cause an immune response; However, if the immune system determines that they are not a threat under the "gate", they may be retained in the body's circulation for a long time, symbiotic or co-evolve with the body.
"There is something wrong with the logic of making comments based on cognition and experience, and if you can't see it, you don't exist." He said, "Understanding the limitations of cognition, not knowing is not knowing, is the core logic, ethics and bottom line of scientists." ”
In fact, in recent years, more and more international studies have found that microorganisms are also present in the blood of healthy people, which breaks the existing knowledge in textbooks.
In March 2023, Nature Microbiology published a study in which scientists sequenced blood samples from 9,770 healthy people and found 117 microorganisms, including 110 bacteria, 5 viruses and 2 fungi, in 8,892 samples.
From Wei's point of view, science is to challenge the original, and only by challenging can progress be made.
A scientist who wants to start a business in his bones
"Serving patients is my core pursuit, it's a source of fulfillment for me, and it's been established since I was a student." Wei Lai bluntly said that his biggest goal is to transform scientific research achievements into products that cure diseases and save people.
After graduating from the University of Tennessee in 2006 with a Ph.D. degree, he joined the National Institutes of Health (NIH) to conduct research on basic immunology, ocular immunity and microbiome.
Although it was stable and comfortable to do scientific research in the United States, what bothered Wei Lai was that scientific discoveries could not be translated into medical products. "It is very difficult for Chinese to start a business in the United States, especially in the biomedical industry, which requires a lot of investment in the early stage, and everyone can only transfer their research results." "In contrast, the environment for entrepreneurship in China is much friendlier. ”
After realizing this, he returned to China in 2013 without hesitation and joined Zhongshan Eye Center as a high-level talent for nearly ten years.
Because he can't let go of the entrepreneurial genes in his bones, Wei Lai has also made some attempts to transform achievements since 2016, and the products developed have now entered the clinical trial stage in China and the United States.
But even if he started his own business, he was still a scientist in the company because he "didn't want to delay his research time". As for other areas of work, such as company operations, he prefers teamwork and brings his own strengths to work. He laughed at himself that as a person who has been beaten by the market for many years, he has a deeper understanding of entrepreneurship and product development, and has also learned to look at product commercialization and return on investment from the perspective of investors.
In 2023, Wei Lai joined the Second Affiliated Hospital of Guangzhou Medical University to explore the establishment of a new model of medical research. At the same time, he has not stopped the pace of transformation of achievements, and a new ophthalmic treatment is ready to go.
Edit | Dai Jialing [email protected]
Issue No. 2107