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Drug: maraviroc

Magazine: Cell

Highlights:

1) First confirmed that CCR5 gene is associated with stroke rehabilitation

2) HIV drug maraviroc can promote recovery of mice from stroke

3) First reported the function of CCR5 in the human brain

 

Stroke is an acute cerebrovascular disease caused by sudden rupture of blood vessels in the brain or blood vessels that cannot flow into the brain due to vascular occlusion. It is the first cause of death in China, with high morbidity and high mortality. High disability rate. Even a mild stroke can cause the patient’s arms and legs to become weak, muscle control ability to deteriorate, and memory loss.

On February 21, published in a paper in Cell, neuroscientists from the University of California, Los Angeles (UCLA) found that blocking CCR5 in stroke mice can help surviving neurons establish new connections. People who carry the CCR5 mutation recover better after a stroke.

 

The new discovery of CCR5 began with a search for “smart mice,” in which scientists wanted to find mice that might enhance learning and memory by carrying certain genetic mutations.

 

UCLA neuroscientist Alcino Silva and his team looked for this “smart mouse” in 148 mice.

 

In 2016, they published a paper on eLIFE that reducing the level of CCR5 in the brains of healthy mice can enhance memory formation and learning. In addition, inhibition of CCR5 enhances the ability of neurons to form new connections and reconnect brains after injury.

 

The study sparked the interest of Dr. Thomas Carmichael, a neuroscientist in the school. He said: “When you see a stroke patient recover, it is like they are re-learning to walk or speak.”

Dr. Thomas Carmichael said: “This is the first demonstration that a human gene is associated with better stroke rehabilitation.”

 

01

 HIV drugs can promote recovery from stroke in mice

In this Cell paper, Silva, Carmichael, and their collaborators found that after a stroke, CCR5 levels in mouse neurons soared and remained high for several weeks, which seems to hinder the recovery of stroke patients. .

Neuron immunologist Robyn Klein of the University of Washington School of Medicine said that a surge in CCR5 is part of the stroke inflammatory response. Inflammatory molecules may prompt neurons to express more CCR5. But at present, the role of CCR5 in the brain after stroke is unclear.

So, is the drug targeting CCR5 a hope for stroke rehabilitation? Silva’s 2016 paper has confirmed that the HIV drug maraviroc targeting CCR5 can improve learning and memory in mice. Therefore, Dr. Carmichael and others speculate that maraviroc can also accelerate the recovery of stroke.

The bottom image shows that maraviroc-treated stroke mice have fewer scars and inflammation (red).

 

In the study, scientists blocked CCR5 with maraviroc and then tested the mice for exercise. At the end of the 9-week trial, the mice in the treatment group had a greater improvement in exercise capacity compared to the control group. Even if the researchers waited for 3 weeks after stroke to treat mice with maraviroc, they could still change their athletic ability. This suggests that maraviroc can promote recovery from stroke in mice.

Blocking CCR5 promotes neural projection of the brain’s motor area (left).

 

Studies have shown that when CCR5 is deleted or blocked, neurons can establish new connections, reconnect the brain, and restore some of the lost function.

 

02

People born with CCR5 mutations recover faster after stroke

 

So, does suppressing or missing CCR5 produce the same results in humans?

 

Since it is known that CCR5 gene deletion is common in German Jews (about 10% of Europeans carry a mutant version of the CCR5 gene, and a higher proportion of Eastern European Jews), UCLA scientists contacted researchers at Tel Aviv University in Israel.

 

A very fortunate coincidence is that the team led by neuroscientist Einor Ben Assayag has been conducting observational studies on 446 stroke patients. The study focused only on patients with mild or moderate stroke, and documented advances in walking, arm and leg control, and other types of exercise to assess their recovery after 6 months, 1 year, and 2 years of stroke.

In the end, the Israeli team identified 68 stroke survivors with at least one copy of the CCR5 mutation. The results of the study showed that people who lacked the CCR5 gene recovered significantly better in motor skills, language and sensory function. One year after stroke, patients with missing CCR5 scored higher in memory, language function, and attention tests.

 

Stroke neuroscientist Argye Hillis of Johns Hopkins University in the United States believes that CCR5 is the first truly molecular target for improving stroke rehabilitation.

 

Next, scientists hope to launch a clinical trial this year to test the efficacy of maraviroc in stroke patients with the CCR5 gene. They plan to have 30 stroke patients start receiving maraviroc treatment after leaving the hospital’s rehabilitation facility (usually after about 4 weeks of stroke). Maraviroc may be the first drug to reverse the physiological and psychological consequences of mild stroke.

 

03

 Has an impact on the world’s first genetically edited baby brain

 

In addition to its impact on stroke rehabilitation, this Cell paper confirms that people who miss at least one copy of CCR5 seem to be learning farther, suggesting that CCR5 may have an impact on everyday intelligence. This is the first study to report the function of CCR5 in the human brain.

Structure of CCR5

 

CCR5, a full name of CC chemokine receptor type 5, is a protein expressed on the surface of white blood cells and plays a variety of roles in the body, such as the “helper” of HIV infection (one of the main co-receptors of HIV virus invading the body cells). .

 

At the end of last year, the birth of the world’s first genetically edited baby (Lulu and Nana) made many people aware of this gene. A Chinese team used CRISPR technology to edit the CCR5 gene, reducing it by 32 base pairs and turning it into a mutant called CCR5Δ32, which aims to make babies naturally resistant to AIDS after birth.

 

He Jiankui, who led the experiment, admitted at the 2nd International Summit of Human Genome Editors that he had read the papers published by Silva in 2016, but he stated that he opposed the use of genetic editing to achieve functional enhancement, that is, he edited The CCR5 gene is not meant to make children more “smart”.

 

Silva said that based on their findings, Lulu and Nana’s brain may have changed, thereby enhancing cognition and memory. He said: “There are many similarities between the mouse and the human brain. Therefore, the answer seems to be affirmative. Editing the CCR5 gene does affect the brain of genetically edited infants. These mutations may affect their cognitive function, but The impact is unpredictable.”

 

Scientists emphasize that the link between CCR5 and educational success is “tempting,” but further research is needed. Changing CCR5 has a particularly large impact, although we can change the average IQ of humans in the future, but now we are not ready.

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