基因疗法 z-bio 2021-02-11 389

　　Arginase deficiency is a rare genetic disease that causes the accumulation of the amino acid arginine in the blood. However, when babies are toddlers, their muscles begin to stiffen, followed by seizures, tremors, and developmental delays. Over time, the disease can lead to severe intellectual disability.

　　Scientists at the University of California, Los Angeles have developed two new methods to deliver copies of the functional arginase gene to mice lacking arginase. One method is to treat mice every 3 days, using tiny nanoparticles to carry arginase RNA into the liver. The other uses a virus to bring arginase DNA to the liver; if the correct medication is administered to mice that are 2-4 days old, a single dose can prevent the symptoms of arginase deficiency in animals.

　　Dr. Gerald Lipshutz, professor of surgery at the University of California, Los Angeles (UCLA) and senior author of the two studies, said: "We are in an era of genomics and genetics innovation, and we can bring new targeted therapies to patients with genetic diseases. These therapies may only benefit a few people with rare or rare diseases at first, but they will eventually be more widely used."

　　Arginase deficiency is caused by the deletion or mutation of the arginase gene ARG1, which affects one in every 1 million babies born in the United States. Arginase is one of the six proteins in the liver. They play a role in the process of breaking down and removing arginine from the body. Without the action of arginase, arginine would accumulate in the blood and cause problems, mainly in the brain.

　　Many people with this disease try to treat it with a strict protein-restricted diet, which helps them avoid nitrogen and arginine from the beginning. There are also some drugs that can remove excess nitrogen from the blood, but they are expensive and not very effective for most people.

　　To help them develop new treatments, Lipshutz and his collaborators first tried to better understand how arginase deficiency affects the brain in a way that leads to disease development and neurological symptoms. In a paper published in the journal JCI Insight, scientists reported that the amount of myelin in the brain of mice lacking arginase was less than a quarter of the normal level. Myelin is a substance that wraps brain cells like an insulator and is the key to communication between various areas of the brain.

　　To test whether the lack of ARG1 can lead to the loss of myelin, Lipshutz’s team designed a virus that can carry a new copy of ARG1 DNA. When the team injected the virus intravenously into 2-day-old mice lacking ARG1, their myelin was no longer defective. The level of bone marrow cells in mice carrying the virus is close to normal.

　　"With one dose, we can prevent these brain abnormalities," Lipshutz said. "From almost no myelination to near normal is very dramatic."

　　Researchers studying other genetic diseases have studied the use of viruses to deliver healthy DNA to patients. Data from these studies indicate that this therapy may fail after many years. Since relatively few patients receiving treatment for genetic diseases receive such treatment, researchers must still determine whether the same phenomenon occurs in humans. However, Lipshutz said that a virus-based therapy that replaces ARG1 does have the potential to work in humans.

　　Lipshutz and his colleagues are currently studying cells taken from patients with arginase deficiency to determine whether they also have defects in myelination. They plan to explore the molecular link between high levels of arginine in the brain and loss of myelin. In order to find other target drugs to treat arginase deficiency.

　　In the second paper published in "PNAS", Lipshutz and Moderna of Cambridge, Mass. developed a nanoparticle that can deliver the RNA code of the arginase protein to the liver. The mice without any functional ARG1 quickly developed symptoms of arginase deficiency and all died within 22 days; however, the mice treated with the nanoparticles were still alive after 11 weeks without any symptoms of disease. However, the drug must be taken every three days to continuously replenish the level of arginase in the liver.

　　"As long as we continue to give treatment, these animals will have completely normal metabolites in their blood," Lipshutz said.

　　He said that this new study confirms that liver-based treatment can effectively treat systemic arginase deficiency. Further research is needed to determine whether nanoparticle-based arginase therapy is safe and effective.