UCLA Scientists Cure Rare Genetic Disease in Mice

September 10, 2019

UCLA scientists have developed two new approaches to deliver functioning copies of the arginase gene to mice with arginase deficiency, a rare genetic disease that leads to seizures, tremors and developmental delays, and eventually, intellectual disabilities.

Arginase deficiency, which is caused by a missing or mutated version of the arginase gene, ARG1, affects about one of every 1 million babies born in the United States. Arginase is one of six proteins in the liver that play a role in breaking down and removing nitrogen from the body. Without arginase doing its job, arginine builds up in the blood and causes problems, mostly in the brain.

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

In a paper published in the journal JCI Insight, the scientists reported that mice with arginase deficiency had less than a quarter of the normal amount of myelin in their brains. Myelin is the material that insulates nerve cells and is key to communication between areas of the brain.

To test whether the lack of ARG1 was causing the loss of myelin, the research team designed a virus that could carry new copies of ARG1 DNA. When the team gave 2-day-old mice that lacked ARG1 an intravenous injection of the virus, they no longer had defects in their myelin. Levels of myelinated cells in the virus-carrying mice were close to normal.

“With just one dose of a drug, we could prevent these brain abnormalities,” said Gerald Lipshutz, a UCLA professor of surgery and the senior author of the study. “Going from almost no myelination to near normal was absolutely dramatic.”

Researchers studying other genetic diseases have investigated using viruses to deliver healthy DNA to patients. Data from those studies suggests that the treatment may lose potency over many years. And because relatively few patients being treated for genetic disorders have received such therapies, researchers still must determine if the same phenomenon occurs in humans. However, Lipshutz said a virus-based therapy to replace ARG1 does have potential to work in people.

Lipshutz and his colleagues are currently studying cells taken from people with arginase deficiency to determine whether they also have myelination defects, and they plan to explore the molecular link between high arginine levels in the brain and the loss of myelin, which could reveal other targets for drugs to treat arginase deficiency.

In a second paper, published in the Proceedings of the National Academies of Science, Lipshutz worked with Cambridge, Massachusetts-based Moderna to develop nanoparticles that carry RNA encoding the arginase protein to the liver. Mice without any functioning ARG1 quickly developed symptoms of arginase deficiency, and all died within 22 days. Mice that received the nanoparticles, however, were still alive after 11 weeks and had no signs of the disease. The drug had to be given every three days to continuously replenish levels of arginase in the liver.

“As long as we continued giving the therapy, the animals had completely normal metabolites in their blood,” Lipshutz said.

The work establishes that a liver-based treatment can effectively treat the symptoms of arginase deficiency throughout the body, he said. Further research is needed to establish whether nanoparticle-based arginase therapies are safe and effective in people.

“We’re at a time of innovation in genomics and genetics when we can bring new targeted therapies to people with inherited diseases,” said Lipshutz. “These therapies may initially benefit the relatively small number of people with rare or orphan diseases, but eventually they will become more widely used.”

Photo: Gerald Lipshutz, a UCLA professor of surgery

Author: Rare Daily Staff

Stay Connected

Sign up for updates straight to your inbox.