Scientists are getting closer to developing genome editing tools and applying them to a new target— the human brain. For the last two years, technological advancements and promising results in mice in treating devastating brain disorders through CRISPR-Cas9 gene editing techniques have been prevalent. Researchers hope that human trials can be started in a few years. According to Monica Coenraads, founder and chief executive of the Rett Syndrome Research Trust in Trumbull, Connecticut, the data have never looked this good.
Gene-editing therapies to treat diseases of the blood, the liver, and the eyes have already been developed by scientists. In May, researchers reported stellar success using a customized gene-editing therapy to treat a baby boy named KJ with a deadly liver disease. The biomolecular components were inserted into fatty particles that naturally heap up in the liver. For the brain, however, similar particles that can selectively target the brain have not yet been discovered. The brain is surrounded by a defensive barrier that can prevent many substances from entering.
According to Coenraads, whose organization focuses on Rett syndrome, a rare disorder that affects the brain, it becomes frustrating for families with patients with neurological disorders, as they expect a cure soon. The group of concerned physicians and families is increasingly turning to genome sequencing and genetic techniques to unravel the mystery of brain disorders.
Studies in mice in which gene-editing methods are being tested are ready to correct some mutations by rewriting small snippets of a cell’s genome. In July, researchers announced that they had repaired mutations in mice that, in humans, cause a disease called alternating hemiplegia of childhood (AHC). The condition usually starts to show symptoms when a child reaches 18 months of age. Symptoms include seizures, learning disabilities, and episodes of partial paralysis. According to David Liu, a chemical biologist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, it is a horrible disease.
Liu and his colleagues implemented prime editing, which is an offshoot of CRISPR technology, in mice with a mutation that causes AHC. The technique corrected the mutation in about half of the brain’s cortex, an area of the brain that controls learning and memory. Their seizure-like episodes became less severe, motor control and cognition improved, and their lifespans lengthened.
Liu’s laboratory is also working to correct mutations that cause two other neurological disorders: Huntington’s disease and Friedreich’s ataxia in mice and humans, in the future. And at the Shanghai Jiao Tong University School of Medicine in China, neuroscientist Zilong Qiu and his colleagues have used base editing, a form of CRISPR technology, to correct a mutation in a gene called MEF2C. In human children, this genetic disorder or mutation causes epilepsy, intellectual disability, and limited verbal ability.
The same mutations in male mice alter how the rodents behave around fellow mice. Base editing, an ultra-precise version of CRISPR genome editing, was used to correct the mutation in Mef2c, correcting single DNA letters, restoring normal social behaviour, and improving the connections between nerve cells.
Liu and Qiu are working independently on gene-editing tools and therapies to cure Rett syndrome. Mutations in the MECP2 gene mostly cause this disease. A gene-editing method is beneficial for this condition, says Coenraads: simply adding an extra, normal copy of the entire MECP2 gene, as any traditional gene therapy would, could cause cells to produce too much of the corresponding protein, which can be harmful in excess. But gene editing would merely correct the natural copy of the gene, and is less likely to cause excess production of MECP2, says Qiu.
It is still a long way to go before reaching human trials. Qiu hopes that the team will be ready to start clinical trials in five years. On the other hand, Liu believes that they can conduct experiments needed to launch studies in people with AHC. Both teams plan to use adeno-associated virus 9 (AAV9) to shuttle gene editing components into the brain. This virus can somewhat cross the blood–brain barrier and infect human brain cells.
However, AAV9 comes with its own set of risks. High doses of the virus can inflict deadly immune responses. Researchers are aiming to develop a virus that can be used in low doses. Coenraad’s organization, on the other hand, is providing funds to experiments aiming to produce virus-free methods of delivery of the biomolecules.
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