Recently, a joint team from Harvard University and Jackson Laboratories in the United States used lead editing technology to achieve precise correction of pathogenic gene mutations in children with alternating hemiplegia (AHC) in a mouse model. Previously, Professor Qiu Zilong's team from the Songjiang Research Institute of Shanghai Jiao Tong University School of Medicine in China confirmed that whole brain base editing technology can reverse behavioral abnormalities in MEF2C mutant mice. On August 15th, an article published on the UK official website pointed out that in the past two years, gene editing technology has continued to make breakthrough progress, and positive results have been continuously obtained in mouse experiments. The use of gene editing technology in humans to combat deadly brain diseases has begun to show signs of hope. However, experts such as Qiu Zilong also emphasized that in order for gene editing technology to truly cast its "magic" in the human brain, scientists still need to cross many technological gaps. Experiments have shown that the potential of gene editing continues to deepen, and scientists have noticed that neurological diseases such as epilepsy are closely related to genetic mutations in the brain. Now, they are trying to point the gene edited 'magic wand' at the most complex organ of humanity - the brain. On July 21st of this year, an academic journal published the important achievements of Liu Ruqian's team at Harvard University and Katherine Lutz's team at Jackson Laboratories. They used lead editing technology to achieve a mutation correction rate of 85% in AHC model mice. AHC, a rare neurological disease, usually occurs in infancy, and patients may suddenly experience paralysis lasting from minutes to days, accompanied by symptoms such as muscle tone disorders, and even fatal epilepsy. After treatment, the protein function in the mouse brain returned to normal, the frequency of epileptic seizures significantly decreased, the survival period was extended by more than twice, and the motor and cognitive abilities were also significantly improved. Coincidentally, the team led by Qiu Zilong and the team led by Cheng Tianlin from Fudan University successfully corrected the abnormal behavior of MEF2C gene mutant mice using another branch of CRISPR technology - base editing. MEF2C mutations can cause epilepsy, intellectual disabilities, and delayed language development in human children. The results showed that this gene editing technique restored MEF2C protein levels in multiple brain regions of the mouse model and reversed behavioral abnormalities in MEF2C mutant mice, opening up a new avenue for treating brain diseases caused by single base mutations. The core advantage of gene editing technology in treating neurological diseases lies in its precise repair ability, as its safety and feasibility have been preliminarily verified. ”Qiu Zilong emphasized that for children with neurodevelopmental disorders and autism caused by a large number of gene mutations, precise repair of pathogenic gene mutations in the brain is the most ideal treatment plan. This precise repair can avoid overexpression of exogenous genes and prevent gene expression in erroneous neurons, thereby avoiding potential side effects. In the study of ATP1A3 gene mutations, Liu Ruqian's team also found that although traditional gene therapy can deliver normal genes, it cannot improve the symptoms of experimental animals. And lead editing technology can directly correct pathogenic mutations, restore protein function, and demonstrate unique advantages. It is exciting that the treatment carried out by Liu Ruqian's team only requires a single brain injection to complete, and the detected off target is minimal. The safety and feasibility have been verified. In addition, they also achieved synchronous correction of 5 mutations (including 4 of the most common AHC pathogenic mutations), which not only optimized the experimental process but also demonstrated the widespread applicability of this technology. Despite frequent successes in mouse experiments, scientists are acutely aware that gene editing technology still needs to overcome key bottlenecks in order to truly benefit patients with neurological disorders. The Qiu Zilong team expects that it will take about 3-5 years to initiate human clinical trials of base editing therapy for the treatment of Rett syndrome. Unlike lipid nanoparticles used in liver disease treatment, brain therapy requires more sophisticated 'molecular couriers'. Currently, scientists are placing their hopes on adeno-associated virus 9 (AAV9). This viral vector has been approved by the US Food and Drug Administration for gene therapy targeting brain cells and has the unique ability to break through the blood-brain barrier. However, high-dose AAV9 may trigger a lethal immune response. To this end, scientists have divided into two paths: on the one hand, improving viral vectors to achieve low-dose efficient delivery, and on the other hand, actively exploring non viral delivery solutions. Monica Kunlarz, founder and CEO of the American Trust for Research on Rett Syndrome, admitted that the biggest obstacle at present may come from outside the laboratory. The biotechnology industry in the United States is facing a capital winter, with long research and development cycles and complex production processes for gene therapy, which has deterred many investors. (New Society)