Huntington's disease develops due to a mutation in the HTT gene and leads to the gradual death of nerve cells, impaired motor function, and decreased cognitive abilities. The huntingtin protein, which encodes the HTT gene, is cleaved into toxic fragments, which are considered one of the main causes of brain damage.
Most modern genetic approaches aim to suppress the HTT gene. However, researchers from the University of Illinois at Urbana-Champaign decided not to completely disable it and instead used base DNA editing technology, which allows for the replacement of a single nucleotide without breaking DNA strands.
Scientists altered a small region of the HTT gene. This modification prevented cellular mechanisms from reading the region that produces the most toxic protein fragments. However, the huntingtin protein itself continued to be produced and retained its important physiological functions.
To find the optimal solution, the researchers tested over 140 variants of base editors. They assessed the editing efficiency and the number of unwanted DNA changes. The most suitable editors were then injected into the brains of mice with the HTT mutation.
Following treatment, the animals significantly reduced the accumulation of toxic protein fragments. Disease symptoms and brain tissue degeneration also decreased.
"These results demonstrate that genetic diseases can be treated without complete gene inactivation or direct mutation correction. Sometimes, even small changes in protein function can be sufficient," the scientists stated. They now plan to make the delivery of the base editing system to the brain less invasive and eliminate the need for viruses for delivery.
Previously, another gene therapy significantly slowed the progression of Huntington's disease in patients in clinical trials.
