Gene editing reduced toxic protein fragments and Huntington’s symptoms in mice, suggesting a possible new approach to treatment.
Unlike other gene-based treatments that aim to switch off the gene, the experimental method changes how cells read it.
The tool alters a specific point in the huntingtin gene so the cell skips a small section prone to producing toxic fragments while preserving enough protein for its normal functions.
Researchers at the University of Illinois Urbana-Champaign developed the base-editing tool and tested it in mice.
The work was led by Pablo Perez-Pinera and Thomas Gaj, professors of bioengineering.
Perez-Pinera said: “Our results suggest a new way of thinking about treating Huntington’s disease: Instead of inactivating the protein completely or targeting collateral pathways, we introduce a very small edit in the gene that changes how the protein is processed by the cells.
“For Huntington’s disease, this is an exciting development because there is no cure and having multiple possible treatments in the pipeline provides a reason for hope.”
Huntington’s disease is an inherited condition that causes a gradual loss of movement control and declining thinking abilities.
It is caused by a mutation in the HTT gene, which makes the huntingtin protein more likely to be cut into toxic fragments that gradually kill brain cells.
Symptoms usually appear in middle age, meaning people may not know they have the condition until they have already passed it to their children.
Gaj said: “Our base editors were developed to target the region of HTT that, when cleaved, can initiate the chain of events that leads to the toxic fragments.
“The result is that instead of turning the protein off completely, we alter how the gene is read so that the most damaging protein fragments are not produced.”
The team screened more than 140 base editors, a form of gene editing that chemically changes one DNA building block into another without cutting both strands of DNA.
Researchers identified the editors that were most effective and caused the fewest unintended effects before injecting them into the brains of mice with mutated HTT genes.
Mice given the treatment had lower levels of toxic protein fragments, fewer symptoms and less brain degeneration than untreated mice.
Gaj said: “This approach not only shows that base editors have the potential to be used for Huntington’s disease, it also opens the door to a new kind of potential treatment for other genetic conditions.
“This study helps to show that treating genetic diseases can be done without inactivating a gene or directly correcting a mutation
“. Sometimes, it is possible to implement modifications to change how proteins function and that could be sufficient to protect the body from further damage.”
The researchers are now refining how the base editors are delivered to the brain, with the aim of making the process less invasive and avoiding the use of viruses to transport them.
Graduate student Kyrollos Shenouda said: “We’re also interested in adapting this approach to target other regions of the HTT gene to decrease other toxic aspects of the protein.”
