RNA-targeted therapy shows promise for childhood dementia

Scientists at The University of Sydney have shown that a new RNA-targeted therapy can halt the progression of a specific type of childhood dementia in mice, and thus holds the potential to reverse some of the detrimental effects of this rare disease.

Childhood dementia claims more young lives each year in Australia than childhood cancer, affecting one in 2900 births. Aicardi-Goutières syndrome (AGS) is among the more than 100 rare neurodegenerative genetic disorders identified as causing childhood dementia, with many patients developing severe neurological issues and lifelong physical impairments within the first two years of life. With no cure currently available, existing treatments for AGS focus on symptom management.

The underlying cause of AGS is interferon, the body’s own defence against infection, which is excessively produced in the brain, leading to neuroinflammation and neurodegeneration. The new approach targets the interferon alpha receptor using antisense oligonucleotides, which are designed to seek out, bind to and degrade messenger RNA (mRNA) in a highly specific manner, reducing the amount of disease-causing protein. Antisense oligonucleotide therapies have shown potential in treating various neurological diseases, including SOD1-dependent ALS.

In a study published in The Journal of Clinical Investigation, the researchers found that when mice received the treatment directly into their central nervous system, it significantly reduced the interferon response in the brain, reducing both neuroinflammation and neuronal damage and restoring the integrity of the blood–brain barrier. Dr Barney Viengkhou, lead author of the paper, said, “The fact that we observed the treatment’s effectiveness in halting and even reversing some neuropathological features in older mice with more advanced disease is particularly exciting.”

This study was conducted in partnership with Ionis Pharmaceuticals, which developed the treatment, and Biogen, with further research underway. With animal studies now complete, the findings look set to inform human trials in the future.

“This groundbreaking research has the potential to change the lives of children with dementia caused by AGS across the world, and the learnings will spill over to therapy development for many other types of childhood dementia as well,” said Dr Kris Elvidge, Head of Research at the Childhood Dementia Initiative.

“We sadly have few options for children who are deteriorating and losing developmental skills, [so] this targeted ASO therapy approach provides hope for these families in the future,” added paediatric neurologist Professor Russell Dale, who cares for children with AGS at The Children’s Hospital at Westmead.

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