Donepezil Shows Promise as Therapeutic Potential for KCNQ2- and KCNQ3-Related Autism

Researchers at the Edith Wolfson Medical Center have conducted a study investigating the therapeutic potential of donepezil, a cholinergic drug used in Alzheimer's treatment, on patients with gain-of-function (GoF) variants of the KCNQ2 and KCNQ3 genes. These variants are associated with developmental encephalopathy and autism. The study suggests that donepezil may suppress M currents in vitro and improve cognitive symptoms in patients with GoF variants.

Key Takeaways:

• The study found that donepezil significantly inhibited the M-current in vitro, with an IC50 of 0.4 mM, and reduced the M-current density of excitatory neurons by 67% at 1 mM.
• Donepezil increased the spontaneous firing frequency of hippocampal neurons by 2.6-fold at 1 mM.
• The study enrolled four children with autism, aged 2.5-8 years, with GoF variants of the KCNQ2 and KCNQ3 genes, and treated them with donepezil for 12 months.
• The results showed a significant improvement in cognitive symptoms, with a decrease in CARS-2 scores by 3.8 ± 4.9 points (p < 0.05) in two patients with KCNQ3 variants.
• The global clinical change was also clinically significant in these patients, with a CGI-c score of 1.

Statistics:

• The IC50 of donepezil for inhibiting the M-current was 0.4 mM.
• Donepezil reduced the M-current density of excitatory neurons by 67% at 1 mM.
• The spontaneous firing frequency of hippocampal neurons increased by 2.6-fold at 1 mM.
• CARS-2 scores decreased by 3.8 ± 4.9 points (p < 0.05) in two patients with KCNQ3 variants.
• The CDI increased by 65% (p < 0.05) in the treated patients.

Sources:

• Frontiers in Cellular Neuroscience, 2024,18. (Frontiers in Cellular Neuroscience - http://www.frontiersin.org/cellular_neuroscience)
• Donepezil as a new therapeutic potential in KCNQ2- and KCNQ3-related autism. DOI: 10.3389/fncel.2024.1380442.