Researchers have used an antisense oligonucleotide (ASO) to restore communication between neurons in lab models of motor neuron disease (MND), according to a study by Keuss et al.
Teams from University College London (UCL), King’s College London, and the Francis Crick Institute identified a single genetic error that breaks signaling between neurons. They used an antisense oligonucleotide (ASO) to correct this error. This method restored functional protein production and neuronal communication in human cells.
MND and amyotrophic lateral sclerosis (ALS) are fatal diseases. This leads to muscle weakness and the loss of ability to speak, swallow, or breathe.
Treatments exist for rare genetic forms of ALS. These forms affect less than 3 percent of patients. No disease-modifying treatment exists for the remaining 97 percent of cases.
The research found that the protein TDP-43 affects another protein called UNC13A. When TDP-43 fails to function correctly, it disrupts UNC13A production. UNC13A is essential for neurons to send signals to one another.
Common genetic variants in UNC13A are already recognized as some of the strongest risk factors for MND.
“Our previous work told us UNC13A is important in ALS progression, but we still did not know in which way and to what extent it plays a role,” said Professor Pietro Fratta, Professor of Cellular and Molecular Neuroscience at UCL and Group Leader at the Francis Crick Institute.
“We have now learned it's the main driver of synaptic release deficits upon TDP-43 dysfunction, and have developed very effective antisense oligonucleotides to rescue this deficit. Excitingly these drugs have already entered clinical trials.”
Researchers used live imaging techniques to monitor how neurons communicate under a microscope. Dr Rachel Jackson performed this research while a Research Associate at King’s College London.
“I used a live imaging technique that allowed me to see neurons signalling to each other under the microscope,” said Dr Jackson. “Using this method, I saw that neurons with a change that mimics MND communicated less than neurons without the change.”
The team designed the ASO to target the error in how UNC13A is produced. This approach restored the production of functional UNC13A protein. The neurons could communicate again.
“It has been a truly collaborative effort across multiple institutes to work out what actually happens to neurons when TDP-43 fails,” said Professor Juan Burrone, Professor of Developmental Neurophysiology at King’s College London. “That we were able to restore signalling between neurons from rescuing a single genetic error gives us a promising molecular target for treatment of this devastating disease.”
Another ASO targeting UNC13A dysfunction through a similar mechanism is in human clinical trials. These trials are in the UK, Europe, and China.