A single genetic error that breaks communication between brain cells can be corrected in lab models, offering therapeutic potential for 97% of people with motor neuron disease who currently lack a disease-modifying treatment.
TDP-43 Proofreading Failure Causes Motor Neuron Degeneration
Amyotrophic lateral sclerosis and motor neuron disease are fatal conditions that cause progressive muscle weakness through the degeneration of motor neurons in the spinal cord and brain. Patients gradually lose the capacity to move, speak, swallow, and breathe. While approved and experimental treatments exist for rare genetic forms representing under 3% of cases, the remaining 97% share a common defect: a proofreading protein called TDP-43 stops working properly.
Without functioning TDP-43, neurons fail to process genetic material correctly, which generates faulty proteins. Recreating this breakdown in lab models showed that the loss of this proofreading mechanism introduces errors in the production of another key protein, UNC13A.
Common genetic variants in UNC13A already rank among the strongest known risk factors for the disease, and researchers found that a single error in how it is produced drastically reduces neuron signaling.
Antisense Oligonucleotide Therapy Restores Neuron Signaling
Investigators designed a specialized drug class called an antisense oligonucleotide to target this specific error. Applying the treatment rescued the production of functional UNC13A protein, which allowed the affected neurons to communicate with each other again under the microscope.
“I used a live imaging technique that allowed me to see neurons signalling to each other under the microscope,” said Dr Rachel Jackson, one of the first authors on the paper who carried out the research while she was a Research Associate at King’s College London. “Using this method, I saw that neurons with a change that mimics MND communicated less than neurons without the change.”
Another antisense oligonucleotide targeting UNC13A dysfunction through a similar mechanism has already entered human clinical trials in the UK, Europe, and China. Last month, the first UK participant was dosed with TRCN-1023 in Trace Neuroscience’s Phase 1/2 FUNCTION ALS clinical trial at University College London Hospitals, with University College London serving as a participating trial site.
Collaborative Research Findings Published in Nature
The study, published in Nature, was co-authored by researchers across King’s College London, University College London, the Francis Crick Institute, Leibniz-FMP, and Trace Neuroscience.
It has been a truly collaborative effort across multiple institutes to work out what actually happens to neurons when TDP-43 fails. 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.
Professor Pietro Fratta, Professor of Cellular and Molecular Neuroscience at UCL and Group Leader at the Francis Crick Institute
Researchers expressed astonishment that intervening at a single genetic event out of hundreds of disrupted pathways was sufficient to restore conversation between neurons.
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. 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.
Professor Pietro Fratta, Professor of Cellular and Molecular Neuroscience at University College London and Group Leader at the Francis Crick Institute
