A novel potential treatment approach for motor neuron disease (MND), similar to the approach being pursued with an investigational drug that recently entered human clinical trials, has been shown to restore broken communication between neurons in lab models of the disease. This could have beneficial therapeutic implications for 97% of people with MND, for whom there is currently no significant disease-modifying treatment.
Findings from a new study published in Nature, co-authored by researchers from King's College London, University College London (UCL) and the Francis Crick Institute, along with Leibniz-FMP and Trace Neuroscience, pinpointed a single error in a key gene involved in MND that causes communication between neurons to break down, and used a drug to restore it in human neurons in the lab.
MND/ALS is a devastating and ultimately fatal disease that causes progressive muscle weakness due to the degeneration of motor neurons in the brain and spinal cord. As the disease advances, patients gradually lose the ability to move, speak, swallow and breathe. It is estimated to affect 1 in 300 people in their lifetime and there is no cure.
Currently, there are approved and experimental treatments for two rare genetic forms of ALS, which account for under 3% of cases. There is no significant disease-modifying treatment available for the remaining 97%. All of these cases share one feature: a key protein called TDP-43 stops doing its job correctly.
Normally, this protein is a proofreader for genetic material. Without this proofreading protein, neurons cannot process genetic material correctly, resulting in faulty proteins that are unable to carry out their normal roles.
By recreating in the lab what happens in human neurons when TDP-43 fails, researchers were able to see the knock-on effects of losing this proofreading protein on how neurons function. They found that without proper proofreading, there were errors in production of another key protein called UNC13A that normally lets neurons send signals to each other. Common genetic variants in UNC13A are already among the strongest known risk factors for MND.
The study found that a single error in how UNC13A is produced drastically reduced neuron communication. The researchers designed a type of drug, called an antisense oligonucleotide (ASO) to specifically target this error and were able to restore production of functional UNC13A protein, letting the neurons communicate again.
Another ASO that targets UNC13A dysfunction through a similar mechanism is already in clinical development in humans in the UK, Europe and China. Last month, the first UK participants were dosed with TRCN-1023 in Trace Neuroscience's Phase 1/2 FUNCTION ALS clinical trial. UCL is a participating trial site.
Regarding the new Nature findings, Professor Juan Burrone, Professor of Developmental Neurophysiology, Institute of Psychiatry, Psychology & Neuroscience at King's College London said:
"We were surprised to see that restoring just one genetic event, out of the hundreds disrupted, was enough to allow neurons to talk to each other again.
"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 said:
"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."
