New advance in UNC13A research: What it means for people living with MND

A new research study published in Nature here has added to growing evidence that UNC13A could be a potential target for future MND treatments.

What we already know about UNC13A

Several years ago, research led by Professor Pietro Fratta at University College London (UCL) and Professor Aaron Gitler at Standford University independently showed that disruption of a protein called TDP-43, found in around 97% of people with MND, affects the normal function of UNC13A, a gene involved in communication between nerve cells.

This finding identified UNC13A as a potential target for MND treatments. Funding provided by us, the MND Association and LifeArc then supported the early research that led to the development of an antisense oligonucleotide (ASO) drug that targets UNC13A, called TRCN-1023.

TRCN-1023 is currently in a Phase 1/2 trial to evaluate the safety and tolerability of TRCN-1023 in adults living with ALS, the most common form of MND. The trial is currently recruiting patients in the UK at two sites, Sheffield and UCL. However, this is an early-stage study so the numbers of patients that will be recruited are very small. The trial is recruiting at four other sites globally, with a total of only around 30 patients being recruited.

What does the new study tell us?

This new study, led by Professor Pietro Fratta, involving researchers at King's College London, UCL and the Francis Crick Institute, showed for the first time that loss of TDP-43 function leads to a dramatic loss of communication between nerve cells, and that UNC13A is a major driver of this. They then showed that correcting UNC13A-related changes restored communication between nerve cells in laboratory models. The findings strengthen the scientific rationale for developing treatments that target UNC13A.

What does this new study mean for the TRCN-1023 trial and other potential treatments that target UNC13A?

This study was led by the same group that have partnered with Trace Neuroscience to develop TRCN-1023. However, the ASOs used in this study are slightly different to TRCN-1023.

The results do not show that an effective treatment is yet available for people living with MND. Further research and clinical trials will be needed to determine whether this approach can translate into meaningful benefit.

The findings support ongoing international efforts to develop UNC13A-targeted therapies, including the programmes being advanced by Trace Neuroscience. While studies such as this increase confidence in the underlying science, many treatments that show promise in the laboratory do not ultimately succeed in clinical trials.

UNC13A is one of a number of promising targets being pursued by researchers worldwide, and we look forward to seeing how this and other approaches progress through clinical trials in the years ahead.

How are we involved?

The publication represents an important milestone in a programme of research that we have helped support. In 2022, alongside the MND Association and LifeArc, we funded research led by Professor Pietro Fratta's team to investigate how disruption of TDP-43 affects UNC13A and whether these changes could be corrected using antisense oligonucleotides (ASOs). That work helped build the scientific understanding, models and experimental tools that have contributed to the findings now published in Nature, as well as supporting the early research that led to the development of TRCN-1023.

Jessica Lee, our Director of Research, said: "This study provides important evidence supporting a promising treatment approach for MND that is currently being explored. While it does not tell us whether an UNC13A-targeted therapy will ultimately be successful in people, it strengthens confidence that researchers are focusing on a biological pathway that is highly relevant to the majority of people living with MND.

"We are proud to have supported this area of research alongside LifeArc and the MND Association and look forward to seeing the results of ongoing clinical studies."

To learn more about Professor Fratta's research that we fund, see here.