Only in cells affected by amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the invisibility cloak removed, enabling the DNA to reprogram the cells and hopefully improve their health. Researchers hope that this will lead to safer treatments for more neurodegenerative diseases, including ALS and frontotemporal dementia (FTD).

ALS is a neurodegenerative disease which in many cases leads to fatal paralysis. There is no cure and current treatments only marginally slow the progression of disease, meaning new approaches to drug development are urgently needed.

“While neurodegenerative diseases have devastating effects, we can estimate that less than 0.00001% of cells in a patient’s body are actually diseased,” says Oscar Wilkins, Research Fellow in RNA biology, UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, who led the study.  “The challenge is finding a way to specifically target treatments to this minuscule fraction of diseased cells, while avoiding unnecessary treatment of the 99.99999% of cells which are healthy.”

The research team developed a new approach centred around the activity of a protein called TDP-43. In healthy cells, this protein resides near the DNA, helping the cells correctly interpret the DNA’s genetic instructions. However, in diseased cells, the TDP-43 protein gets stuck in distant parts of the cells, keeping it far from the DNA and corrupting the interpretation of genetic messages.

Through careful design and use of AI prediction tools, they created DNA sequences which behave in the opposite manner - in healthy cells, the messages from the DNA are corrupted, whereas in diseased cells, the messages can be interpreted correctly.  The researchers hope that by cloaking instructions that counteract disease, gene therapy treatments will be made safer and more effective, as they will only be activated in the small fraction of diseased cells.

Pietro Fratta, Head of the Molecular Neurodegeneration Laboratory at the Crick and Professor of Cellular and Molecular Neuroscience, UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, who co-invented the approach, said: “We hope this new technology will enable much bolder therapeutic approaches for motor neuron disease. Many potential therapies also alter important cellular processes and this may cause toxicity. Therefore, limiting their action to diseased cells, while leaving healthy cells untouched, will increase the safety of gene therapies and allow researchers to pursue many more treatment options.”
“There’s huge potential in precision medicine approaches that only target the cells that need treatment,” adds Oscar. “Whether it’s cancer, heart disease, or motor neuron disease, the key challenge is finding something unique about the diseased cells that we can use for our own purposes - in this case, we chose the TDP-43 protein, as it becomes dysfunctional in so many different neurodegenerative disorders.”
Max Chien, who worked on the project during his PhD, is hopeful that the approach can also improve research into these diseases: “As well as potentially delivering gene therapies, our approach can also be used to detect diseased cells. This could help scientists test whether their treatments perform correctly, before entering into a clinical trial.”

U.S. collaborators Claire Le Pichon and Josette Wlaschin from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, also contributed to this novel therapeutic approach.

“Gene therapy holds promise for treating neurodegenerative diseases like ALS and FTD, which are relatively common but for which there are few treatments,” says Claire. “TDP-43 controls many aspects of cellular health, and its dysfunction is a key driver of disease. Therefore, correcting TDP-43 function only in the cells that have lost it is an important step toward a safer precision medicine. Successful therapies depend on thorough preclinical studies, and we look forward to additional work to validate and build upon our findings.”

Work to further develop gene therapies for ALS using this system is being supported by the Crick Translation Fund and by the UCL Neurogenetics Therapy Programme.

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