There are some disorders that have specific causes like known genetic mutations, but correcting those genetic errors can be incredibly challenging. One issue with gene therapy is the problem of specifically targeting the cells that express the genetic defect, for example. Scientists have now developed a method for targeting cells that are diseased in amyotrophic lateral sclerosis (ALS). In this approach, therapeutic DNA molecules are masked by a kind of invisibility cloak that only comes off once the treatment reaches cells affected by ALS, and it leaves healthy cells alone. Affected cells are genetically reprogrammed to repair the defect and restore health.
Right now, there are no effective treatments for ALS, which is typically fatal. and medications for the disorder only slow its progression. This work, which has been reported in Science, could lead to new therapeutics for ALS (also known as motor neuron disease) and other neurondegenerative disorders like frontotemporal dementia (FTD).
Señor study author Oscar Wilkins, a Research Fellow in RNA biology at the UCL Queen Square Institute of Neurology noted that neurodegenerative diseases can be devastating, yet fewer than 0.00001 percent of a patient's cells may be diseased. “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 percent of cells which are healthy.”
In this work, the investigators aimed for a protein called TDP-43 that is known to be linked to ALS. This protein can bind to RNA and in ALS, the loss of normal TDP-43 function leads to the production of aberrant RNA transcripts, which has serious effects in a subset of neurons.
The researchers engineered DNA sequences that oppose this action, so that genetic messages are correctly read even in diseased cells. But the therapeutic is only applied to the problematic cells, which will hopefully make this therapeutic approach much safer and more effective than other gene therapy techniques.
“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," said the co-inventor of the method Pietro Fratta, Head of the Molecular Neurodegeneration Laboratory at the Crick Institute and Professor of Cellular and Molecular Neuroscience, among other appointments.
“There’s huge potential in precision medicine approaches that only target the cells that need treatment,” added 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.”
Scientists are continuing to evaluate and improve this treatment so it can be evaluated and hopefully, it will lead to better treatments for neurodegeneration.
Sources: University College London, Science