Researchers led by Prof Adrian Isaacs (UK DRI Group Leader at UCL) have developed a way to monitor the success of therapies targeting the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The test has been recently utilised in an early-stage clinical trial to evaluate a new treatment for the diseases.
Biomarkers, short for ‘biological markers’, are a measure – or a flag – of a biological state, helping us identify and monitor healthy biological processes or, crucially, harmful changes occurring in disease.
Prof Henrik Zetterberg, UK DRI Group Leader at UCL, and a collaborator on the study, said:
“In neurodegenerative diseases, biomarkers are particularly important. The diseases are complicated and clinical symptoms appear when neuronal networks break down, which takes time. Direct markers of the molecular processes that cause the disease may change rapidly in response to disease-modifying therapies and may predict rather than reflect clinical onset and disease progression.”
In this recent study, published in the Journal of Neurology, Neurosurgery and Psychiatry, the team set out to develop a biomarker test for the presence of an aberrant protein generated by a faulty copy of the C9orf72 (C9) gene.
In people with FTD and ALS the C9 gene can be mutated or faulty. A large section of DNA is repeated, leading to the production of a dysfunctional protein. This mutation is responsible for approximately 25% of familial FTD cases and 40% of familial ALS cases, causing debilitating symptoms such as progressive cognitive decline in FTD and deterioration of muscle control in ALS.
In efforts to treat FTD and ALS, researchers have developed methods to interfere with the faulty C9 gene and stop the production of these abnormal proteins. One therapeutic approach involves delivering a single strand of DNA, known as an ‘antisense oligonucleotide’, into targeted cells. This oligonucleotide specifically binds messenger RNA (mRNA), which is crucial for translating DNA code into new proteins, blocking this process and reducing the amount of abnormal protein produced.
Studies using this technique are now underway (including at UCL) and represent the first time such patients have been able to enter into a trial that could potentially treat such a devastating illness. However, a significant challenge is knowing whether the antisense oligonucleotide therapy has succeeded in disrupting the generation of the faulty protein.
