Novel therapeutic strategies to target RAN translation of pathological C9ORF72 repeat transcripts and associated neurodegeneration

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The basic units of life, cells, convert food and oxygen into energy to produce proteins, constituents indispensable to the building and functioning of cells. The diverse roles of proteins and their levels account for health or diseases. The blueprint providing the information for making up thousands of proteins is housed under the form of genes in the cell centre (nucleus). Small messenger molecules copied from the blueprint are transported out of the nucleus where they serve as individual instruction manuals for manufacturing each protein within specialized factories called ribosomes.Extensions of a short repeated motif in a gene called C9ORF72 are the most common changes causing two incurable and lethal neurodegenerative diseases in adults, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Approximately 10,000 individuals suffer from ALS and FTD at any time in the United Kingdom. Progressive injury and death of nerve cells in the front and side parts of the brain provokes characteristic changes in the personality and behaviour of patients suffering from FTD. On the other hand, the progressive paralysis observed in ALS is due to the death of motor nerves that control movements by transmitting signals from the brain and spinal cord to the muscles. A proportion of patients with ALS disease also develop FTD, and conversely, many patients with FTD will eventually develop ALS. Whilst no treatment is available for FTD, the current standard of care for ALS patients, riluzole, only marginally extends survival. The identification of therapeutic targets to cure or slow down the progression of these neurodegenerative diseases is therefore of paramount importance. A prominent mechanism by which large extensions of the C9ORF72 repeated elements are thought to cause death of nerve cells involves the production of aberrant C9ORF72 messengers guiding the building of toxic proteins that provoke multiple cellular damage mechanisms. Although riluzole might moderately increase the survival of patients with C9ORF72 related ALS, it does not provide a cure and does not prevent the production of abnormal biomolecules.We recently identified some of the specialized molecules serving in the factories where the C9ORF72-repeated proteins are produced. We also found that reducing their number can halt the manufacture of the toxic proteins and stops cells from dying. These findings were made in a human kidney cell model routinely used in laboratories around the world. We now want to test whether this groundbreaking discovery holds true in disease-relevant models of C9ORF72-ALS/FTD using a fruit fly animal model and human nerve cells made with cutting-edge scientific technologies from the skin of C9ORF72-ALS/FTD patients. In this project, we also want to study the global effects that reducing the levels of the specialized molecules may have on the production of the other normal proteins and test whether they are directly involved in the manufacture of the abnormal repeated proteins.In summary, this research will test a novel concept for a potential treatment of patients suffering with C9ORF72-linked ALS/FTD in the near future. This novel strategy could also potentially be useful for other diseases including Fragile X-associated Tremor/Ataxia syndrome, Alzheimer's disease and some forms of cancer. Several collaborating communities of researchers including scientists and clinicians will be involved with the research. Furthermore, this state-of-the-art science will lead to inspirational communications, presentations and publications that will benefit the academic community, the general public, local schools, the tertiary sector and potentially in the longer term, healthcare professionals and the pharmaceutical industry.