ANTISENSE RNA-INDUCED EXON-SKIPPING FOR THE GENE THERAPY OF FRONTOTEMPORAL DEMENTIA AND PARKINSONISM ASSOCIATED WITH CHROMOSOME 17 (FTDP-17)

With a rapidly ageing population in many developed countries, the study of neurodegenerative illness and dementia is becoming increasingly important. One group of neurodegenerative diseases, collectively referred to as tauopathies, is characterized by abnormal tau protein filaments within certain regions of the brain. These include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD) and Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17). FTDP-17 is a rare genetic disease, clinically characterized by behavioural, cognitive, and motor disturbance, with no cure available. Tau is a protein constitutively and abundantly expressed in the nervous system, which has a function in neurogenesis, axonal maintenance, and axonal transport. The cause of about half the cases of FTDP-17 is the aberrant inclusion of exon 10 in the tau mRNA, which in turn causes the accumulation of tau protein in neurons. This research project intends to advance scientific research towards a cure for FTDP-17, by exploring the feasibility of an antisense RNA-based gene therapy approach for the correction of tau mRNA in FTDP-17. An animal model of FTDP-17 was just recently generated and will be used to test the therapeutic efficacy of the viral vector administration to the brain, by evaluating improvement in the pathological hallmarks and behaviour. The development of a general strategy to modulate specific splicing events would have broad implications, since about 15% of genetic diseases are due to pre-mRNA splicing defects.