Every day in Australia, two people are diagnosed, and two people die from motor neuron disease (MND), a devastating condition that destroys motor neurons in the brain and spinal cord responsible for controlling every voluntary movement in the body. MND patients gradually lose the ability to walk, speak, swallow, and eventually breathe. Sadly, there are no effective treatment options for the majority of cases, and most people diagnosed with MND survive for only two to five years. We have worked with consumers from a family that has lost six members to an inherited form of MND to guide our research to address this critical need for safe and effective new medicines.
Antisense oligonucleotide (AO) drugs are single-stranded synthetic RNA molecules designed to modulate the expression of target genes and offer unprecedented precision in therapeutics to treat some of the worst diseases afflicting humanity. Up to 30% of inherited MND and 25% of inherited frontotemporal dementia (FTD) are caused by the expansion of a G4C2 repeat in intron 1 of the C9ORF72 gene, leading to loss of function of the C9ORF72 protein, and production of damaging G4C2-containing RNA and dipeptide repeat proteins that cause death of motor neurons. We have designed a novel splice-modulating AO, called C9-PMO, that has shown a >90% reduction in G4C2 RNA foci in C9ORF72-MND patient-derived iPSC-motor neurons and spinal cord organoids. We have also performed comprehensive pharmacokinetic studies in rodents to evaluate safety and biodistribution of the C9-PMO. We administered the C9-PMO into the cerebrospinal fluid in rodents (mice and rats) via an intracisternal magna injection (300 µg to 20 mg; single and multidose cohorts). Using customised in situ hybridisation and bioanalytical assays, we showed broad distribution of the C9-PMO across the brain, and of particular importance in MND, uptake in layer 5 neurons of the motor cortex, and in alpha-motor neurons in the ventral horn of the spinal cord. Significantly, there were no adverse events or clinical signs in the rodents following injections of the C9-PMO at all doses tested. The maximum dose of C9-PMO tested (20 mg in rats) was the highest feasible dose (maximum tolerated dose was not reached) and was well tolerated.
Preclinical evaluation in laboratory models has shown that the C9-PMO is safe and effective in reducing the hallmarks of C9ORF72-linked disease. Our next steps are to perform formal GLP-toxicology studies to enable first-in-human trials.