ALS PROGRAM
Science and Clinical Program
The Science of 3K3A-APC in Amyotrophic Lateral Sclerosis ('ALS')
In 2009, researchers in Professor Zlokovic’s lab demonstrated in mutant mice superoxide dismutase-1 (SOD1) mice that administration of APC or 3K3A-APC after disease onset slows ALS disease progression and extends survival.
In 2014, researchers at Professor Zlokovic’s lab were able to show that blood brain barrier breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BBB integrity via 3K3A-APC during an early disease phase retards the disease process.
In 2019, researchers at the University of Southern California demonstrated that Induced Motor Neurons (iMNs) from C9ORF72 and several sporadic ALS patients share two common defects – impaired autophagosome formation and aberrant accumulation of glutamate receptors. It was shown that 3K3A-APC treatment lowers C9ORF72 dipeptide-repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs; and that 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models.
A Phase 2 Trial of 3K3A-APC in ALS 2021
Professor Dominic Rowe at Macquarie University Hospital runs the largest motor neuron diseases clinic in Australia. As Principal Investigator, Professor Rowe has completed a Phase 2 clinical trial (NCT05039268) of 3K3A-APC in ALS looking at several biomarkers of disease activity. The trial was completed in August 2022 and is evaluated an escalating acute dose regimen of 3K3A-APC in patients to determine safety and tolerability. Chemical and cellular biomarkers were evaluated for efficacy in the acute phase and other long-term biomarkers were tested for feasibility in later chronic-dosing studies.