Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by systematic loss of motor neurons in spinal cord, brainstem, and motor cortex. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. We developed two lines of transgenic rat model of ALS overexpressing mutant SOD1 protein ubiquitously. The rat models have facilitated preclinical research employing various interventions such as intrathecal protein administration, cell transplantation, and gene transduction to the affected central nervous system.
Hepatocyte growth factor (HGF) is an endogenous pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. Previous study showed expression of HGF and its receptor c-Met in residual spinal motor neurons and also in reactive astrocytes in autopsy cases with both sporadic and familial ALS. In order to investigate its neuroprotective effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. Even from the onset of symptoms, continuous intrathecal infusion of hrHGF suppressed the degeneration of motor neurons and the disease progression. Intrathecal administration of exogenous hrHGF to a non-human primate model of contusive spinal cord injury also revealed a substantial clinical effect with functional recovery.
After dose-finding and safety studies in non-human primates, the clinical translation of hrHGF for ALS is currently in a novel phase I trial in Tohoku University Hospital.