Trial of Oxaloacetate in ALS

Overview This is a safety and dose finding study looking at Oxaloacetate (OAA) in patients with Amyotrophic Lateral Sclerosis (ALS). This study will aim to determine the maximal dose that a subject can tolerate. The investigators will also learn how OAA affects mitochondria in subjects with ALS. This is a 28-day study in which the investigators will attempt to enroll approximately 24 participants. There is no placebo control.

Specific Aims (Hypothesis and Objectives)

The overall goal of this proposal is to determine if reducing mitochondrial stress is a viable treatment strategy for ALS. This study will determine the maximal tolerated dose of OAA and whether OAA improves biomarkers of mitochondrial stress. ALS is a progressive fatal neurodegenerative disorder caused by loss of motor neurons in the brain and spinal cord. Despite multiple clinical trials and advances in understanding of the pathogenesis of ALS, riluzole and edaravone, the only Food and Drug Administration (FDA) approved ALS drugs, the former only extends life by a few months, and the latter possibly slows down functional decline. Hence there is a clear need for new treatments for ALS.

While the exact underlying cause of this motor neuron degeneration remains uncertain, candidate mechanisms include glutamate excitotoxicity, free radical-mediated oxidative cytotoxicity, neuroinflammation, mitochondrial dysfunction, autoimmune processes, protein aggregation, and cytoskeletal abnormalities. Mitochondrial dysfunction in particular may play a critical role in ALS neurodegeneration, an observation supported by both human and animal model studies. The characteristic pathological ALS finding of cytoplasmic inclusions (Bunina bodies) in motor neuron cell bodies may represent mitochondria-containing autophagic vacuoles. Functional studies of ALS mitochondria were also reported: calcium levels in motor neuron synaptic terminals of ALS subjects were found to be elevated despite increased numbers of local mitochondria, suggesting a defect of mitochondrial calcium sequestration; increased complex I activity was seen with familial ALS; and reduced cytochrome oxidase activity was shown in sporadic ALS patients. In mutant SOD mouse model, evidence of mitochondrial dysfunction appears before motor neuron degeneration. Similar observations have been noted in human sporadic ALS tissue. In humans with pathogenic mutations in TARDBP and C9ORF72, mitochondrial functionality is abnormal in peripheral fibroblasts. The dexpramipexole trial in ALS, while negative, is based on the mitochondrial ALS pathogenesis theory. The investigators performed an open label study of rasagiline in ALS and demonstrated target engagement of several blood mitochondrial biomarkers. KUMC completed an 80 patient randomized controlled trial of rasagiline in ALS and again measured mitochondrial biomarkers.