Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry progressively degenerates, affecting mostly motor neurons in the brain (upper motor neurons) and spinal cord (lower motor neurons). There are no effective cures, although three drugs, riluzole, edaravone, and AMX0035, have been FDA approved, but with limited improvement in patients. Death generally occurs within 2-5 years from disease diagnosis. About 10% of patients have familial ALS (hereditary; fALS) and the remainder have sporadic ALS (sALS) with no known genetic cause. Greater than 150 gene mutations have been identified in fALS.
Protein aggregation is a hallmark of all neurodegenerative diseases. We carried out a phenotypic high-throughput screen to identify compounds that inhibited protein aggregation caused by mutation of the sod1 gene, which leads to ALS in about 2% of ALS patients. Screen hits were filtered computationally, and three hit series were optimized.
In this lecture, I will discuss the development of two of these lead series, leading to two advanced compounds, for which one we have identified its target and the other, called NU-9, has been subjected to numerous preclinical studies related to efficacy, pharmacokinetics, and toxicology, and IND approved by FDA. The standard mouse model is used to show life extension by compound treatment; however, there is no translation from success in this mouse model and in patients. Therefore, we have taken a different approach, one that interogates the effectiveness of compounds to improve the health of the upper motor neurons in mouse models, which we anticipate should translate to patient efficacy. Preclinical results with NU-9 toward the treatment of ALS and Alzheimer’s disease will be presented.