Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder that causes progressive muscular paralysis, eventually leading to respiratory failure and death. It has no cure or effective treatment.
One hallmark of this disease is the presence of a mutated form of the protein TDP43. It is understood that Casein Kinase 1 (CK1) and Cell Division Cycle 7 (CDC7) play a key role in the activation of pathological TDP43, so drugs targeting this process could represent a new ALS treatment.
- To develop two families of CK1 and CDC7 inhibitors capable modulating pathological TDP-43.
Problem to Solve
ALS is a debilitating and fatal neurodegenerative disease with no cure or effective treatment. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralysed. Onset typically occurs after the age of 40 and progresses rapidly. 75% of patients die within 5 years of diagnosis.
With a prevalence of 5.2 per 100,000 and an incidence of 1.89 per 100,000 per year, there is an urgent need to find a cure for ALS, a devastating illness that places a tremendous socioeconomic burden on patients, family members, caregivers and health systems.
Two families of CK1 and CDC7 inhibitors have been identified that have the potential to modulate pathological TDP43 in ALS.
In both human cellular models and in vivo experiments, these small molecules have proven effective in decreasing pathological TDP43, while also increasing levels of unmodulated TDP43, restoring its normal physiological role, and protecting motor neurons.