Complex neurodegenerative disorders, such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis, are devastating for patients and their loved ones, and pose an increasing threat to a rapidly aging society. Unfortunately, treatment options for these diseases are limited and available drugs may slow disease but they do not cure or reverse its progression. One reason it is a challenge to develop treatments for degenerative disease is because— unlike with infectious diseases where there is a clear causative agent to point to — it is hard to know what differences between healthy people and patients cause disease and which are mere consequences.

An extensive literature connects specific viral infections with specific subsets of neurodegeneration in which specific protein aggregates are associated. For example, prior serious influenza infections are associated with a Parksinson’s Disease pathology that includes presence of alpha-Synuclean aggregates, herpes infections are associated with an Alzheimer’s Disease characterized by ab42 and hyperphosphorylated tau aggregates, and endogenous retroviral activation has been associated with Amyotrophic Lateral Sclerosis (ALS) in which TDP-43 aggregates are pathognomic.

We hypothesized that the protein aggregates linked to neurodegeneration may be a variant of the dysfunctions in protein assembly our compounds modulate. If there is overlap in the assembly pathways exploited by viruses and the pathways responsible for degeneration, we could use “viruses as truffle hounds” and Prosetta compounds would show activity against non-viral neurodegenerative disease.

By applying Prosetta’s collection of assembly-modulating compounds towards prevention or reversal of aggregation in neurodegenerative diseases, we have identified compounds active against Parkinson’s, Alzheimer’s, and ALS. Prosetta’s approach to treating neurodegenerative diseases has serious potential to cure, rather than slow, serious neurological conditions by addressing the underlying issue.

In the ALS Program, Prosetta has identified three separate classes of drugs which diminish mislocalization and aggregation of TDP-43 in fibroblast cell lines derived from both familial and sporadic ALS patients.