Neurodegenerative diseases are triggered by protein aggregation in the CNS, but developing therapies has been challenging. Since key disease mechanisms change during disease progression, halting further neuron loss has not been achieved and may not even improve the symptoms and survival. Causal therapy is most realistic for monogenic disease variants. About 10% of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases are caused by repeat expansion in the C9orf72 gene. We have shown that the expanded repeat is translated into multiple aggregating dipeptide repeat (DPR) proteins. Poly-GA, the most abundant DPR species, is a key driver of downstream pathology. We had previously shown that a poly-GA vaccine reduces aggregates and largely prevents motor deficits in our mouse model (Zhou et al., EMBO Mol Med 2020). A patent application is pending (WO2020221937A1). In DPR-VAX, extensive discussions with potential manufacturers of our vaccine and regulatory consultants shaped the roadmap towards commercialization of our invention and identified key bottlenecks. Therefore, we started optimizing the peptide/carrier-conjugate to improve the manufacturing properties to facilitate regulatory approval. Testing solubility, manufacturability and antigenicity of over 20 different formulations revealed a new lead candidate with greatly improved biophysical properties. In addition, we made progress towards a poly-GA biomarker assay in mice, which upon further development, may facilitate clinical trials. During the project, we pitched our approach to several biotech companies, large pharma partners and potential investors. Eventually, we teamed up with Intravacc, a Dutch vaccine company, for co-developing our project with funding from a EIC Transition grant. This will allow us to further optimize the antigen, setup manufacturing and conduct toxicology studies. Efficacy studies of the drug product will complete the data-package for clinical trial application to finally test our approach in C9orf72 ALS and FTD patients.
