First in class disease-modifying agents for Parkinson’s Disease

Recent advances in the understanding of Parkinson’s disease (PD) have identified a-synuclein (asyn) as a key player in the pathology and progression of this neurodegenerative disease. Asyn aggregate is the major component of Lewy bodies, a pathological hallmark of PD. Mutations causing overexpression of the native state (wild-type) asyn, including genomic amplifications and promoter polymorphisms, have been linked to both the early onset and the severe forms of PD. Furthermore, a recent study showed that asyn mRNA is elevated 4-fold in sporadic PD patients relative to normal controls. It is now well accepted that asyn-mediated cytotoxicity is mechanistically relevant to the neurodegenerative process characteristic of PD.

Expression of human asyn in yeast recapitulates the neurotoxic phenotype, with copy-number dependent toxicity, asyn accumulation in inclusions, and proteasome impairment. Drugs able to rescue asyn toxicity in yeast are valuable lead compounds for the development of drugs for PD by protecting neurons from asyn protofibril induced toxicity. Using asyn-expressing yeast strains, FoldRx has screened several compound libraries and identified multiple chemical series that strongly rescue asyn-induced toxicity in yeast. These lead series also inhibit asyn-induced toxicity in human cell lines expressing asyn.

FoldRx has implemented an animal model of Parkinson-like neurodegeneration induced by unilateral targeted overexpression of asyn in the nigrostriatal system of rats. In this model, a time-dependent decline in striatal dopamine and nigral dopaminergic neurons is observed after nigral AAV delivery of a-synuclein. Lead compounds have shown an excellent dose-dependent, statistically significant neuroprotective effect in this model.

Further characterization and optimization around these compounds are ongoing at FoldRx and we expect to identify first-in-class drug candidates with disease-modifying properties and the unique potential to slow or stop Parkinson’s disease progression from this prototype.