Pre-clinical evaluation of lonafarnib as a treatment for Parkinson's disease
Cure Parkinson's
Northwestern University
Genetic and pathological evidence strongly suggests that alpha-synuclein (a-syn) accumulation and lysosomal dysfunction are major contributors to Parkinson’s disease pathogenesis. Dr Mazzulli's group recently discovered a novel mechanism for a-syn-induced toxicity and lysosomal dysfunction using patient-derived iPSC-midbrain neurons. They found that a-syn accumulation impedes the trafficking of lysosomal hydrolases by disrupting a SNARE protein called ykt6. Ykt6 preferentially enhances the trafficking of lysosomal proteins, including beta-glucocerebrosidase (GCase) between the endoplasmic reticulum (ER) and the Golgi. However when a-syn accumulates, it aberrantly interacts with ykt6 and impedes its ability to traffic hydrolases. This results in lysosomal dysfunction, further perpetuating and augmenting a-syn accumulation. The team have discovered a novel way to rescue lysosomes by activating ykt6 through small molecule farnesyltransferase inhibitors (FTIs). Ykt6 is a unique SNARE in that it is inhibited by farnesylation, which keeps it in a locked, inactive conformation. Non-farnesylated ykt6 promotes an open, active conformation allowing it to bind to its cognate binding partners syntaxin 5 and bet1 at the cis-Golgi and promote trafficking. Blocking ykt6 farnesylation, either genetically or pharmacologically, was found to dramatically rescue lysosomal hydrolase trafficking and function including GCase activity. Using a previously established farnesyltransferase inhibitor (FTI) called LNK-754, 1-to-10 nanomolar concentrations could activate ykt6 and enhance lysosomal GCase by 2 fold in patient cultures and mouse brain, which was sufficient to reduce pathological a-syn. Dr Mazzulli's group's new, unpublished data shows that ykt6 is present in red blood cells, and that FTI treatment actives ykt6 in blood and brain to a similar extent. This provides a unique opportunity to track active ykt6 in RBCs as a marker of mechanistic target engagement for future clinical trials. While LNK-754 is a promising FTI, it requires extensive long-term safety assessment prior to treating PD patients. However, another FTI called Lonafarnib, has already passed long-term clinical safety tests and is FDA approved for the treatment of Progeria. To determine if FTIs hold promise as a disease altering PD therapy, we will determine if Lonafarnib can activate ykt6 and lysosomes in patient cultures and brains of a-syn transgenic mice. They will measure RBC ykt6 from lonafarnib-treated mice, to assess its potential as a biomarker for future clinical trials.  At the end of the funding period, the project aims to determin if Lonafarnib can activate the ykt6-lysosomal pathway and reduce a-syn pathology in the brain, after oral administration. Since the mechanism for how FTIs enhance lysosomal function was uncovered here, they are uniquely positioned to assess the utility of RBC ykt6 as a blood biomarker to track mechanistic target engagement. If successful, they hope to translate these findings into PD patients as a novel disease modifying therapy within 2 years.
2.1 Biological and endogenous factors