Study Rationale: Progranulin (PGRN) regulates cell growth, survival and changes. They are usually secreted or transported to the lysosome. Its deficiency and inflammation leads to a decline in the GCase enzyme and the reduced circulating levels are associated with higher risk to developing Parkinson’s disease (PD). AZP2006 is a small molecule with high affinity for lysosomes. AZP2006 is able to strongly bind the complex PGRN/PSAP (prosaposin) in lysosome and its interaction with PGRN/PSAP physically blocks PGRN inflammation and death.
Hypothesis: AZP2006 has been proved to stabilize PGRN in the lysosomes and to increase the central level of PGRN. We hypothesize that elevating of PGRN levels could have a beneficial effect in PD/GBA1 patients, thus that AZP2006 could protect dopaminergic neurons from α-syn accumulation and death via PGRN.
Study Design: The target engagement and the involvement of PGRN in the rescue of GBA1 phenotype with AZP2006 will be studied with SH-SY5Y cell line carrying the GBA1L444P mutation. Additionally, a PGRN KO/GBA/GBAL444P double mutant, will be generated to confirm the role of PGRN in the protective effect of AZP2006. As in-vivo POC, AZP2006 will be studied in aged small models injured by a bilateral infusion of α-syn protofibrils in the SNpc and treated with CBE in order to induce a chronic loss of function of GBA, which will enforce the lysosomal phenotype.
Impact on Diagnosis/Treatment of Parkinson’s disease: AZP2006 in Phase 2a (PSP patients) has proved to increase PGRN brain in many models of neurodegenerative diseases. Our preliminary results support the rational of AZP2006/PGRN for a PD/GBA1 development. In addition, AZP2006 has shown an excellent safety profile, the PK is well known, then we plan to go fast in PD/GBA1 patients at the end of these preclinical step (a POC clinical study is planned for end of 2022, at the end of our Phase 2a in PSP patients, results expected for mid-2022).
Next Steps for Development: AZP2006 has successfully passed GLP toxicology studies and has been tested in humans (Phases 1 and 2). This project will allow us to further document the positive effects of AZP2006 in cellular and small models of PD with GBA1 mutation. Our objective is to initiate a first Phase 2 on PD patients carrying a GBA1 mutation.