The development of a best-in-class iron chelator to prevent oxidative stress, iron regulated cell death (ferroptosis) and synucleinopathy as a treatment for Parkinson’s Disease, to-gether with the integration of biomarkers of target engagement and efficacy.
Cure Parkinson's
Centre Hospitalier Universitaire de Lille
Excessive labile iron in the Substantia Nigra pars compacta (SNpc) is a pathognomonic hallmark of PD and leads to increased production of noxious reactive oxygen species. Alpha-synuclein regulates dopamine and iron transport, with PD associated mutations in this protein causing functional disruption of these processes. It has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell death pathway with unique lipid peroxidation signatures called ferroptosis. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher-affinity acceptors in cells or extracellular transferrin.  Promising preclinical and clinical proof of concept trials have led to several current large randomized clinical trials (FAIR PARK II) that aim to demonstrate the concept of conservative iron chelation. A new iron chelator, SP-420 (invented by Prof. Ray Bergeron, University of Florida, and in clinical development by AbFero Pharmaceuticals) has significant advantages over deferiprone, including superior potency, tolerability, and safety (lack of neutropenia/agranulocytosis). A European consortium has been set up to launch the preclinical validation of SP420 in PD models and is funded by the European Commission (Eurostars program). The Eurostars work package will allow definition of 1) the pharmacokinetics (Pronexus AB, Dr. Kehr, Sweden), the in vitro molecular mechanisms (CHUL, Prof. Devos, France) 3) the in vivo validation in the subchronic MPTP mouse, 6-OH dopamine rats and in the preformed fibrils of the alpha synuclein mouse model (Erasmus University, Prof. Mastrobaradino, The Netherlands). Despite the quality of the Eurostars initiative, additional challenges to the success of a P2 trial remain. Indeed, while the concept of effective neuroprotection in PD has continued to excite interest, there has been more than 40 years of failure in neuroprotection. A key solution to overcome this major challenge is to better characterize the best population and the best doses, thus enhancing the chances of a successful clinical trial. Thus, the goal of this project is to validate neuroprotection induced by SP-420 in two additional pivotal in vivo PD models (i.e. the subchronic MPTP-treated aging mouse and the Thy1-a-syn mouse model, not funded by the Eurostars program) and associated with target engagement and the theragnostic biomarkers (not studied in the Eurostars program). Several new dry and wet biomarkers will be additionally be assessed including: MRI sequence of magnetization transfer associated with the T2* sequence (i.e. iron in and outside neuromelanin), PET scan [64Cu]-ATSM (i.e. lipid peroxidation preceding cell death) associated with GFAP (i.e. astrocytosis) associated with light chain neurofilament (i.e. axonal destruction), selenium (i.e. selenoprotein GPX4 = major antioxidant enzyme for lipid) associated with 4-HNE, MiRNA involved in ferroptosis associated with ferritin and alpha synuclein. The results will further validate the potential of SP-420 as a viable PII PD candidate, allowing AbFero to facilitate regulatory interactions necessary to support clinical trials in patients with PD, and increasing confidence in the investor and clinical community who will be key partners for AbFero as the substantial financial commitments are sought for PII and PIII studies.
5.1 Pharmaceuticals