Objective/Rationale:
ReS9-S7, a novel disease-modifying drug candidate directed against alpha-synuclein instigated neuronal toxicity, is planned to enter clinical Phase I studies in 2009/2010. Successful clinical development requires an accurate estimation of therapeutic dose in order to determine the dosage regimen for patients and safety margin. The objective of this project is to determine the PK-PD relationship of ReS9-S7 using a transgenic alpha-synuclein model of Parkinson’s disease.
Project Description:
A dose-response study will be carried out using transgenic alpha-synuclein mice. Since ReS9-S7 affects alpha-synuclein pathobiology by lowering particular (noxious) species of alpha-synuclein a detailed biochemical characterization will be performed. From different brain regions several protein fractions (total, soluble, membrane and insoluble) will be prepared and analyzed by Western analysis and ELISA using antibodies directed against alpha-synuclein (and also modifications thereof). During treatment blood samples will be taken for PK analysis in function of dose.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
ReS9-S7 is a first disease-modifying drug candidate directed against alpha-synuclein triggered toxicity. It has demonstrated neuroprotection in 3 different models of Parkinson’s disease, and has promising PK and toxicological properties allowing a once-a-day oral administration. Therefore ReS9-S7 holds a huge promise for decelerating or even stopping degeneration in PD patients. The outcome of this study is essential for clinical development of ReS9-S7, and hence brings testing of this candidate drug a step closer to reality.
Anticipated Outcome:
The outcome of this work is a detailed understanding as to the relation of the pharmacodynamic effects of ReS9-S7 and the corresponding plasma exposure and other pharmacokinetic properties. In this way the lowest plasma exposure responsible for the desired pharmacological effect in the animal model can be taken as a guide to define the desired plasma exposure (and thus dose) in patients. In addition, together with the preclinical toxicology data, the safety margin can be accurately determined.
Progress Report
ReS9-S7 is a drug candidate with disease-modifying potential to treat patients afflicted with PD or other alpha-synuclein pathologies. In several pre-clinical models of PD with alpha-synuclein pathology, treatment with ReS9-S7 was shown to preserve dopaminergic signaling circuitry. The underlying mechanism for the observed neuroprotective activity relates to the fact that ReS9-S7 facilitates degradation of specific and apparently noxious alpha-synuclein species that, when left unchecked, would trigger a cascade of events leading to neuronal degeneration. A major goal of the awarded project is to obtain insights as to the relationship between ReS9-S7 plasma exposure and its effects on alpha-synuclien pahthobiology. To this end a dose-response study is being carried out using a human alpha-synuclein transgenic model. The data obtained so far revealed a potent activity of ReS9-S7 which translates into a very robust safety margin and anticipates a low daily oral dose in patients. Collectively, the MJFF-funded study revealed ReS9-S7 having an excellent pharmacodynamic/pharmacokinetic relationship and therefore constitutes a promising drug candidate.