Objective/Rationale:
Parkinson’s disease progresses through the death of brain cells caused by “oxidative stress.” This takes place in dysfunctional mitochondria - structures within each cell functioning as their “respiratory power plants” – activating the signal protein HIF-1. Hence reducing levels of HIF-1 can be a viable therapeutic strategy to avoid brain cell damage and achieve neuro-protection. IMD-026259 inhibits HIF-1 intending to counteract the molecular mechanisms behind PD on the level of oxidative stress and mitochondrial dysfunction.
Project Description:
The symptoms of PD are caused by loss of brain cells (dopaminergic neurons) which are involved in the control of e.g. motor skills and speech. Avoiding their demise through oxidative stress should slow or stop the progressive decline seen in PD. IMD-026259 has already demonstrated potent neuro-protective capabilities in several biological models. This project examines the relevance of IMD-026259 to the treatment of PD in a Proof-of-Concept study: A standard animal model of PD will be used to demonstrate IMD-026259´s capability to protect dopaminergic neurons from oxidative toxicity. Further studies will examine the molecular mechanism by which IMD-026259 takes its effect. In addition, IMD-026259´s metabolization will be studied. Together these studies will provide better insights into IMD-026259´s mechanism of action, helping it’s further characterization before moving towards clinical use.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Existing treatments Symptoms & Side Effectsally mitigate the loss of motor control resulting from loss of dopaminergic cells. Substituting the body´s own dopamine supplies by eg. using L-DOPA (artificial dopamine) reduces common symptoms like tremor, akinesia and rigidity, but causes side-effects without stopping disease progression. Hence present treatments, while relieving symptoms, do not eliminate the cause of dopaminergic neurons´ decay, being the cause of PD.
IMD-026259 should inhibit the mechanisms causing dopaminergic neuronal death making it a novel therapeutic, disease-modifying approach to PD.
Anticipated Outcome:
This project seeks to demonstrate first that IMD-026259 can significantly reduce the death of dopaminergic neurons in a model of clinical relevance to PD and further seeks to establish the drug candidate´s innovative mechanism of action and metabolic characteristics. After this project additional studies will investigate the toxicological and safety profile of IMD-026259. The project would therefore be intended to accelerate the time to clinic and provide valuable data to help design appropriate clinical trials.
Progress Report
We confirmed previous results that the small molecule compound IMD-026259 substantially reduces the death of dopaminergic nerve cells that is responsible for the motor symptoms in Parkinson’s disease. The Parkinson’s disease in vivo model we used is based on application of the neurotoxin MPTP. While in earlier studies IMD-026259 was shown to be neuroprotective using lower doses of MPTP, the protective IMD-026259 effect could be most convincingly confirmed when much higher doses of the neurotoxin were applied. Moreover, we found that in line with the pharmacokinetic properties of IMD-026259 in the cerebrospinal fluid, a single dose per day is sufficient to protect the dopamingeric neurons from cell death. We thus provide further evidence supporting that IMD-026259 is a promising new therapeutic candidate molecule for the treatment of PD. Based on these results we have started to further elucidate the compound’s mechanism of action, its molecular target structure as well as its metabolism and safety in preparation of a clinical pilot study. Such studies are currently in progress or planning.
Final Outcome
We could confirm previous results that the small molecule compound IMD-026259, known to be a potent inhibitor of Hif1- and NF-kB-signalling as well as strong anti-inflammatory agent, substantially reduces the death of dopaminergic nerve cells that is responsible for the motor symptoms in Parkinson’s disease using the MPTP Parkinson’s disease in vivo model. The protective IMD-026259 effect could be most convincingly confirmed when much higher doses of the neurotoxin were applied. Moreover, we found that in line with the pharmacokinetic properties of IMD-026259 in the cerebrospinal fluid already a single dose per day is sufficient to protect the dopamingeric neurons from cell death. We thus provide further evidence supporting that IMD-026259 is a promising new therapeutic candidate molecule for the treatment of PD. In addition metabolism and in vivo safety studies were conducted demonstrating the excretion mechanisms as well as safe dosing ranges of the test item differing for various pre-clinical models. We furthermore investigated the compound’s mechanism of action towards ID of the molecular target structure via pull down experiments indicating towards a unique mechanism of action; this activity is currently still in progress.