Assessment of new therapeutics for diseases such as Parkinson’s disease (PD) is based mainly on the utilization of young rodents (mice or rats) in restricted and well controlled conditions. Regardless to the chosen model (6-HODA, MPTP, Rotenone, transgenic mice), the obtained results have certain inheritance that limit the predicting values. While in a pre-clinical setting a group of 10-15 animals per arm is claimed to predict response (neuroprotective, neurorestorative or symptomatic), in reality the assessment of efficacy in early clinical phases requires a much larger population size.
Furthermore, most of the pre-clinical animal models lack the desired combination of pre-disposed risk factors that are claimed to be relevant to the pathogenesis and the progress of the disease. For example, aging is considered to be one of the major risk factors of PD. Furthermore, immune-inflammatory processes are considered to be involved in the accelerated dopaminergic aging of the nigrostriatal pathway and possibly in the pathogenesis of PD.
The described is a battery of animal models combining the relevant risk factors with applicable observatory tests, referred to as “Not Young but Relevant” (NYBR®). These models are based on a modified series of tests that are pooled together to assess efficacy and safety and eventually define therapeutic ratios and asses clinical attrition rates. In these models, in addition to the standard efficacy behavioral end points, additional evaluations will be included in order to asses effect on clinical and commercialy unmet needs such as: dyskinesia development following chronic L-DOPA treatment, cognitive decline and depression.
Moreover, behavioral results will be supported by bio-analytical and immune-histological (IHC) sophisticated techniques. These include HPLC analysis of dopamine metabolite content obtained by microdialysis from striatal or brain fluids and IHC of brain slices. The integration of these abilities provides a better understanding as to the proof of mechanism, principle, concept and relevancy in these models. The ability to measure toxicological parameters in comparable to age and other risk factors will provide a unique tool to better predict the therapeutic ratios.