This grant builds upon the research from a prior grant: Prospective study of nonsteroidal antiinflammatory drugs and risk of PD
Promising Outcomes of Original Grant:
The aim of the original grant was to identify compounds specifically targeting one or more neuronal nicotinic receptors (NNRs) in the central nervous system for their ability to reduce L-dopa-induced dyskinesias (LIDs). Using a well-validated model of dyskinesias, unilateral 6-hydroxydopamine-lesioned pre-clinical models treated with L-dopa, we demonstrated that NNR-selective agonists targeting alpha-6-beta-2- and alpha-4-beta-2-containing NNRs reduced LIDs with no detrimental effect on motor function. The most promising compound, TI-314049, shows good efficacy in the pre-clinical LID model and potential for further drug development. These data are consistent with our original hypothesis by supporting a role for selective nicotinic compounds in treatment of LID in Parkinson's disease patients.
Objectives for Supplemental Investigation:
This supplement will extend earlier findings by assessing TI-314049 in a pre-clinical model of LID. Compared with the first pre-clinical models used, these pre-clinical models are more similar to clinical models, especially with respect to targeted NNRs expressed in the nigrostriatal pathway. Long-term treatment of MPTP-lesioned NHPs with L-dopa results in the development of discrete observable behaviors that are essentially identical to L-dopa-induced dyskinesias in humans. In addition to LIDs, assessments related to compound interactions with L-dopa (potentiating or confounding anti-parkinson effects) on successive treatment days will also be performed. Measurement of plasma drug levels during the course of the study that are temporally linked to behavioral observations will be used to determine the pharmacokinetic/pharmacodynamic profile of TI-314049 as well as its safety, selectivity and therapeutic window. Finally, incorporation of a head-to-head comparison of TI-314049’s anti-dyskinetic efficacy and general side effect profile with a drug that has been reported to exhibit anti-dyskinetic effects in pre-clinical models (Hill et al., 2004) and clinical models (Sawada et al., 2010) in the same experiment will enable a direct assessment of its therapeutic potential.
Importance of This Research for the Development of a New PD Therapy:
The advantage of investigating L-dopa-induced motor fluctuations in the MPTP-pre-clinical model is that the rating scales for parkinsonism and dyskinesia in pre-clinical models are broadly equivalent to clinical rating scales in PD. Thus, their translational value is high. Results from these studies will provide a firm basis for the planning and organization of potential clinical trials to test TI-314049 in PD patients, thereby increasing the opportunity for positive clinical outcomes.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
