The objective of this project is to develop a genetic test, involving the protein, RGS9, to identify patients that are at risk for developing tardive dyskinesia (TD) or L-DOPA induced dyskinesia (LID). Antipsychotic drugs have revolutionized the treatment of schizophrenia and psychotic disorders but a debilitating side-effect of """"""""typical"""""""" antipsychotics is TD, an irreversible movement disorder of unknown pathophysiology. Unfortunately, the second generation """"""""atypical"""""""" antipsychotics have their own serious cardiovascular and diabetic side-effects. LID is a similar unexplained motor side-effect of the treatment of Parkinson's disease with L-DOPA that can become so severely disabling as to negate any clinical benefit from L-DOPA therapy. While alternative therapy of Parkinson's disease with dopamine receptor agonists produces a lower incidence of motor complications, their clinical efficacy is inferior to L-DOPA. Thus there is an urgent need for tools to estimate dyskinesia risk in the pharmacotherapy of both psychoses and Parkinson's disease. Evidence exists for a genetic component in the susceptibility for TD and LID and the rationale for the present investigation is provided by data recently published by this principal investigator and others. These data suggest that RGS9 is a key factor in the development of TD and LID and include the following observations: 1) in brain, RGS9 is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement and is critical in the development of TD and LID, 2) RGS9 specifically modulates basal ganglia signaling pathways activated by dopamine receptors, which are principal targets of the typical antipsychotic and antiparkinsonian drugs and 3) the RGS9 knock-out mouse is the most representative rodent model for TD and LID. In Phase 1 the RGS9 gene and regulatory regions from individual patients will be examined to determine if polymorphisms (differences in DNA sequence among individuals) can be correlated to the development of TD or LID. The results will be utilized in subsequent phases to develop, validate and commercialize a valuable clinical test that can be used to estimate the risk for developing TD or LID. The test will assist psychiatrists in deciding between treatment with atypical antipsychotics and the cheaper typical drugs which can be administered in depot formulations for increased compliance. It could similarly help neurologists decide between L-DOPA and direct dopamine receptor agonists in the therapy of Parkinson's disease. Estimation of dyskinesia risk will be very valuable in the development of new antipsychotic and antiparkinsonian drugs: by enabling better stratification of human subject subsets in drug trial randomization designs it will reduce the size of test populations, reduce risk to human subjects, lower drug development costs and ultimately lower market pricing of new drugs. Movement disorders are common, serious and debilitating side effects of antipsychotic drugs which are used to treat schizophrenia and L-DOPA which is used to treat Parkinson's disease. This research will help to develop a genetic test that will estimate the risk of a developing these debilitating side effects in a patient by analyzing the gene for a protein, RGS9, that is important in the development of drug-induced movement disorders. Such a test will allow physicians to individualize therapy by assisting in the selection of drugs with the greatest benefit and least harm. In addition, the ability to estimate dyskinesia risk will be very valuable in the development of new and improved antipsychotic and antiparkinsonian drugs. ? ? ? ?
| Waugh, Jeffrey L; Celver, Jeremy; Sharma, Meenakshi et al. (2011) Association between regulator of G protein signaling 9-2 and body weight. PLoS One 6:e27984 |
| Sharma, Meenakshi; Celver, Jeremy; Kovoor, Abraham (2011) Regulator of G protein signaling 9-2 (RGS9-2) mRNA is up regulated during neuronal differentiation of mouse embryonic stem cells. Neurosci Lett 502:123-8 |
| Masuho, Ikuo; Celver, Jeremy; Kovoor, Abraham et al. (2010) Membrane anchor R9AP potentiates GTPase-accelerating protein activity of RGS11 x Gbeta5 complex and accelerates inactivation of the mGluR6-G(o) signaling. J Biol Chem 285:4781-7 |
