Dyskinesia

Our Research

All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase. Prolonged treatment of Parkinson’s disease with L-DOPA may result in a characteristic movement disorder known as dyskinesia. By studying the effects of L-DOPA on the brain, we are developing gene therapy solutions to treat L-DOPA-induced dyskinesias. Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.
Monkey Brain with AADC expression Panel A: AADC expression (bright yellow-red patches) in one of three monkeys with focal AADC expression. One site in the caudate nucleus and 2 sites in the putamen were targeted bilaterally with AAV2-hAADC. Panel B: AADC-transduced regions in the caudate as shown in panel A. AADC expression is restricted to medium spiny neurons. Thus, L-DOPA administration (L-DOPA is converted to dopamine by AADC-expressing cells) results in activation of dopamine receptors only within the focal region of the striatum. L-DOPA administration in these monkeys resulted in a significant induction of dyskinesias.

The Causes of Dyskinesia

As Parkinson’s disease progresses, most if not all patients begin taking . L-DOPA is converted to in the brain by the enzyme, . Over time, the potency of the drug wanes. Patients require steadily increasing amounts of Sinemet. Along with this phenomenon is the appearance of disabling involuntary movements called dyskinesias. Two-thirds of all patients develop this motor complication within several years of initiation of therapy, the most prominent of which are so-called L-DOPA-induced dyskinesias (LIDs). Several patterns of dyskinetic movements have been identified: (i) peak-dose-dyskinesias, (ii) dysphasic-dyskinesias, and (iii) end-of-dose. There is also the phenomenon of low-dose dyskinesias that pose particular clinical and treatment difficulties. Patients with early-onset parkinsonism appear to be at the highest risk for developing debilitating dyskinesias.

Our Project

The broad aim of our project is to test the hypothesis that dyskinesias in Parkinson’s disease (PD) arise at least in part from non-uniform dopaminergic innervation of the striatum. It is possible that irregular loss of dopamine (DA) terminals within the motor-related posterior putamen results in “hotspots” of dopamine synthesis, leading to uneven patterns of neuronal activity that in turn generate abnormal dyskinetic motor output. This hypothesis is consistent with data from several groups that focal generation of DA in the posterior striatum following fetal tissue engraftment leads to a significant risk of severe medication-resistant dyskinesias in previously non-dyskinetic individuals with PD. Over a number of years, we have developed an adeno-associated virus containing the cDNA encoding aromatic L-amino acid decarboxylase (AAV2-hAADC). Transduced with this vector, striatal neurons gain the ability to produce DA from exogenous L-DOPA, a dopamine precursor. We have observed severe L-DOPA-induced dyskinesias (LID’s) in animals when AAV2-AADC was infused into the striatum in a way that generated focal regions of high AADC activity. In contrast, diffuse expression of AADC throughout the striatum does not increase the propensity for dyskinesias in animals. Through our ability to manipulate the anatomical distribution of striatal AADC while avoiding the complexities associated with cell grafting techniques, we propose testing whether focal hotspots of DA production within the posterior putamen and/or inter-regional disparities in DA availability increase the propensity for dyskinesias. This research program seeks to test important hypotheses regarding the mechanistic and anatomical origins of L-DOPA-induced dyskinesias. It also integrates behavior, neurophysiology, imaging, and anatomy in an unprecedented manner that is likely to yield significant new insights into the genesis and maintenance of one of the most serious sequelae of L-DOPA therapy. This work is supported by a grant from the NIH-NINDS.