Investigators/Authors: Robert E. Burke, MD, Departments of Neurology and Pathology, Director of the Udall Parkinson's Disease Research Center at Columbia University
Objective/Rationale: Based on modern data, it is now estimated that only 30% of dopamine neurons are lost at the time of first diagnosis of PD (Ann Neurol, 2010). Thus, at disease onset, and throughout its course, there is an opportunity to re-establish function by restoring axons of surviving dopamine neurons. It has been believed that axons, the long fibers that connect one neuron to another, cannot be re-grown in the mature brain. However, we have shown that they can be induced to grow by using a gene therapy approach to re-invigorate the mechanisms that are active during development (Ann Neurol, 2011). The object of this proposal is to further develop these gene therapy approaches.
Project Description/Methods/Design: We have shown that two molecules that normally induce axon growth during development, a kinase called Akt and a GTPase called Rheb, can induce robust re-growth of axons in the mature brain (Ann Neurol, 2011). These molecules function in just one of the major pathways for new axon growth. In another pathway, a molecule called Rap1B is especially abundant in dopamine neurons. We propose to investigate the ability of Rap1B to induce re-growth of dopamine axons. We will first make an adeno-associated viral (AAV) vector that will contain a highly active form of Rap1B. We will make a lesion of the dopaminergic axons in mice by use of a neurotoxin, 6OHDA. After 3 weeks most of the axons have been destroyed. At that time, we inject AAV Rap1b into the dopaminergic neurons and wait 12 weeks for the AAV to take effect. We then study the behavioral recovery of the mice, and following these tests, we will study the brains, to see if there has been axon re-growth.
Relevance to Treatment of Parkinson’s Disease: While there are now many medical treatments and deep brain stimulation (DBS) therapy for the symptoms of PD, these approaches only treat the symptoms; they do not restore the axon circuitry damaged by the
disease. Not surprisingly, these treatments lose efficacy over time, and they begin to cause adverse effects. A more lasting and complication-free treatment can be achieved by restoring the normal anatomical circuitry of the brain by inducing the endogenous surviving neurons to re-grow their axons and restore this circuitry. We have had preliminary success in achieving this goal by stimulating intrinsic neuronal mechanisms of growth. We anticipate that this approach will make restoration of neural circuitry and robust, lasting clinical benefit a reality.
Expected Outcome: We expect that AAV Rap1b will induce re-growth of dopaminergic axons following their destruction in a neurotoxin model. We further anticipate that this anatomical restoration will lead to a functional, behavioral improvement in motor deficits. These results will represent a first step towards the development of a gene therapy for patients with PD, in which the intended therapeutic goal is the restoration of the axonal circuitry destroyed by the disease. In the future, we plan to optimize this
new approach to therapy by seeking the most effective stimulators of axon growth and by designing vectors that will minimize the possibility of adverse effects.
Cheng HC, Ulane CM, Burke RE (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67:715-725.
Kim SR, Chen X, Oo TF, Kareva T, Yarygina O, Wang C, During MJ, Kholodilov N, Burke RE (2011) Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration Ann Neurol 70 110-120.
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|Investigators/Authors: Nader Pouratian, MD, PhD, UCLA Neurosurgery, Jeff Bronstein,
MD, PhD, Director of Movement Disorders, UCLA
Objective/Rationale: While DBS has revolutionized advanced Parkinson’s disease management, the therapy remains imperfect and time-consuming, requiring physicians to evaluate countless combinations of stimulation parameters to achieve “best” therapy. Ideally, patient-specific biomarkers could help optimize individualized therapy by identifying the optimal site and parameters for stimulation. Local field potentials (LFP), which are a measure of population-level neuronal activity, can easily be measured with DBS electrodes and hold great promise as such a biomarker. Our objective is to evaluate LFP across time, activity states, and therapeutic states to elucidate their role in developing self-programming DBS systems that improve therapeutic efficacy and efficiency.
Project Description/Methods/Design: Electrophysiological signals (LFP) will be recorded from patients’ brains who are electively undergoing clinically indicated DBS surgery. LFP will be recorded using two mechanisms. (1) Our laboratory has already established a program to record LFP during surgical implantation of DBS electrodes. After surgical implantation but before closing the wounds, LFP signals are recorded from deep brain electrodes and an electrode placed on the brain surface while the patient performs various tasks and with various stimulation parameters. (2) Ten patients will be implanted with a specially designed generator that not only stimulates like standard generators, but also records LFP chronically (Activa PC+S) for one year. Biosignals will be compared to the clinical effect of stimulation at each contact (as determined by a movement disorders neurologist) to identify biomarkers associated with the site of optimal stimulation and ideal stimulation parameters. Signals will be evaluated for changes with activity, medication, and time.
Relevance to Treatment of Parkinson’s Disease: Current DBS practice requires patients to follow-up for months postoperatively to optimize therapy. This process is time-consuming, varies based on programmer experience, and places geographical constraints on DBS eligibility. Moreover, generator power consumption is not necessarily optimized, potentially leading to early generator replacement. The electrophysiological biomarkers that we will characterize aim to guide programming, making therapy more effective, efficient, and therefore more accessible to those who are remote from implanting centers. In the future, such signals will ideally be integrated into closed-loop stimulation systems that rapidly respond to real-time patient needs and obviate the need for human programming.
Expected Outcome: Preliminary work in our laboratory has identified two critical biomarkers in the LFP signals of the globus pallidus (one of the principal DBS targets for Parkinson’s disease). These LFP biomarkers are specific to the DBS target (i.e., not seen in other places) and they respond to movement (results submitted to Journal of Neuroscience). Through the proposed work, we will further characterize these LFP biosignals. We will demonstrate the stability of these signals over time to ensure their long-term reliability. Moreover, we expect LFP signals to change with clinical condition, providing a biomarker of effective therapy.
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