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Funding from The Parkinson Alliance helped to finance the following Parkinson's research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.
Project Title: Evaluating New Technology for Deep Brain Stimulation (DBS): Constant Current or Constant Voltage. Is one better than the other for treating symptoms of PD patients?
Investigators/Organizers: The Parkinson Alliance will sponsor an International Meeting of DBS experts. Organizers include Jeffrey Wertheimer, Ph.D Chief Research Consultant, Carol Walton, CEO, Michele Tagliati, MD, Jeff Bronstein, MD, Ph.D.
Objective: To evaluate the pros and cons of programming in the constant-current versus constant-voltage modes given the fact that there is now new programming opportunities.
Background: DBS for PD was FDA approved in 2002 and the only method of delivering electricity was constant voltage. Constant current, a new approach to delivering electricity with DBS, is available on all devices now for DBS for PD. The challenge or major question now is to understand if one delivery method---constant current or constant voltage---might actually provide better control of PD symptoms.
Methods/Design: This 1 and ½ day meeting will convene DBS experts from around the world including neurosurgeons; movement disorder specialists; scientists/engineers from industries that make medical devices. The meeting will commence with a dinner on the first day where everyone will meet each other and the outline for the full day meeting will be reviewed. Presentations pertaining to theory, current research, and clinical experiences related to DBS therapy will be made in 30 minute increments with time for questions/discussion after each topic.
Projected Results: Very little appears to be known about delivering electricity with constant current and the programming parameters. The objective of this meeting is to determine if there might be a significant difference between constant current and constant voltage, particularly as it relates to patient outcomes. If there is agreement that there might be a difference, then a strategy needs to be developed to validate this assumption. This would include clinical trials as well as other strategies/programs to support these conclusions. At the conclusion of the meeting a summary will be prepared by the meeting leaders and will be available on the website: www.dbs-stn.org. In addition, there may be a white paper or opinion paper that may be published as a result of this meeting.
Project Title: Development of molecular tweezers towards disease-modifying drugs for Parkinson’s disease
Principal Investigator(s): Gal Bitan, PhD., David Geffen School of Medicine at UCLA
Objective: A major pathological process in Parkinson’s disease is the aggregation of the protein alpha-synuclein in the brain. Alpha-synuclein is not only the main component of Lewy bodies, but also is believed to be directly related both to early, “pre-manifest” symptoms and to loss of dopaminergic neurons and classical symptoms, such as rigidity and tremor. Therefore, inhibition of alpha-synuclein aggregation is a promising strategy for therapy development. We propose to develop our novel “molecular tweezers,” which previously have been shown to prevent alpha-synuclein aggregation and toxicity in the test tube, in cell culture, and in animal models, towards FDA approval of initiation of human clinical trials.
Project Description/Methods/Design: Our research thus far has shown that:
- The molecular tweezer termed CLR01 is a broad-spectrum inhibitor of abnormal protein aggregation.
- CLR01 inhibits alpha-synuclein aggregation and dissociates pre-formed alpha synuclein aggregates.
- CLR01 inhibits alpha-synuclein killing of nerve cells, regardless of whether alpha-synuclein is outside or inside the cells.
- CLR01 protects zebrafish genetically engineered to have human alpha-synuclein in their nerve cells from the toxic effect of the protein with no side effects.
- CLR01 improves motor deficits in mice genetically engineered to have human alpha-synuclein in the brain with no side effects.
All of these are very encouraging findings that support further development of molecular tweezers in general, and CLR01 in particular, towards human trials. Two questions that need to be formally answered now are the extent of blood–brain permeability and the safety margin of CLR01. We have all the necessary expertise and tools either in the Bitan laboratory or in core facilities at UCLA and we are asking the Parkinson Alliance/Team Parkinson for funding that will allow performing these experiments and expedite the process towards beginning human trials.
Relevance to Treatment of Parkinson’s Disease: The project will provide answers for two key questions needed for initiation of formal studies required by FDA for initiation of clinical trials and examine molecular tweezers as novel, disease-modifying therapy for Parkinson’s disease.
Expected Outcome: Based on our current preliminary data, we expect to be able to determine the extent to which CLR01 enters the brain, the rate of entry, and the rate of clearance from the brain. In addition, we expect to determine the safety margin of CLR01 in mice. Both these measurements are crucially required for initiation of the studies required by FDA.
Project Title: Can Induction of Autophagy Slow the Progression of Parkinson’s Disease?
Principal Investigator(s): Jeff Bronstein, MD, PhD, Director of Movement Disorders, UCLA
Objective/Rationale: The precise cause of Parkinson’s disease (PD) is not certain but likely involves the accumulation of toxic aggregates of a protein called a-synuclein. These aggregates are believed to move from neuron to neuron leading to the disease spreading throughout the nervous system causing many symptoms beyond the cardinal features of PD. We have taken 2 therapeutic approaches to stop the progression of PD; preventing aggregation (e.g. tweezer) and increasing the clearance of the aggregates by a process called autophagy. Autophagy usually has a low activity but can be induced by a number of medications. We have preliminary evidence that some calcium channel blockers can induce autophagy and protect against a-synuclein neurotoxicity. We propose to test this hypothesis in our zebrafish model by testing already approved medications for their ability to stimulate autophagy and protect the fish.
Project Description/Methods/Design: We will utilize our zebrafish model to test L-type Ca2+ blockers (e.g. isradipine) and mTOR inhibitors (e.g. rapamycin) for their ability to induce autophagy and protect against a-synuclein neurotoxicity. Since zebrafish embryos are transparent, we will use genetically modified fish that express fluorescent reporter genes to measure a-synuclein expression, autophagatic activity, and neuronal survival. We will also utilize morpholinos (nucleic acids that target DNA) to specifically regulate autophagy to further test our hypothesis. If time permits, we will test these drugs’ ability to reverse a-synuclein’s actions using a novel transgenic fish where a-synuclein expression can be turned on and off using a non-toxic chemical. This inducible model is currently under development.
Relevance to Treatment of Parkinson’s Disease: We desperately need drugs that slow the progression of PD. Approaches such as preventing aggregation are very promising and maybe the ultimate answer but are likely some years away from becoming available to patients. Repositioning already approved medications that can slow the disease down could provide a disease modifying therapy almost immediately until more definitive therapies are approved. Dr. Surmeier 1st identified Ca2+ blockers as a potential treatment for PD but the effects of these drugs on a-synuclein toxicity and their mechanism of action are unknown. Positive results from the studies proposed here would help validate this therapeutic target and provide support for the use of these drugs to slow the progression of PD.
Expected Outcome: We anticipate that some Ca2+ blockers will induce autophagy and attenuate a-synuclein toxicity. We predict that inhibiting the induction of autophagy using morpholinos will block the drugs beneficial affects. Other drugs that induce autophagy by a different pathway (mTOR-dependent) will be tested as well and our studies should determine which class of drugs is most promising.
Project Title: Development of novel gene therapies to restore neural circuits in Parkinson’s disease
Principal Investigator(s): 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.
Project Title: Electrophysiological biomarkers of efficacious stimulation therapy: a DBS study
Principal Investigator(s): 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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