The 2009 Parkinson's Unity Walk Funds Research Grants
Through the generous support of its corporate sponsors, 100% of all donations made to the Parkinson's Unity Walk are distributed among the major U.S. Parkinson's disease foundations for Parkinson's disease research. The foundations include: (1) the American Parkinson Disease Association; (2) the National Parkinson Foundation; (3) the Parkinson's Action Network; (4) the Parkinson's Disease Foundation; (5) The Michael J. Fox Foundation for Parkinson's Research; (6) The Parkinson Alliance; and (7) The Parkinson's Institute and Clinical Center.
We are excited to share with you information about the following grants —all of which are made possible from 2009 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us.
2. National Parkinson Foundation is using its distribution to fund the following:
Project Title: NPF Quality Improvement Research Initiative
Jay Nutt, MD, Medical Director, NPF Center of Excellence at Oregon Health Sciences University.
Project Description: NPF, in partnership with 43 top medical centers (NPF's Centers of Excellence), has launched the first data-driven quality improvement research initiative to systematically improve care for every patient diagnosed with Parkinson’s disease. With a goal of tracking every patient seen in every NPF Center of Excellence (35,000-50,000 patients worldwide), this research initiative will generate the largest outcomes database in Parkinson’s disease. Our ultimate aim is to create and share models of excellent care, so that every Parkinson’s patient receives the most effective treatment options available, whether they are seen by a specialist at a NPF Center of Excellence, a general neurologist or their primary care physician. Financial support from the Unity Walk will support the initial pilot test of NPF's Quality Improvement Research Initiative, which involves collection and analysis of 600 patient records to be completed by January 2010.
September 2011 Project Update:
Objectives: Identify correlations between therapeutic choices and improved outcomes
3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.
PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.
4. Parkinson’s Disease Foundation is using its distribution to fund the following:
Project Title: Testing the neurotrophic and neuroprotective effects of SGK on the nigrostriatal dopaminergic system in vivo
Objective: The goal of this study is to test whether the enzyme SGK can protect the neurons lost in animal models of Parkinson’s disease.
Conclusion/Relevance to Parkinson’s Disease: By identifying key cellular elements that might alter the neurodegeneration pathway in Parkinson’s, the work of the Burke lab will lead to a better understanding of how to develop new treatments for Parkinson’s disease.
Results: We increased the levels of SGK by using a form of the enzyme that was constitutively active. Consistent with our hypothesis, high levels of SGK protect neurons from degradation in our model of Parkinson’s disease. A manuscript describing our results is currently in preparation.
September 2011 Project Update:
Results: The project is now completed and the manuscript has been prepared. It is planned to be submitted for peer-review in August, 2011.
5. The Michael J. Fox Foundation for Parkinson's Research is using its distribution to fund the following:
PD Online Research is an efficient Web-based platform for research professionals across the globe to engage daily on key research hurdles and breaking scientific findings. This virtual workplace has a simple goal: enable quicker knowledge turns and therefore faster progress toward transformative therapies.
Investigators: MJFF staff, Tim Clark, Massachusetts General Hospital
6. The Parkinson Alliance is using its distribution to fund the following:
Project Title: Creating dopaminergic neurons with authentic Parkinson's disease - A new path to drug discovery and understanding mechanisms of neurodegeneration
September 2010 Project Update:
Progress in specific areas: Over the last nine months we have made a exciting progress towards the goal of this study that is modeling pathology of Parkinson’s disease in a culture dish.
Project Title: Novel, small-molecule inhibitors of a-synuclein assembly and toxicity for disease-modifying therapy of Parkinson's disease.
Investigator: Dr. Gal Bitan
Project Description: The generous gift of The Parkinson Alliance and Team Parkinson will support exciting research in the Bitan Laboratory geared towards development of disease-modifying therapy for Parkinson's disease (PD). Current treatment of PD focuses on compensation for dopamine deficiency, predominantly by using L-dopa. Though this kind of treatment is successful in alleviating major symptoms, such as tremor, it does not address “non-dopaminergic” symptoms, including falling and freezing, which affect 80-90% of patients with PD and 100% of patients with early-onset PD, or dementia which afflicts ~30% of patients with PD. These non-dopaminergic symptoms are major causes of mortality and morbidity in PD. In addition, treatment with L-dopa causes complications such as “off-time” and dyskinesia (involuntary movement). To address these unmet needs, disease-modifying, rather than symptomatic, therapy is needed. We have discovered a new experimental drug that disarms what most researchers believe to be real culprit causing PD - toxic aggregates of a protein called alpha-synuclein. These toxic aggregates are the main component of Lewy bodies, the hallmark pathologic lesion in the brain of patients with PD. The new drug inhibits the formation of these toxic aggregates and thereby prevents the initial processes that lead to development of PD. Through collaboration with Dr. Bronstein's group, the new drug was found to block the toxic effect of alpha-synuclein aggregates in cultured cells and zebra fish. The fish, which without the drug are severely deformed and die within a few days, appear healthy and normal by simple addition of the drug to the water in which they swim. Related experiments in mice show that the drug can get into the brain and remove toxic protein aggregates.
September 2010 Project Update:
September 2011 Project Update:These experiments included extensive collaboration with Drs. Jeff Bronstein and Marie-Françoise Chesselet, Department of Neurology, UCLA.
1. CLR01 inhibited ?-synuclein aggregation completely at a 1:1 concentration ratio and partially at a 1:10 concentration ratio, respectively.
2. CLR01 inhibited the toxicity of both exogenous a-synuclein oligomers and endogenously expressed in cell culture.
3. CLR01 showed significant rescue of the phenotype and survival of zebrafish embryos expressing human, wild-type a-synuclein. The mechanism of rescue was shown to be maintaining a-synuclein in a soluble form, preventing formation of toxic aggregates, and enabling degradation of a-synuclein via the proteasome.
4. CLR01 was found to significantly ameliorate motor deficits in transgenic mice expressing human, wild-type a-synuclein in the brain when administered subcutaneously for 28 days at a low dose (0.4 mg/kg/day). The mechanism is still under study but initial results suggest that it involves reduction in the levels of soluble, likely oligomeric, a-synuclein.
5. Upon ICV administration for 28 days, the effect of CLR01 was particularly significant in the challenge beam test, where is was consistent in all 5 trials and also increased by 2.2-fold relative to subcutaneous administration. The data demonstrate the efficacy of CLR01 and suggest that blood–brain barrier penetration likely needs to be optimized in future medicinal chemistry and/or formulation studies.
Conclusion/Relevance to Parkinson’s disease: The data accumulated so far suggest that CLR01 is a novel and promising therapeutic candidate for Parkinson’s disease and support its further development for human clinical trials.
A manuscript describing the data summarized in points 1–3 above has been submitted for publication and is now being revised to address reviewers’ comments. The mouse experiments are still being analyzed and will be published in the near future.
Project Title: Is there abnormal network activity in the motor cortex of 6-OHDA lesioned mice.
Investigator: Dr. Carlos Portera, M.D., PhD
Project Description: The current treatments for Parkinson disease (PD) offer some symptomatic relief, but often at the cost of serious side effects, including dyskinesias. The introduction of deep brain stimulation (DBS) in the treatment of PD two decades ago has arguably been the most effective treatment strategy since the discovery of levodopa. Understanding the exact mechanisms of how DBS helps PD patients will help improve this therapeutic strategy. A recent study using the 6-hydroxydopamine (6-OHDA) rodent model of PD (Gradinaru et al., 2009) suggests that DBS may help by reducing the activity of the subthalamic nucleus (STN) through its effects on the firing of neurons in motor cortex, which is the part of the brain that controls movement. This raises the possibility that neurons in the motor cortex of PD patients fire less than normal, leading to an overactive STN that produces some of the symptoms of PD. I propose to test the hypothesis that neurons are hypoactive in the motor cortex of mice that had been rendered parkinsonian by injection of the neurotoxin 6-OHDA into the substantia nigra. Specifically, I intend to examine the spontaneous activity of neurons in the motor cortex of mice before and after administering 6-OHDA. We will use the cutting-edge technique of two-photon calcium imaging to record the activity of large numbers of cortical neurons non-invasively.
These experiments will shed light into the mechanisms of circuit dysfunction in PD and may lead to improved treatments for this devastating disorder.
September 2010 Project Update:
We originally proposed to test the hypothesis that neurons in the motor cortex of Parkinsonian mice are hypoactive. In a way, this is expected in patients with Parkinson disease (PD), because the low levels of dopamine lead to reduce activity in a part of the brain called the thalamus, which normally stimulates the motor cortex to initiate movement. Specifically, we proposed to render mice Parkinsonian by injecting the neurotoxin 6-hydroxy-dopamine (6-OHDA) into the substantia nigra. Next, we planned to examine the spontaneous activity of neurons in the motor cortex of mice before and after the 6-OHDA injection. However, after discussions with UCLA investigators and PD research experts Marie-Francoise Chesselet and Michael Levine, we decided instead to examine neuronal activity in motor cortex of the Alphasynuclein over-expressing transgenic mice (the so-called ASO mice). Drs. Chesselet and Levine considered the ASO mice to be a better model of PD.
September 2011 Project Update:
In addition to acute two-photon calcium imaging experiments using the synthetic calcium indicator dye Oregon Green BAPTA-1, we also intend to pursue chronic recordings of neuronal activity in the neocortex of ASO mice with the genetically encoded calcium indicator GCaMP3. Using viral mediated transfections we will be able to record the firing of cortical neurons over periods of several weeks.
7. The Parkinson’s Institute and Clinical Center is using its distribution to fund the following:
Project Title: Epidemiologic Studies of PD Etiology
September 2010 Project Update:Methods/Design: We conducted analyses on the effects of genes and environment, taking advantage of extensive work in several large epidemiologic studies totaling nearly 2000 individuals. Detailed lifelong information on environmental risk factors was collected, and DNA tested for over 1500 variations in 120 genes thought to play a role in PD. We investigated the following specific hypotheses: 1) Does exposure to occupational solvents increase the risk of PD? 2) Is the effect of head injury on PD dependent on genetic makeup?
Results: (1) Studying 100 pairs of twins in which one twin had PD and one did not (i.e., twins discordant for PD), we found that occupational exposure to the common solvent trichloroethylene (TCE) was associated with a more than 6-fold increased risk of PD. Those exposed to either TCE or tetrachloroethylene (PERC) were at more than 10-fold increased risk. (2) We investigated the effect of head injury with loss of consciousness or concussion in two large studies. Overall, the effect of head injury was modest. However, in those who had both a head injury and a common variant of the alpha-synuclein gene, the risk of PD was increased more than 6-fold.
2011 Project Update: