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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.
November 2013 Project Update:
The results of this meeting have been summarized and currently being submitted for publication.
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.
November 2013 Project Update:
We have achieved both objectives set for the project. Our data demonstrate that CLR01 has a high safety margin, supporting its future development towards disease-modifying therapy for Parkinson’s disease. The BBB-permeability experiments indicate that CLR01 penetrates the brain at ~1.5% and persists in the brain longer than expected, providing a plausible explanation for the therapeutic effects observed in mouse models of Parkinson’s disease and Alzheimer’s disease. Though the data suggest that the compound could be used “as is” for human treatment, the BBB permeability likely can be improved by medicinal chemistry, “pro-drugging,” and/or formulation approaches. These experiments will be important to ensure that the best candidate is chosen for clinical trials.
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.
November 2013 Project Update:
Epidemiological data support the potential disease-modifying effect of exposure to calcium-channel blockers used to treat high blood pressure (including isradipine) in Parkinson’s disease (PD). Prior studies suggest this effect may be mediated through modulation of calcium toxicity in “pacemaker” dopaminergic neurons, despite the presence of Lewy pathology in other neuron types. We hypothesize that isradipine induces autophagy (a protein degradative process) to help destroy toxic oligomers of alpha-synuclein which are believed to be the cause of PD.
We are investigating the effect of isradipine on a genetic model of PD pathology in zebrafish. Isradipine treatment resulted in improved survival in fish overexpressing human alpha-synuclein. In order to measure autophagic activity in living fish, we generated a transgenic zebrafish line that expresses LC3-GFP. We found using these fish that isradipine induces autophagy and appears to clear at least some of the neuronal alpha-synuclein aggregates. As would be predicted by our hypothesis, inhibiting autophagy using LC3 morpholino knockdowns blocked isradipine’s protective effects.
In summary, isradipine treatment rescues alpha-synuclein neuronal toxicity in an overexpression model of Parkinson’s pathology in an autophagy-dependent fashion. It is therefore a promising disease modifying therapy in the treatment of PD.
September 2014 Project Update:
We have hypothesized that the disease-modifying effect of calcium-channel blockers (such as isradipine) detected in epidemiological studies is, at least in part, conferred by upregulating a process known as autophagy. Autophagy is important because it is one of the ways in which cells break down large molecules and even organelles that may be toxic, such as aggregates of alpha-synuclein and the damaged mitochondria found in Parkinson’s disease neurons.
We have been investigating the effect of isradipine on a zebrafish model of Parkinson’s disease pathology in which human alpha-synuclein is overexpressed (as it has been found to be in some human cases of the disease). Initial studies showed that isradipine treatment improved the survival of these fish, and also appeared to induce autophagy. We have been able to replicate and expand these observations with the addition of important controls to demonstrate the specificity of this effect. In particular, we have confirmed through the use of chemicals that inhibit the maturation of autophagic vesicles that isradipine enhances autophagic flux. We have also confirmed our preliminary observation that the inhibition of autophagy with a knockdown morpholino for LC3 (an important molecule for autophagy) blocks the isradipine effect on survival in a statistically large number of samples. Currently we are expanding a preliminary finding that isradipine treatment reduces the formation of alpha-synuclein aggregates observed in individual neurons.
In summary, isradipine treatment rescues neuronal toxicity and reduces alpha synuclein aggregation due to alpha-synuclein overexpression in a vertebrate model of Parkinson’s disease pathology via an autophagy-dependent mechanism. Isradipine therefore has promise as a disease modifying therapy for Parkinson’s disease.
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.
September 2013 Project Update:
We have previously shown that, contrary to the long-held belief that the adult central nervous system is incapable of long-range axon re-growth, lesioned dopamine neurons can be induced to grow new axons when they are transduced by adeno-associated viral (AAV) vector to express highly active forms of the kinase Akt or the GTPase Rheb These molecules are known to play a role in the growth of axons during development. Our work has shown that even in maturity dopamine neurons remain responsive to these genes and generate new axons. In order to investigate the promise of this approach for the treatment of PD patients, we sought to determine how long after axon destruction the dopaminergic neurons remain capable of growing new axons. In order to more accurately model chronic human PD, we assessed the axon growth response following AAV treatment at six weeks following lesion. In the rodent lesion model, about 70% of dopamine neurons have degenerated at that time, so this would be comparable to PD of about ten years duration. We found in the lesion model that even after this long delay in AAV treatment there was a significant axon growth response (published in Molecular Therapy, 2012).
In order to make this approach safe for clinical use in the treatment of PD patients, we need to be able to control where the genes are expressed. Ideally it would be best to limit expression to the dopamine neurons where they are needed. One approach to achieve this specificity is to put the gene that induces axon growth under the control of a promoter that is expressed exclusively in dopamine neurons. One such promoter is the tyrosine hydroxylase (TH) promoter, which is active exclusively in catecholaminergic neurons such as dopamine neurons. This year we have successfully evaluated the ability of the rat TH promoter to express genes in dopaminergic neurons. In addition, we have cloned three candidate human TH promoter constructs and have finished an initial evaluation of strength and specificity of expression.
This year we have demonstrated that the rat TH promoter does show regional specificity of staining; it mediates expression in the SN, but not in regions that do not contain dopamine neurons, such as striatum and cortex. Within the SN, it drives expression equally well in two subtypes of dopamine neuron that make up the dorsal and ventral tier of the SNpc. In addition, we have shown that transgene expression driven by the rTHp is stable over time; there was no change in expression patterns between 6 weeks and 6 months. We have begun to assess three published components of the human TH promoter: a 522bp sequence in the 5’ flanking region, a 1.5 kb sequence that contains 5’ and 3’ elements, and a 3.3 kb 5’ flanking sequence. Using AAV vectors to examine the strength of these promoters in vivo (in mice), we find that the 3.3 kb hTHp is the strongest. We are currently evaluating its specificity.
September 2014 Project Update:
We have shown that lesioned dopamine neurons can be induced to grow new axons when they are transduced by adeno-associated viral (AAV) vectors to express highly active forms of molecules that ordinarily induce axon growth during development, including the kinase Akt and the GTPase Rheb.
In order to make this approach safe for clinical use in the treatment of PD patients, we need to be able to control where the genes are expressed. Ideally it would be best to limit expression to the dopamine neurons where they are needed. One approach to achieve this specificity is to put the gene that induces axon growth under the control of a promoter that is expressed exclusively in dopamine neurons. One such promoter is the tyrosine hydroxylase (TH) promoter, which is active exclusively in catecholaminergic neurons such as dopamine neurons. Last year we successfully evaluated the ability of the rat TH promoter to express genes in dopaminergic neurons.
This year we have cloned three candidate human TH promoter constructs and have finished an evaluation of their specificity of expression. We have worked with three published components of the human TH promoter: a 522bp sequence in the 5’ flanking region, a 1.5 kb sequence that contains 5’ and 3’ elements, and a 3.3 kb 5’ flanking sequence. For each of these candidate promoters we have demonstrated that expression is achieved in dopamine neurons of the SN. Like the rat TH promoter, previously studied, they each show regional specificity of staining; they mediate expression in the SN, but not in regions that do not contain dopamine neurons, such as striatum and cortex. Within the SN, each drives expression equally well in two subtypes of dopamine neuron that make up the dorsal and ventral tier of the SNpc. In addition, within the SN, none of them transduce glia, indicating that the combination of an AAV vector and the TH promoter restricts expression to neurons, thereby avoiding the risk of oncogenic transformation of glia. Thus all three candidate promoters look promising, and our next steps will be to quantitatively evaluate their specificity and efficiency of expression in SN dopamine neurons.
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.
September 2013 Project Update:
Ongoing research in this field has extensively characterized electrophysiological biomarkers of disease in Parkinson’s disease that could potentially be used as signals to automatically control deep brain stimulation system. Although most studies have focused on the subthalamic nucleus (STN), the the globus pallidus (GPi) is considered an equally efficacious site for therapy. Our preliminary analysis of electrical signals in the GPi suggested very high frequency activity that may be a viable biomarker for PD. Using invasive recordings in patients undergoing DBS, we have identified and characterized a previously undescribed electrical activity centered at approximately 235Hz that responds to patient movement. We propose that this newly identified activity in the GPi could have a functional role in the basal ganglia and could be contributing to abnormal signal processing within the basal ganglia and contribute to disease in patients with PD.
In addition to analyzing signals limited to the GPi, the next step in our work has focused on characterizing electrical signals across multiple points in the motor network in patients with PD. We have shown for the first time that electrical activity with distinct frequencies within the GPi are interacting with one another and that this interaction is also modulated by patient arm movement. We have found a similar pattern of electrical activity and regulation in the motor cortex of PD patients. Finally, we have found that the motor cortex and GPi signals are intimately linked to one another through a phenomenon known as coherence. This information once again provides a critical understanding into the electrophysiological underpinning of network pathophysiology in PD and provides critical biomarkers that can be used for self-programmed deep brain stimulation.
These biomarkers will be used in our initial investigations of closed-loop neuromodulation in patients with PD when such patients are implanted with the planned Activa PC+S systems.
September 2014 Project Update:
Last year, we reported having identified a novel electrical signal in the globus pallidus internus (GPi) of patients with Parkinson’s disease. We found that this signal was only detected when the deep brain stimulation electrode was optimally positioned within the GPi and that this signal could be further confirmed by observing changes in its strength when the patient moves.
In the last year, we have further investigated the electrical activity of the GPi in order to better understand how we can use these signals to automatically program and control a deep brain stimulator system. As planned last year, we have begun to characterize how the electrical activity across different parts of the motor control network relate to one another. In these studies, we have found additional novel “signatures” that confirm the optimal DBS position in GPi. Specifically, we have found that electrical activity within the GPi is synchronized with activity seen in the motor cortex (the part of the brain that specifically and directly controls voluntary movement). The synchronization is quite complex, and can be identified using multiple sophisticated analysis techniques. The synchronization of these signals is decreased when the patient moves their hands. Even more interesting, we have explored what happens to these complex relationships across the motor network when the patient is placed under anesthesia, knowing that anesthesia abolishes the abnormal movements associated with Parkinson’s disease. Anesthesia decreases the synchronization across the network, suggesting that this synchronization is a potentially important source of abnormal brain activity in Parkinson’s disease and contributing to disease characteristics. This information once again provides a critical understanding into the electrophysiological underpinning of network pathophysiology in PD and provides critical biomarkers that can be used for self-programmed deep brain stimulation.
While the original intent of the proposed research was to study signals using the Activa PC+S system, regulatory approval for this device is still pending. Nevertheless, using opportunities during deep brain stimulation surgery, we have made great progress in understanding the signals that will be critical for studies in patients who ultimately receive the Activa PC+S system.
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