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Parkinson's Disease Research Community Goals

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Overview

Since March of 2000, the National Institutes of Health (NIH) has expended tremendous effort and has made significant progress on the implementation of the Parkinson's Disease (PD) Research Agenda. As part of the implementation process, NIH convened a summit with several outstanding scientists in late July 2002 - to gain a better sense of where the field of PD research stands internationally, and to collect information on the "roadblocks" that may still be impacting progress. To this end, the meeting was very successful, and it served as an excellent complement to the PD Agenda implementation review consortium meeting that was held by NIH in January 2002.

As the next step in the NIH PD planning effort, the National Institute of Neurological Disorders and Stroke has developed the following recommendations from the July meeting into a matrix of short-to-long range, and low-to-high risk action items in order to address some of these roadblocks. While this matrix will help to guide further PD planning at NIH, it is designed primarily as a tool for the entire PD community. It includes important responsibilities for voluntary and private funding organizations, and will hopefully lead to opportunities for collaboration with other government agencies and the international community as well. This matrix is intended to be a living document that can be revised and expanded as current goals are achieved and new goals are identified.

Participants at the January 2002 consortium meeting reviewed the original Agenda, and although they identified several areas of research for additional focus, it was clear that the research goals highlighted in the Agenda are still critically important and relevant to progress in the field. Thus this matrix does not supplant the Agenda, but rather identifies additional goals that can help facilitate PD research by focusing on potential roadblocks and places them within a general timeframe against which the community can measure progress.

Core Facilities and Resources - Expanded and accelerated implementation

General comments on core facilities/resources from participants at the July meeting: Greater access to resources such as molecular tools, gene banks, transgenic animals, cell lines, gene vectors, brain banks, and primate facilities, etc. continues to be an urgent need of the Parkinson's disease (PD) field. The primary goal of improved access is to help scientists achieve research goals such as the discovery of remaining PD genes/proteins, susceptibility genes/proteins, dopaminergic and non-dopaminergic cellular "actors" in the pathogenesis of PD, as well as the translation of preclinical studies of cell replacement, gene therapy and other therapeutic approaches. Increased, broad access to core resources and the development of new resources will result in greater synergy and productivity among researchers, reduce the costs of research, and facilitate the entry of new investigators into the PD field.

General Resources
Goal A: By the end of FY2003, expand website-based resource sharing to include additional resources recommended at both the 2002 PD Summit meeting and the 2002 Udall meeting (see above list). (Low Risk/Short Term) Primary lead: NINDS

4/05: The National Institute of Neurological Disorders and Stroke (NINDS) Parkinson's Disease Research Website now contains links to a number of resources, including: animal models, antibody resources, clinical research information, gene therapy, and genetic resources. See: http://www.ninds.nih.gov/funding/research/parkinsonsweb/index.htm for more information.

Gene Therapy Resources
Goal B: By the end of FY2003, develop links on the NINDS PD Web to enable investigators to access application forms for obtaining vectors from the National Gene Vector Laboratories, and to obtain information from the Food and Drug Administration that can instruct investigators in the use of these vectors for translational research. (Low Risk/Short Term) Primary leads: NINDS, NCRR

6.16.03: A link to these forms is currently available on the NINDS Parkinson's Disease Research Web: http://www.ninds.nih.gov/funding/research/parkinsonsweb/gene_therapy.htm

Animal Models
Goal C: By the end of FY2004, form steering committee and develop guidelines to facilitate greater sharing of mouse models of PD among NIH-funded investigators, and continue to promote the deposition of the most successful models into genetically-engineered mouse resources (e.g., the Jackson Laboratory, and the Mutant Mouse Research Resource Centers) (Low Risk/Short Term) Primary leads: NINDS, NCRR

4/05: Creation of PD Mouse Model Repository: NINDS has recognized the burden placed on investigators by the financial and logistical realities of distributing other high demand research resources.Accordingly, NINDS and the University of California at Los Angeles created a resource in FY 2003 that will distribute PD mouse models that are not available through other resources such as Jackson Laboratories. NINDS sent a letter in October 2003 to approximately 2500 researchers to strongly encourage contributions to this resource. Models presently available in the repository include a knockout model of the DJ-1 gene, developed by NIMH and recently implicated in familial PD; a knockout model of the alpha-synuclein gene, and an alpha synuclein transgenic mouse based on a form of familial PD, generated by NHGRI. Information about the Repository can be found: http://www.ninds.nih.gov/funding/research/parkinsonsweb/amr/amr_mice_ucla_repository.htm

NIH is committed to ensuring that the research resources developed with NIH funding are made readily available in a timely fashion to the research community for further research, development, and application. In order to ensure that animal resources, including mouse models of disease, are shared widely throughout the research community, NIH has developed a "Model Organism Sharing Policy." This policy, which is available at: http://www.nih.gov/science/models/sharingpolicy.html, became effective with all grant/proposal submissions as of October 1, 2004, and requires grant applicants to include a plan for sharing model organisms developed as a result of the grant. The adequacy of plans for sharing model organisms will be considered by reviewers as an administrative note when a competing application is evaluated.

Other Resources: The National Center for Research Resources (NCRR) also strongly supports the development of animal models of PD, and contributes to the availability of mutant mouse models for the study of PD and Parkinson's-related diseases through its animal resource programs. Specifically, the Induced Mouse Resources Program (IMRP) maintains several mutant mouse strains with applications to PD research, including genetically-modified mice that express the human form of a mutant alpha-synuclein gene. These mice exhibit behavioral impairments, intracellular accumulation of alpha-synuclein throughout the nervous system, and nerve fiber degeneration. In addition, a mouse model of PD produced by "knocking out" a type of dopamine receptor is also available. More information on the IMRP can be obtained at: http://www.ncrr.nih.gov/ncrrprog/cmpdir/RODENT.asp#induce.

Brain Banks
Comments from participants at the July meeting: As part of the PD research community's continuing effort to coordinate brain banks, research centers, etc., a set of core assessments for individuals with PD should be established and validated. This would include standardized diagnostic criteria using neuro/neuropsych/psych assessments, autopsy/pathology/access procedures that can be used across research centers, improved diagnostic tools (e.g., biomarkers), and better links with clinical centers. In addition, the PD community should to be encouraged to educate patients and their families on the research benefits of donation.

Goal D: By the end of FY2003, develop partnerships with PD voluntary organizations to initiate outreach efforts to the PD patient community regarding the need for increased participation in making donations to brain banks. (Low risk/Short term) Primary lead: Parkinson's Disease Foundation, The National Parkinson Foundation

Goal E: By the end of FY2003, convene a meeting of the extramural research community and NIH staff to develop consensus on standardized assessment tools for PD, including clinical and imaging diagnostic definitions of PD for brain banking, brain banking protocols, etc. following the groundwork established by Lees, Gilman, and others. (Medium risk/Short term) Primary lead: NINDS

2.1.04: On March 1-2, 2003, NINDS sponsored a meeting of outside researchers and National Institutes of Health (NIH) staff to discuss the development of minimum data sets for the clinical diagnosis and pathological diagnosis of PD, among other issues (see below for additional details, or access the Agenda and Participant List at: http://www.ninds.nih.gov/funding/areas/neurodegeneration/2003_03_udall.htm).

Working groups assigned at this meeting have since completed these data sets, which can now be used by the research community to improve the accuracy of collecting PD tissues. The data sets can be accessed at: http://www.ninds.nih.gov/funding/research/parkinsonsweb/Parkinsonism_Clinical_Data_9_26_03.pdf (Parkinsonism Clinical Data) and http://www.ninds.nih.gov/funding/research/parkinsonsweb/Neuropathology_of_PD_Form.pdf (Diagnosis of Pathology).

Goal F: By the end of FY2006, establish a minimum of five coordinated brain banks internationally to serve the entire PD community. Standardized assessments developed at the 2003 meeting would be incorporated into methodology used by all banks. (Low risk/Medium term) Primary leads: NINDS, NIA

2.1.04: In March 2002, NINDS (along with the National Institute of Drug Abuse (NIDA), Office of Rare Diseases and National Institute on Aging (NIA)) sponsored an International Workshop on Brain Banking. One focus of this workshop was the banking of tissue for neurological diseases, including PD. Following the meeting, NINDS staff developed a summary of brain banking issues relevant for neurodegenerative diseases, which has been published in Current Opinion in Neurology: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12869803&dopt=Abstract. The issues identified in this paper provided important guidance for NINDS staff as they evaluated options for expanding brain banking efforts in PD.

In order to increase the availability of PD tissues, and capitalize on the brain banking infrastructure already existing in the PD community, NINDS is offering competitive supplements to Udall Centers that can be used to establish or expand brain banking resources. These supplements are available as part of a broader program - announced in July 2003 - in which NINDS raised the funding ceiling that may be awarded to Centers in order to encourage investigators to expand their clinical research efforts (see: http://grants2.nih.gov/grants/guide/notice-files/NOT-NS-03-020.html). It is expected that the development of the minimum data sets described above will enable Udall centers and other researchers to bank PD tissues in a standardized fashion. In addition, the planned Parkinson's Disease Data Organizing Center (see: http://grants2.nih.gov/grants/guide/rfa-files/RFA-NS-05-001.html) will oversee the coordination of these efforts, and will manage a catalogue of brain bank resources for the entire PD community.

4/05: A breakout meeting at the 2004 Udall Centers meeting was held to discuss brain banking efforts across centers, and how the Parkinson's Disease Data Organizing Center may best facilitate their coordination. Investigators with existing brain banks outside of the Udall program participated, and international brain banks were represented.

Participants in the breakout session focused on the needs for coordination and infrastructure. Suggestions were made as to how the NIH could help by building an informational webpage that could serve the needs of both patients/families and physicians/researchers. It was agreed that standards, as developed in the minimum data set for PD, should be adhered to and that the Parkinson's Disease Data Organizing Center (PD-DOC) would be an appropriate venue for coordination. It was also suggested that groups outside of the Udall Centers that have successful PD brain banking programs should be included.

Integration of PD Research Centers

Comments from participants at the July meeting: A network of integrated centers could link basic, translational, and clinical research, and could further the development of outcome tools, brain banks, and biomarkers. These centers could potentially include cores (e.g., for clinical pathology), tissue and data banks, and formal coordinating mechanisms (including a data coordinating center, development of standards for data collection, joint center meetings, mechanisms for community outreach, acceleration of clinical trials, add-on studies for clinical trials, and links with industry). Importantly, the ultimate goal of improving the integration of centers is to create a patient-centric system in which community physicians, research centers, and NIH are all part of a cohesive network. With such a system, information on patients can be better captured and managed, and research can be integrated at both the basic and clinical levels.

Goal A: By the end of FY2003, hold a data-gathering meeting/workshop including Udall Center investigators, Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER) investigators, representatives from the Alzheimer's Disease Research Centers (ADRCs), NIH staff, and the voluntary community, to identify needs for better organization and integration of PD research centers. Topics of focus at the meeting could include center priorities (basic/translational/clinical), brain banking, cores, data coordination, and the development of biomarkers. An additional topic of discussion would be methods of better integrating the patient component into studies, maximizing the usefulness of clinical databases, and involving community clinicians in research efforts and clinical trials. Follow-up would include consideration of a coordinating PD center as a possible mid/long-range goal. (Low Risk/Short Term) Primary leads: NINDS, NIEHS, NIA

2.1.04: On March 1-2, 2003, NINDS sponsored a meeting of outside researchers and NIH staff to begin to develop a minimum data set for both clinical diagnosis and pathological diagnosis of PD that can be used to improve the accuracy of collecting PD tissues. Participants also discussed ways in which PD research centers can be more collaborative, in order to streamline the collection of PD material and other joint projects. Working groups assigned at the meeting were asked to develop a minimum clinical and pathological data set, for use in developing future grant solicitations that include the collection of PD tissues by coordinated research centers. The Agenda and Participant List for this meeting can be accessed at: http://www.ninds.nih.gov/funding/areas/neurodegeneration/2003_03_udall.htm, and the data sets developed by the working groups can be accessed at: http://www.ninds.nih.gov/funding/research/parkinsonsweb/Parkinsonism_Clinical_Data_9_26_03.pdf (Parkinsonism Clinical Data) and http://www.ninds.nih.gov/funding/research/parkinsonsweb/Neuropathology_of_PD_Form.pdf (Diagnosis of Pathology)

Goal B: Include ADRC and CCPDER investigators in annual meeting of NIH Udall Center investigators. (Low Risk/Short Term) Primary lead: NINDS

2.1.04: The annual meeting of Udall Center and other PD Center investigators was held September 9-11, 2003, at Duke University. The meeting was well-attended by representatives from each of the Udall centers, as well as members of the NIH, Department of Defense (DoD) and PD voluntary communities. In addition, NINDS also invited investigators outside of the Udall research community - including ADRC and CCPDER researchers - to the meeting, to expand the scope of the discussion. A full report is available at: http://www.ninds.nih.gov/news_and_events/proceedings/udall_2003.htm

4/05: The 2004 annual meeting of Udall Center investigators was held November 30th -December 2nd in Maryland, and included representatives of PD research centers from outside the Udall Centers program. Breakout sessions for this meeting included brain banking, emerging technologies, and primate studies for PD. For a summary and participant list, see http://www.ninds.nih.gov/funding/areas/neurodegeneration/events_2004.htm

Goal C: By the end of FY2003, release a Notice in the NIH Guide (or utilize another competitive solicitation mechanism) as a means to address some of the immediate needs identified at the 2003 data-gathering meeting (described above). Coordinate this effort with all interested agencies, including PD Voluntary organizations. (Low Risk/Short Term) Primary lead: NINDS

2.1.04: Subsequent to the March meeting, NINDS has announced an increase in the funding ceiling that may be awarded to Centers, in order to aid the Udall researchers in carrying out the types of clinical research that will be needed to capitalize on the increasing number of findings in the basic sciences. More information on this announcement can be accessed at: http://grants2.nih.gov/grants/guide/notice-files/NOT-NS-03-020.html

NINDS, along with the National Institute of Environmental Health Sciences (NIEHS), has also announced the solicitation of a Parkinson's Disease Data Organizing Center, which will enable the systematic collection of clinical data from existing PD Centers (Udall Centers, NIEHS centers, the NIA Alzheimer's Disease Research Centers) and, eventually, from other sources where longitudinal data are collected. More information on this announcement can be accessed at: http://grants2.nih.gov/grants/guide/rfa-files/RFA-NS-05-001.html

4/05: NINDS solicited applications for the first Parkinson's Disease Data Organizing Center (PD-DOC) in November 2003, and awarded this cooperative agreement to the University of Rochester in September 2004. The Center is intended to serve as a 'data clearinghouse' for the Udall Centers program, as well as other Parkinson's research centers. The PD-DOC will collect clinical data on PD patients for research use and sharing by the community, as well as create virtual catalogs of biological materials of interest to PD.

Since the award was made, the PD-DOC has explored ways to dovetail the University of Rochester's databasing efforts with the existing NINDS genetics repository, and has begun to create patient confidentiality forms to ensure the protection of PD patients whose data will be collected. Udall representatives and others from the previous working group continue to evaluate and revise the set of clinical data elements previously developed by the Institute. The PD-DOC investigators have also begun initial contacts with the VA to determine if any commonalities could be taken advantage of, given their similar efforts on data banking. In December 2004, the PD-DOC investigators presented their strategy and plans at the 6th annual Udall Centers meeting, to collect additional feedback from the Center Directors and Staff. A link to information about the PD-DOC should soon be available at: www.PD-DOC.org

Goal D: By the end of FY2003, develop NIH and PD community consensus on the data set (i.e., the clinical information agreed upon as that best collected to accompany DNA samples, brain tissue, or for other clinical studies) for PD that will be used by the Udall Centers, CCPDERs, and ADRCs. (Medium risk/Short term) Primary leads: NINDS, NIEHS, NIA

2.1.04: At the meeting held in March 2003, working groups were asked to develop minimum data sets for both the clinical and pathological diagnosis of PD. These data sets can be used to improve the accuracy of collecting PD tissues, and are available at: http://www.ninds.nih.gov/funding/research/parkinsonsweb/Parkinsonism_Clinical_Data_9_26_03.pdf (Parkinsonism Clinical Data) and http://www.ninds.nih.gov/funding/research/parkinsonsweb/Neuropathology_of_PD_Form.pdf (Diagnosis of Pathology)

Public-Private Partnerships

Improved Coordination
Comments from participants at the July meeting: In addition to improved core resources and improved centers structure, another short-term organizational goal includes formal management at the level of the NIH director to ensure coordination between NIH agencies and outside agencies worldwide (including patient groups and industry), and the international research community. A "PD Champion," located at NIH, could be responsible for coordinating Parkinson-related activities across the NIH Institutes and Centers, and between the NIH, extramural investigators, the private foundations, and international contacts - with direct reporting and accountability to the NIH director. He/she could also help to continually assess the international portfolio of PD research, and define gaps in knowledge and infrastructure that could impede progress. Lastly, this individual would provide leadership and research support to quickly exploit research advances, as well as interact intensively with both intramural and extramural researchers and patient advocates

Goal A: By the end of FY2003, establish a formal mechanism for continuing dialogue between NIH, PD voluntary groups, other federal agencies, industry, etc. to identify opportunities for public-private partnership (e.g., facilitation of the outside groups' efforts to educate and raise awareness regarding recruitment for PD clinical trials). Achievement of this goal would require continued regular meetings of the NIH PD Coordinating Committee and the PD Implementation Committee. (Low Risk/Short Term) Primary leads: NINDS (federal coordination), Parkinson's Disease Foundation and the American Parkinson Disease Association (coordination of the voluntary community)

6.16.03: NIH staff and representatives of a number of PD voluntary organizations continue to hold regular conference calls on a number of subjects of mutual interest, including the development of an international meeting for PD, education and outreach to patients for clinical trial participation, and potential research co-funding opportunities.

Topics for discussion during a June 9th call with the PD voluntary groups included clinical trial recruitment, updates on the PD Matrix, plans for an international meeting on PD, and patent issues. For example, the Parkinson's Disease Foundation discussed its leadership of US PD voluntary organizations in developing materials that can educate the patient population about the NINDS PD Neuroprotection Trial (NET-PD), and identifying mechanisms for effectively distributing this information. The Parkinson's Disease Foundation and NINDS staff also discussed plans for an international meeting on PD that would bring together the basic science, clinical research, and voluntary PD communities in a forum that would foster learning and exchange between these groups.

2.1.04: In addition to these efforts, NINDS staff has engaged in regular conference calls with program staff from the Department of Veterans Affairs (VA) and the DoD to identify collaborative opportunities for fostering PD research.

On January 9, 2004, representatives from NINDS, NIEHS, the DoD, and the VA participated in a conference call to exchange information on activities of mutual interest, including: progress in animal models research, upcoming conferences and program announcements, the ongoing analysis of the federal-wide PD grant portfolio, and research collaborations between NINDS and the DoD.

4/05: NIH continues to hold regular meetings of the federal-wide Parkinson's Disease Coordinating Committee, to share information to avoid redundancy of efforts across institutes and agencies. Most recently, this group met on November 8, 2004. Representatives from multiple NIH ICs attended, along with representatives from the DoD program staff. Topics of discussion included ongoing activities in PD research, as well as common areas of concern, e.g., animal modeling, and comorbid conditions of PD, like dementia.

Goal B: By the end of FY2003, the NIH director will identify a member of the NIH staff who will help to coordinate PD activities across Institutes and Centers and will help to facilitate communications between NIH, outside agencies and investigators, and the PD voluntary organizations. This staff person will report directly to the NIH Director in addition to his/her own Institute/Center Director. (Medium risk/Short term) Primary lead: NINDS

2.1.04: Dr. Diane Murphy, Program Director in the Neurodegeneration Cluster at NINDS, continues to serve as a point-person for coordinating communications on PD research issues across NIH and to the PD voluntary agencies. Dr. Murphy reports to the leadership of NINDS, as well as the NIH Director, on PD issues. Information on Dr. Murphy's research interests can be accessed at: http://www.ninds.nih.gov/biography/pdbio_diane_murphy.htm

In addition the activities described above, Dr. Murphy is also working to improve coordination between intramural investigators across NIH who are actively researching the causes and treatments of PD. For more information on these researchers, see: http://www.ninds.nih.gov/funding/research/parkinsonsweb/intra_research.htm

International Meeting
Comments from participants at the July meeting: An annual meeting of the PD international community is needed; in particular one that would include representatives of industry, academia, NIH, private foundations, and members of the international PD research community.

Goal C: By the end of FY2004, private voluntary PD organizations will evaluate the current international meetings on PD and sponsor a large global meeting that addresses current perceived deficiencies. (Medium risk/Short term) Primary lead: Parkinson's Disease Foundation, The National Parkinson Foundation

4/05: The Parkinson's Disease Foundation continues to work with NINDS staff and PD research scientists in planning the World Parkinson Congress, to be held in Washington, DC February of 2006. The goals of this meeting include: 1) bringing together the basic science and clinical research communities to discuss research findings at the international level; 2) providing a forum for members of the voluntary PD community to learn about recent scientific findings and discuss quality of life and other issues of interest; and 3) encouraging a productive dialogue between these different groups.

The World Congress organizers have developed a draft agenda for the meeting and are currently exploring funding mechanisms for supporting the event. More information on the meeting is currently available at: http://www.worldpdcongress.org/

Basic Cell Biology Research - Understanding cell death, alpha-synuclein, parkin, ubiquitin pathways

Comments from participants at the July meeting: It will be important to address a number of basic questions in the cell biology of PD that remain unanswered. These include achieving a better understanding of the normal function of alpha-synuclein and parkin, elucidating the role of the ubiquitin system and its regulators in PD, and identifying cellular mechanisms (e.g., mishandling of proteins) that may be common to PD and other neurodegenerative diseases, like Alzheimer's disease and triplet repeat disorders.

Goal A: By the end of FY2003, convene a meeting of investigators funded under the FY2001 joint "fast-track" R21 program to share data and assess progress on the topics listed above and others. (Low Risk/Short Term) Primary lead: NINDS

2.1.04: On March 15, 2003, NINDS sponsored a meeting to showcase the work being conducted by the R21 grantees. This event was held jointly with a larger meeting of the American Society for Experimental NeuroTherapeutics (ASENT). A program and summary of the R21 portion of the meeting can be accessed at: http://www.ninds.nih.gov/funding/areas/neurodegeneration/r21_web_book.htm; more information on ASENT is available at: http://www.asent.org/

7/04:The researchers supported through the R21 fast-track grant program are contributing their findings on an ongoing basis. Important discoveries have been made into the cellular and molecular pathways that may be important in PD: (Nature Cell Biology 5, 118 - 125 (2003), J Neurochem. 2002 Oct;83(1):186-92, J Neurosci. 2002 Dec 15;22(24):10690-8, Neurosci Lett. 2004 Apr 8;359(1-2):124-6).

New PD models have been created and tested (Science. 2003 Dec 5;302(5651):1772-5., Eur J Neurosci. 2004 Feb;19(4):845-54, J Neurosci. 2003 Nov 26;23(34):10756-64), and studies related to stem cells and implants for PD have been published (J Comp Neurol. 2004 Feb 9;469(3):311-24, Cell Transplant. 2004;13(3):273-82, Exp Neurol. 2003 Aug;182(2):435-45).

Studies related to speech impairment or bladder dysfunction in PD have also been completed (Semin Speech Lang. 2004 May;25(2):169-80, Br J Pharmacol. 2003 Aug;139(8):1425-32).

Goal B: By the end of FY2003, convene a separate meeting of investigators funded under the FY2000 NINDS parkin and synuclein RFAs, as well as other investigators in the field, to share data and assess progress. (Low Risk/Short Term) Primary lead: NINDS

2.1.04: On June 12-13, 2003, NINDS and the NIA sponsored a meeting in Bethesda, MD, entitled "Cell Biology of Parkinson's Disease And Related Neurodegenerative Disorders." Presenters at this meeting included grant recipients from both the parkin and synuclein RFAs. A full report on this meeting is available at: http://www.ninds.nih.gov/news_and_events/proceedings/cell_biology_summary.htm

7/04: Recent advances resulting from the parkin RFA include the creation and analysis of parkin knock-out mice (J. Biol. Chem., 2004, 279(18):18614-22; and J. Biol. Chem., 2003, 278(44):43628-35), the creation of fly models of parkin (Proc. Natl. Acad. Sci. USA, 2003, 100(7):4078-83) and the discovery of parkin binding proteins (Brain Res. Mol. Brain Res., 2003, 117(2):179-89)

Recent publications from the synuclein RFA include the creation and analysis of a synuclein/toxin combination model of PD (Brain Res., 2002, 956(1):156-65; and Brain Res., 2004, 1004(1-2):61-72) and studies of the ubiquitin proteasome system at the synapse (Curr. Biol., 2003, 13(11):899-910.)

Goal C: By the end of FY2003, give a presentation at the NIH symposium during the annual meeting of the American Society for Cell Biology focusing on the emerging applications of basic cell biology (e.g., protein clearance, etc.) to PD and other degenerative disorders of the nervous system. (Low Risk/Short Term) Primary lead: NINDS

6.16.03: In December 2002, an NIH session was held at the American Society for Cell Biology (ASCB) annual meeting in which NINDS encouraged basic cell biologists to apply their expertise to Parkinson's Disease research.

Gene Discovery

Comments from participants at the July meeting: It is important to continue to search for new families with PD in order to identify more genes and their protein products implicated in the disease, to perform linkage analyses in families with cases of PD that have not been linked to currently known chromosomal loci, and to carry out fine-mapping and rapid gene identification studies in all PD families (the development of appropriate guidelines for genetic testing must be a priority in this process). Specific goals could include the molecular cloning of disease genes for known loci (e.g., PARK 3 to 9) and the identification of additional genes with a role in PD. The development of transgenic animal models based on these discoveries will help to elucidate pathogenic mechanisms.

2.1.04: Given the availability of the first genetic test for PD, and the issues that surround genetic testing in general, an open discussion of these issues involving scientists, clinicians, genetic counselors, ethicists, industry and individuals impacted by PD stands to benefit the entire PD community. In order to provide a forum for this discussion, NINDS is organizing a satellite workshop entitled "Genetic Testing for Parkinson's Disease and Related Disorders," which will be held at the annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT) in March 2004.

7/04: In order to provide a forum for discussion of the first genetic test for PD, and issues that surround genetic testing in general, NINDS organized a satellite workshop entitled "Genetic Testing for Parkinson's Disease and Related Disorders," which was held at the annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT) in March 2004. Participants at the workshop included scientists, clinicians, genetic counselors, ethicists, industry and individuals impacted by PD, and the meeting description and minutes can be found at: http://www.asent.org/meetings/am04/nindssymposium.php and http://www.ninds.nih.gov/funding/areas/neurodegeneration/20040313GeneticsMinutes.htm

Goal A: By the end of FY2003, issue a Program Announcement with Set-aside funds (PAS) on Gene Discovery for Complex Neurological and Neurobehavioral Disorders, including PD. This PAS will include standards for collection and sharing of samples that are consistent with those established in other PD goals. (Medium risk/Short term) Primary lead: NINDS

4/05: On March 31, 2003, NINDS, NIA, NIDA, and NIEHS issued a joint Program Announcement with Set-aside to solicit applications promoting the identification of susceptibility genes for complex neurological and neurobehavioral disorders http://grants2.nih.gov/grants/guide/pa-files/PAS-03-092.html. NINDS has since made one award on PD through this mechanism: a genetic study of the relationship of a particular variation in the gene for the tau protein to the development of Parkinson's disease.

In addition to this solicitation, numerous NIH-supported intramural and extramural researchers have made significant recent discoveries relevant to the genetic basis of PD. As an example, intramural and extramural researchers from the NIA, NINDS, and NHGRI have also collected data that suggests that abnormal levels of the alpha-synuclein protein can contribute to PD, even if the protein is the product of the normal alpha-synuclein gene. In 2003, these investigators found that select families with early-onset PD have a triplication of the alpha-synuclein gene on one chromosome, leading to an approximate doubling of the production of this protein. These data are consistent with the hypothesis that the "dose" of alpha-synuclein present in these individuals' brains is the primary cause of their PD (Singleton et al., Science, 2003, 302:841). In addition, this same group of NIA researchers has also demonstrated that people with the synuclein triplication (four copies of the gene instead of two) have twice as much blood synuclein as their unaffected brothers and sisters (Miller et al., Neurology, 2004, 62: 1835-8). This suggests that blood synuclein levels may serve as a critically needed biomarker for disease.

Intramural researchers from the NIA have also published the initial characterization of the gene responsible for PD in five families from England and Spain, which codes for a protein called dardarin (derived from the Basque word for tremor; Paisan-Ruiz et al., Neuron, 2004,44(4):595-600). This work was independently replicated by researchers from the Mayo Clinic Udall Center, who termed the gene LRRK2 (Zimprich et al., Neuron, 2004, 44(4):601-607). Although little is known about this gene at present, it does appear capable of causing late-onset forms of the disease, is expressed throughout the brain, and may function as a kinase - an enzyme that is capable of modifying proteins inside the cell that have been implicated in PD, such as alpha-synuclein and tau. Intramural scientists from NIA, in collaboration with NINDS funded scientists from Indiana and a group from the United Kingdom, have recently produced data that shows as much as two percent of sporadic PD cases may be caused by a single mutation in LRRK2 (Gilks et al., 2005, The Lancet, 365:415-416).

Goal B: By the end of FY2005, identify multiple families with PD and collect a minimum of 50 samples for the NINDS Human Cell Line and DNA Repository. (Medium risk/Short term) Primary lead: NINDS

6.16.03: In September 2002, NINDS awarded a contract with the Coriell Institute for Medical Research to develop a repository of data, cell lines, and DNA samples, to enhance the study of the genetic factors contributing to neurological diseases. PD is one of three diseases that has been included in the "ground floor" development of this resource.

4/05: The repository continues to archive samples from individuals with PD, and a catalog of samples is available at: http://locus.umdnj.edu/ninds/catalog/. The success in collecting PD samples has been phenomenal; seventy percent of the more than 2500 subjects collected have PD; and contributors have also submitted DNA from more than 600 controls. In addition, thanks to individuals who generously agreed to brief grace periods or none at all, 300 samples from individuals with PD, and 152 samples from controls are now available for sharing with the research community.

NINDS also offered administrative supplements to assist researchers with an ongoing NINDS clinical project to perform additional blood sample collection. The goal of the supplement was to defray some of the added costs of collecting and characterizing samples for submission to the NINDS Human Genetics Repository. A special award was made under this announcement to allow for the collection of DNA from the patients enrolled in NET-PD.

The repository homepage can be found at: http://ccr.coriell.org/Sections/Collections/NINDS/?SsId=10

Translational Research/Therapeutics Development

Comments from participants at the July meeting: The translation of novel therapies (including but not limited to cellular and gene therapies) from preclinical studies to clinical trials continues to be an important priority of the PD field.

Goal A: By the end of FY2004, complete the first set of milestones for the NIH-funded Parkinson's gene therapy translational project, including stable gene delivery to the brains of parkinsonian animal models and construction of regulatable vectors. (Medium risk/Short term) Primary lead: The Parkinson's Disease Gene Therapy Study Group

6.16.03: As part of its efforts to enhance translational research in PD, NINDS has awarded a grant to the Parkinson's Disease Gene Therapy Study Group for a large, multi-center, multidisciplinary, preclinical investigation of both dopaminergic enzyme gene therapy and neurotrophic gene therapy in non-human primate models of PD. Goals of the project include comparison of the different genes, and the testing of different gene delivery approaches. Investigators are also evaluating the safety, toxicity, efficacy, and longevity of these delivery vehicles, as well as their ability to turn gene expression on or off as needed. NIH anticipates that by supporting a rational, coordinated and integrated approach to the development of gene therapy treatments for PD, researchers can achieve the ultimate goal of laying the groundwork for an Investigational New Drug application to the U.S. Food and Drug Administration, necessary to proceed to clinical trials in humans.

In addition to this information, a press release from the University of Rochester on this project can be accessed at: http://www.rochester.edu/currents/V31/V31N05/story01.html

2.1.04: The Parkinson's Disease Gene Therapy Study Group has already accomplished its first-year milestones, including the creation of a stable colony of parkinsonian non-human primates, and the molecular creation of regulatable viral vectors to be used in the study.

7/04: In order to develop safe approaches for gene therapy in humans with PD, it is essential for the Parkinson's Disease Gene Therapy Study Group to identify a gene delivery vehicle, or vector, that can turn this delivery on and off in a controlled fashion. Study Group investigators examined three different molecular configurations of vectors to determine which, if any, showed promise for tight control of gene delivery. Although two of the vectors tested were "leaky" - in that gene delivery still occurred when the vector was theoretically turned off - one of the vectors showed considerable promise for further investigation. These findings were recently published (Gene Therapy, 2004, 11:1057-1067), and are an important early milestone for gene therapy for PD. Next steps will include testing in primates.

Goal B: By the end of FY2010, evaluate the effectiveness of four or more interventions to slow the progression of PD or other neurodegenerative diseases in patients. (High risk/Long term) Primary lead: NINDS

4/05: NINDS launched The Neuroprotection Exploratory Trials in PD (NET-PD) in April 2003; NET-PD is a major series of cooperative clinical studies designed to evaluate drug therapies that have the potential to slow the progression of PD.

Prior to the initiation of any phase II trials in NET-PD, NINDS undertook an extensive process of planning, infrastructure development, and rigorous review of candidate therapies. Specifically, a team of pharmacologists, clinicians, and clinical trial experts - including NINDS staff - developed specific criteria for the evaluation of potential therapies, ncluding scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. The team of reviewers solicited suggestions from scientists and clinicians in academia and industry, as well as patient and foundation groups, in order to identify as many potential therapies as possible. A Steering Committee for this trial selected a small number of compounds to be evaluated in pilot studies: minocycline (an antibiotic related to tetracycline), creatine (a common nutritional supplement and possible antioxidant), coenzyme Q10 (a health supplement and antioxidant), and GPI-1485 (a proprietary compound with growth factor properties). Information on all drugs evaluated can be found at: http://www.ninds.nih.gov/funding/research/parkinsonsweb/drug_summaries/ Fifty-one sites participated in the enrollment of individuals with early, untreated PD for these studies and recruitment was completed ahead of schedule. Initial results are anticipated in mid-2005, and the NET-PD research group will proceed with phase III trials of drugs that show promise in these first four phase II studies. In addition, the compound evaluation team is already engaged in a second round of drug assessments, to provide an additional group of compounds to test should none of the initial compounds prove successful in the phase II studies.

More information on these studies can be obtained by calling: 1-800-352-9424, or by visiting the weblink: http://www.parkinsontrial.ninds.nih.gov/

General Roadblocks to Advancing PD Research

Intellectual Property (IP) issues
Comments from participants at the July meeting: As the field has moved to implement the PD Agenda, numerous patent/intellectual property issues have arisen that threaten to hamper research in PD and many other areas of neuroscience. Translational research is particularly vulnerable to these roadblocks. Convening a summit to discuss IP roadblocks would facilitate discussion between the involved parties (e.g., pharmaceutical company representatives, academicians, federal agency representatives, and their international counterparts). Other approaches include the development of a "national IP clearinghouse," and/or a more systematic approach to licensing. Other fields have successfully managed these IP issues (e.g., cancer) and the neuroscience research community could benefit from these precedents.

Goal A: Address the IP/tech transfer concerns summarized above. (High risk/Medium term) Primary lead: NIH Office of Technology Transfer

2.1.04: The NIH Office of Technology Transfer has been engaged in a range of activities to address critical intellectual property (IP) issues. These include the negotiation of Memorandums of Understanding with international and domestic stem cell providers and others to make cells available under reasonable terms for both intramural and extramural investigators, participation in the development of a proposed Mouse Sharing Policy for NIH funding recipients, consultation with extramural and intramural research communities to provide guidance on NIH technology transfer policies, organization of educational seminars on IP issues for professional associations and other groups, and the development of a conference for members of industry to foster partnerships between the private sector and the NIH.

Stem Cell Distribution
Comments from participants at the July meeting: A priority in the field of stem cell research that would facilitate progress in PD is the establishment of an NIH-funded stem cell bank. Access to such a resource could facilitate more extensive evaluations of the potential for stem cells in replacement therapies as well as localized delivery of therapeutic compounds to the nervous system.

Goal B: Address the concerns related to stem cell distribution summarized above. (High risk/Medium term) Primary lead: NIH Stem Cell Task Force

6.16.03: In order to effectively implement the President's stem cell policy, NIH has established a Stem Cell Task Force, whose purpose is to: 1) enable and accelerate the pace of stem cell research by identifying rate limiting resources (both material and human) and develop initiatives to enhance these resources, and 2) seek the advice of scientific leaders in stem cell research about the challenges to moving the stem cell research agenda forward and strategies NIH may pursue to overcome these challenges. As part of the Task Force's efforts, NIH has established several working groups to discuss issues of particular importance. One of these working groups is devoted to issues related to research resource access, including an evaluation of the need for a center or a virtual stem cell repository. Information on the Stem Cell Task Force can be accessed at: http://stemcells.nih.gov/fedPolicy/NIHTaskForce.asp; information on the Resource Access Working Group can be found at: http://stemcells.nih.gov/policy/taskforce/workinggroups/resourceaccess/

2.1.04: In order to help researchers identify the stem cell lines that are most suitable for their intended experiments, the NIH Intramural Research Program established an NIH Stem Cell Unit in April 2003. Specifically, the Unit will use a standardized paradigm to conduct side-by-side comparisons of the available cell lines on the NIH Human Embryonic Stem Cell Registry, and will share the results with the scientific community. These data will give researchers critical information about the properties of available lines, so they can make an informed choice when ordering one or more of these lines. Although the assays performed by this Unit will be overseen by a steering committee of leading stem cell biologists in both the extramural and NIH intramural research communities, a scientist in the NINDS intramural research program will provide day-to-day direction for this unit. More information on the Stem Cell Unit can be obtained at: http://stemcells.nih.gov/scientificResources/nihscunit.asp, or individuals can contact the Unit at: NIHStemCellUnit@mail.nih.gov.

In addition to the NIH Stem Cell Unit, intramural researchers at the NIA are also engaged in comparisons of the available stem cell lines, in order to identify conditions that will optimize the potential of these cells for therapeutic use.

4/05: The many potential uses of human ES cells have prompted national research agencies in several countries to stimulate the rapid development of this field. In the U.S., NIH has awarded support to many universities to stimulate the use of the federally-approved human ES cell lines. In addition, the NIH has established a group - the NIH Stem Cell Characterization Unit - at the Bethesda campus to acquire federally-approved human ES cells from multiple sources and compare their properties. Different groups have used a variety of techniques to generate these cell lines, and as a result, the cells are difficult to grow. To address this issue, a central function of the NIH facility is to define general strategies that allow these cells to be widely and confidently used in research. The NIH stem cell facility now has 20 of the 22 federally-approved lines and cell stocks have been established for many of these lines. The supplier's original protocols (used to maintain individual cell lines) have now been replaced with a universal protocol that researchers can use (with minor modifications) to grow all of the lines. In addition, embryonic stem cells readily differentiate, making the undifferentiated cells hard to sustain. However, researchers have also established simple tests to identify cells in this undifferentiated state. Like other cells, ES cells are living organisms and can develop genetically alterations over time, and the ability to isolate new strains or sustain the parent strain depends on growing consistent stocks derived from a single cell. The Unit has now developed procedures to analyze the integrity of the genome in these cell lines. To provide information on all of these developments to investigators around the country, the Unit has established a website at: http://stemcells.nih.gov/research/NIHresearch/scunit/

To complement their cell characterization activities, the Unit has also established collaborations with other NIH intramural labs, and has provided human ES cells to advanced courses attended by scientists from many countries.

Individuals can also email questions to: NIHStemCellUnit@mail.nih.gov

Training
Comments from participants at the July meeting: The field of PD research would benefit from increasing the number of talented researchers in the field, in particular new investigators and individuals who are experienced in designing and managing clinical trials.

Goal C: Evaluate options for the recruitment of new investigators to the field of PD research, and for the training of investigators who are managing clinical trials and/or conducting observational studies in PD; conduct further investigation into existence of unique roadblocks for investigators in the PD field that are not currently addressed by federal and non-federal training opportunities. (Low risk/Short term) Primary lead: NINDS

4/05: NINDS issued a Request for Information in August 2004, to plan for a "Clinical Trial Methods in Neurology" course. NINDS ultimately seeks to develop a short course in clinical trial methodology targeted to junior neurology and neurosurgery faculty and fellows. This course would provide needed training for clinicians with neurological expertise in the methodologies critical to clinical research design and management.

Clinical Trials of Non-motor Symptoms

Goal: Use mechanisms available through clinical trial programs and intramural research programs at the individual NIH ICs to facilitate clinical trials of non-motor symptoms in PD. (Low risk/Medium term) Primary leads: NINDS, NIMH

4/05: NINDS and NIMH are interested in reviewing extramural applications for studies and trials that evaluate treatments for non-motor symptoms in PD.

Clinical depression contributes to a reduced quality of life and increased disability for many individuals with PD. As a first step in improving the diagnosis of depression in PD patients, NINDS sponsored a workshop in December 2003 to discuss the merits of existing depression rating tools with the extramural research community. Participants identified concerns with some of the most commonly-used tools, and will work with NINDS staff to develop provisional diagnostic criteria, evaluate existing rating scales, and make subsequent recommendations to the clinical community. Improvements in the ability to diagnose depression in individuals who have PD will be essential to design clinical trials of therapeutic interventions. A summary of the meeting on depression and PD is available at: http://www.ninds.nih.gov/news_and_events/proceedings/depression_summary.htm, and a paper outlining provisional diagnostic criteria for the diagnosis of depression in individuals with PD has been submitted for publication.

The National Center for Complementary and Alternative Medicine (NCCAM) also continues to sponsor research on complementary and alternative medicine (CAM) practices to treat PD and its accompanying symptoms - including depression. A significant number of individuals with PD experience depression, making therapies critically important. However, commonly prescribed antidepressants are often not appropriate for individuals with PD because some can exacerbate already compromised motor functions. To address this need, NCCAM is supporting a clinical trial to determine if S-Adenosylmethionine (SAM-e; sold as a dietary supplement) is a safe and effective therapy for depression in PD. This study is also investigating the underlying mechanism of SAM-e as it relates to depression and the motor function symptoms of PD. In addition to this work, NCCAM is also supporting research on trans-cranial magnetic stimulation for individuals with PD and severe depression.

In addition, NINDS and the National Heart, Lung, and Blood Institute recently issued a Program Announcement with Set-aside (PAS) to encourage the development of studies on sleep disturbances in parkinsonian disorders. Although this announcement is not designed to recruit applications for clinical trials per se, data collected in pilot studies could lead to clinical trials in the future. More information on this PAS can be found at: http://grants1.nih.gov/grants/guide/pa-files/PAS-03-131.htm NINDS continues to receive applications in response to this announcement.

Understanding Gene/environment Interactions

Comments from participants at the July meeting: In addition to enhancing our understanding of the genes that contribute to PD, it will also be critical to understand the relationship between genetic contributions and influences of environmental toxicants. Possible areas of study could include further development of animal models of gene-environment interactions, the study of cohorts at high risk for PD (possible use of "hot spot" populations), prospective large-scale population studies involving collaborations between geneticists and epidemiologists, expanded evaluation of known cohorts (e.g., Nurses' Health Study, Physicians' Health Study, Honolulu-Asian Aging Study, Agricultural Health Study, 1999 Tanner et al. study of PD in twins, the Northern California Kaiser Permanente Medical Care Program, etc.), and/or a more comprehensive evaluation of familial and environmental clusters. Large-scale cohort studies may be prohibitively expensive at present, however other methods may be amenable to more immediate consideration.

Goal A: By the end of FY2003, establish an annual forum (e.g., workshop, conference) for the discussion/presentation of emerging topics in environmental influences in PD. (Low Risk/Short term) Primary Lead: NIEHS

2.1.04: In mid-2004, the NIEHS will sponsor a meeting on "Environmental Influences in Neurodegenerative Disease: Synthesis and Next Steps," to bring together current NIEHS grantees studying neurodegenerative diseases such as PD and AD - as well as other non-grantee experts - to highlight recent progress in elucidating environmental etiologies of neurodegeneration, promote cross-fertilization of ideas among researchers, diseases and disciplines and identify and prioritize data gaps, future resource needs and research opportunities. The results of this meeting will help gauge the effectiveness of recent NIEHS targeted program activities and will provide a template for crafting a five-year research agenda for understanding environmental contributions to neurodegenerative disorders. NINDS, NIA and NIMH will be invited to participate in this meeting to facilitate joint program planning for future initiatives.

Goal B: By the end of FY2003, issue a PAS on Gene-Environment interactions in PD and other Neurodegenerative Diseases. This PAS will encourage the development of novel animal models that combine genetic susceptibility with relevant exposures as well as the use of cutting edge technologies for identifying changes in genes, proteins and metabolites that link exposures to the death of specific neuronal populations. (Low Risk/Short term) Primary Lead: NIEHS

2.1.04: A new NIEHS program announcement, "Gene-Environment Interactions in Neurodegenerative Disease" will focus on promoting research in identified gaps in neurodegenerative disease. The first year of this initiative is emphasizing support for research in gene-environment interactions in amyotrophic lateral sclerosis. Next year's focus will be influenced by the results of the 2004 planning meeting on "Environmental Influences in Neurodegenerative Disease: Synthesis and Next Steps," as described above.

Goal C: By the end of FY2005, determine the feasibility of resampling cohort studies to include assessment of PD, and detailed exposure histories, within appropriate bioethical considerations (e.g., Nurses' Health Study, etc.). Encourage collaborations between existing funded PD epidemiologic cohorts to collect complementary genetic and risk exposure data (e.g., using administrative or competitive supplements). (High Risk/Short term) Primary leads: NIEHS, NINDS

2.1.04: On March 9th, 2004, the Michael J. Fox Foundation will hold a meeting entitled "Innovative Epidemiological Approaches to Parkinson's disease." Discussion of how existing epidemiological cohorts may be best utilized for innovative studies is on the agenda, and NINDS staff will attend the meeting.

Biomarker Development

Comments from participants at the July meeting: The development of biomarkers for PD has already been identified as a priority for the PD community. This issue could be addressed through several different approaches, including a more extensive investigation of possible peripheral markers for PD (e.g., in the blood), further evaluation of biomarkers through the field of proteomics, integration of biomarker investigations with ongoing clinical trials, and the development of a cohort at high risk for PD that could undergo a more in-depth assessment of biomarkers (e.g., imaging, cell loss, cerebrospinal fluid, etc.).

Goal: By the end of FY2005, evaluate the results of grants (funded publicly or privately) on biomarker development in order to determine if any of these approaches should be developed on a large scale. Incorporate models used successfully in the NINDS-sponsored neuroprotection clinical trial. (High risk/Short term) Primary leads: NINDS, The Michael J. Fox Foundation for Parkinson's Research

6.16.03: In January 2003, The Michael J. Fox Foundation for Parkinson's Research committed $1.6 million to fund eight research projects for the development or validation of a biomarker for PD. More information on these grants is available at: http://www.michaeljfox.org/research_MJFFfundingPortfolio.cfm

4/05: As a first step to explore the use of imaging tools as biomarkers in PD, NINDS sponsored a workshop in July 2003 to consider the use of imaging as an additional measure or endpoint in clinical trials; the capabilities of current imaging technology, including molecular "tags;" and the feasibility of using imaging measures consistently in multicenter clinical trials. Following this meeting, the participants and NINDS staff published a paper which outlines recommendations on: 1) methodological changes in studies to determine how imaging measures relate to clinical endpoints, and 2) development of new markers to better capture the degenerative process and more of the clinical features of PD (Ravina et al., Neurology, 2005, 64:208-215).

Last updated August 13, 2008