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Parkinson

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Title: Parkinson


1
Parkinsons Disease Research Agenda
  • National Institutes of Health
  • National Institute of Neurological Disorders and
    stroke

2
  • A new optimism that Parkinsons disease can be
    defeated is energizing the research community and
    patient advocates. Halting the progression of
    Parkinsons disease, restoring lost function, and
    even preventing the disease are all realistic
    goals. This hope is fueled by the accelerating
    pace of discovery in neuroscience research
    generally, by advances in understanding what
    causes Parkinsons disease, and by a wide range
    of new treatments on the horizon, including stem
    cell transplants, precision surgical repair,
    chronic brain stimulation, and natural growth
    factors, to name a few. Optimism is tempered by
    the recognition that we cannot yet cure any major
    neurodegenerative disorder, and defeating
    Parkinsons disease requires crossing a major
    frontier of medicine.

3
  • The National Institute of Health conducts a
    vigorous and expanding program of research
    focused on Parkinsons disease. At a landmark
    meeting in November 1999,the directors and staff
    of the major components of NIH conducting
    Parkinsons disease research, working together
    with patient advocates, initiated a planning
    process to ensure that extraordinary
    opportunities to move toward a cure are not
    neglected and that critical obstacles to progress
    are addressed. On January 4-6,2000 a Workshop
    including intramural, extramural, and industry
    scientists and representatives from several
    Parkinsons advocacy groups discussed an agenda
    for Parkinsons disease research which formed the
    basis for this document.

4
What is Parkinsons Disease
  • 1817, James Parkinson first observed this disease
    and called it The Shaking Palsy. His seminal work
    was based on his clinical observation of six
    cases. The cardinal symptoms include tremor at
    rest, bodily rigidity, marked slowness of move-
    ment, postural changes, gait disturbances, and
    difficulty initiating voluntary movement. How-
    ever, it can cause a wide spectrum of other
    symptoms, including dementia, abnormal speech,
    sleep disturbances, swallowing problems, sexual
    dysfunction, and depression.

5
UNDERSTANDING PARKINSONS DISEASE
  • Parkinsons disease is a devastating and complex
    disease that progressively affects the control of
    movement and also produces a wide range of other
    problems for patients. The symptoms reflect the
    gradual loss of nerve cells in particular areas
    of the brain. Among these, cells that produce the
    neurotransmitter dopamine die in a small brain
    area called the substantia nigra. What triggers
    the death of these nerve cells is unknown.

6
  • Using genetics to understand Parkinsons disease
    Although most people do not inherit Parkinsons
    disease, studying the genes responsible for the
    inherited cases is advancing our understanding of
    both common and familial Parkinsons disease.
    Identifying genes that can cause Parkinsons
    disease is crucial for understanding the disease
    process, revealing drug targets, improving early
    diagnosis, and developing animal models that
    accurately mimic the slow nerve cell death in
    human Parkinsons disease. Beyond single genes,
    we must unravel the complex interactions between
    genetic predisposition and environmental
    influences that cause most cases of Parkinsons
    disease.

7
  • Epidemiology to determine entvironmental risk
    factors for parkinsons disease Epidemiological
    investigations can provide essential clues to
    what causes Parkinsons disease, to risk factors
    that predispose people to this desease, and to
    preclinical characteristics of this disorder. In
    the short term, case control studies that compare
    people with and without Parkinsons disease can
    provide valuable information about environmental
    risk factors and the interaction of genetic and
    non-genetic factors. In the long run, a
    prospective study, which follows people who do
    not yet have the disease, will help identify the
    causes of Parkinsons disease and provide other
    needed epidemiological information. It would be
    highly efficient in such a study to include other
    disorders.

8
  • Life and death of neurons involved in Parkinsons
    disease Parkinsons disease selectively kills
    only certain types of brain cells. Understanding
    the normal biology of neurons susceptible to
    Parkinsons disease is crucial for understanding
    this selectivity and for developing new therapies
    that rescue of even replace those cells. Studying
    how inherited defects in genes for proteins such
    as synuclein and parkin can cause Parkinsons
    disease are important inroads to understanding
    the disease. Other important areas for research
    include the role of mitochondrial
    impairment,protein aggregation, excitotoxicity,
    the immune system and apoptosis pathways in
    Parkinsons disease.

9
  • Neural circuits and systems in Parkinsons
    disease While there has been considerable
    progress in understanding how the normal brain
    controls movement, there is a great deal we do
    not yet understand about the brains movement
    control stystems. Moreover, we do not understand
    how Parkinsons disease disrupts these systems to
    produce the major symptoms and other problems
    associated with this disease. A variety of
    studies using anatomical, electrophysiological,
    neurochemical, and imaging methods are needed.

10
DEVELOPING NEW TREATMENTS FOR PARKINSONS DISEASE
  • Developing therapies to prevent Parkinsons
    disease, to suppress symptoms, to halt disease
    progression, and to repair damage are all
    fundamental goals. Available drugs suppress
    symptoms early in Parkinsons disease, but
    progressively fail as more nerve cells die. A
    wide range of therapeutic approaches are now at
    various stages of development, including
    precision surgical ablation, chronic electrical
    stimulation, cell implantation, and several types
    of drugs. To achieve therapeutic goals, many
    separate studies are required, from the first
    steps in translating basic research advances,
    animal testing, preliminary safety studies in
    human patients, and finally large trials to
    evaluate the effectiveness of a therapy.

11
  • Pharmacological approaches A series of small
    Phase II clinical trials could help to rapidly
    identify promising candidate drugs for large
    scale clinical trials. Major large randomized
    controlled clinical trials aimed at proventing
    the progression of Parkinsons disease can
    evaluate the efficacy of drugs already approved
    by the FDA. NIH must also foster studies to
    evaluate which known symptomatic treatments for
    non-motor symptoms are best for people with
    Parkinsons disease. Delaying or preventing
    Parkinsons disease is an improtant goal, but the
    relative rarity of the disease requires very
    large numbers of people to assess prevention
    therapies. Prevention trials focusing on people
    at high risk, such as large families with genetic
    markers for Parkinsons disease, are likely to be
    more efficient.

12
  • Deep brain stimulation and other surgical
    approaches Neurosurgical approaches are becoming
    increasingly important in the treatment of
    Parkinsons disease, including precision ablation
    therapies, deep brain stimulation and cell
    transplantation. An emerging field is the direct
    micro-delivery of neuroactive substances to the
    brain. A wide range of studies are needed to
    understand how these interventions affect the
    brain, to improve the technologies involved, and
    to evaluate the results of the various approaches
    in patients.

13
  • Cell implantation Restoration of Function is
    critical for people who now have Parkinsons
    disease, and cell implantation is one promising
    approach to brain repair. Early results from
    embryonic tissue transplantation trials present a
    proof of principal that this strategy is worth
    pursuing, but also show that, at the present
    stage of development, these approaches produce
    insufficient benefit and unexpected complications
    which preclude their widespread use.
    Transplantation strategies based on stem cells
    present enormous potential, but we must better
    understand the fundamental biology of stem cells
    before they can safely and effectivel be used for
    therapy of Parkinsons disease.

14
  • Gene therapy In the long run gene therapy offers
    potential for Parkinsons disease and many other
    brain disorders. Although holding promise, the
    development of efficient and safe means to
    deliver genes to brain cells is needed before
    gene therapy can be used. 
  • Outcomes research and evidence based medicine in
    Parkinsons disease NIH can work with other
    appropriate government agencies and private
    sector organizations to use evidence based
    methods to develop recommendations for treating
    Parkinsons disease. Another goal is to determine
    the resources needed to treat this disease which
    is essential for planning to care for the aging
    US population.

15
CREATING NEW RESEARCH CAPABILITIES
  • Several resources and tools must be provided
    to promote research on Parkinsons disease. 
  • Array technologies Gene array technologies allow
    simultaneous monitoring of the activity of
    thousands of genes. Methods are also becoming
    available to tract the protein components of a
    cell. Researchers studying Parkinsons disease
    must apply these methods to understand at the
    molecular level the causes and progression of
    disease and the responses of neurons to
    treatment.

16
  • Models of Parkinsons disease Non-human models
    of Parkinsons disease are essential for
    understanding the causes and progression of nerve
    cell death and for efficiently developing new
    therapies. Present models do not adequately mimic
    the cause of human Parkinsons disease, the
    gradual cell loss, or the destruction of
    non-dopamine cells. A range from in vitro
    molecular and cellular models, through simple
    organisms like fruitflies and nematode worms, to
    transgenic mice and primates is needed.

17
  • Biomarkers Better biomarkers, that is, reliable
    indicators of risk, disease state, and disease
    progression, would accelerate research on the
    causes and progression of Parkinsons disease and
    the development and testing of therapies. To be
    most useful, biomarkers must not only be specific
    and sensitive, but also sufficiently risk-free
    and simple that they may be used routinely. 
  • Neuroimaging At present the most mature
    biomarkers for Parkinsons disease rely upon
    neuroimaging. Beyond biomarkers, there is a wide
    spectrum of imaging methods that may yield
    insights into the causes and treatment of this
    disease.

18
  • High throughput drug screening for Parkinsons
    disease Recent spectacular advances in robotic
    and synthetic chemistry, combined with increased
    understanding of molecular targets of drug
    therapy, make it possible to rapidly screen large
    numbers of potential drugs. NIH should encourage
    the development of molecular and, especially,
    cellular assays for screening drugs for
    Parkinsons disease and explore ways to make the
    technology for high throughput screening more
    widely available. 
  • Brain banks and other repositories The
    systematic collection, maintenance, and
    distribution of biological and clinical materials
    are essential resources for advancing basic and
    clinical research on Parkinsons disease.

19
ENHANCING THE RESEARCH PROCESS
  • Ethical issues in research involving persons with
    Parkinsons disease NIH is committed to being a
    leader not only in basic and clinical research on
    Parkinsons disease, but also in the ethical
    dimensions of the research it funds. Ethical
    issues arise from both research and, more
    broadly, from care of patients with this
    disease. 
  • Innovative funding mechanisms Advancing research
    against Parkinsons disease will require
    innovative funding mechanisms such as providing
    seed money to draw new investigators into the
    field, supplements to rapidly enhance the
    research of current investigators, and
    accelerated review for some types of proposals.

20
  • Public-Private partnerships Private
    organizations play a critical role in Parkinsons
    disease research that complements the NIH
    mission. NIH is committed to coordinating efforts
    in partnership with private organizations.
    Private organizations play particularly important
    roles in recruiting patients for genetic,
    epidemiological and clinical studies, in funding,
    especially for pilot projects and new
    investigators, in interactions with industry, in
    disseminating reliable information, and in
    planning the research agenda.

21
CONCLUSION 
  • This document will inform Congress about the
    exceptional opportunities for making progress
    against Parkinsons disease. The professional
    budget estimate highlights approximately 70
    million of new spending for FY2001, approximately
    a 40 increase over NIH projected spending levels
    for Parkinsons disease. Subsequent increases
    bring the level to about 282 million in the
    fifth year. It must be noted that this estimate
    is based on our assessment of scientific
    opportunities. We have not taken into account
    economic constraints and the need to address
    other public priorities and NIH responsibilities.

22
  • The task of finding a cure for Parkinsons
    disease is all the more difficult because we
    cannot yet cure any major neurodegenerative
    disorder. Many of the critical research needs
    highlighted by the Workshop, if solved for
    Parkinsons disease, would immediately apply to
    other disorders. For others there is substantial,
    though not complete, overlap. While this document
    is properly focused on Parkinsons disease
    research, the relevance of this research agenda
    for other diseases should be noted. Parkinsons
    disease research and lead the way in the fight
    against all forms of neurodegeneration.
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