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.