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Parkinson’s Disease Research Agenda
National Institutes of Health
National Institute of Neurological
Disorders and stroke
• A new optimism that Parkinson’s disease can be
defeated is energizing the research community and
patient advocates. Halting the progression of
Parkinson’s 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 Parkinson’s 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 Parkinson’s disease requires
crossing a major frontier of medicine.
• The National Institute of Health conducts a vigorous
and expanding program of research focused on
Parkinson’s disease. At a landmark meeting in
November 1999,the directors and staff of the major
components of NIH conducting Parkinson’s 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 Parkinson’s advocacy groups discussed an
agenda for Parkinson’s disease research which formed
the basis for this document.
What is Parkinson’s 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 movement, postural changes, gait disturbances, and
difficulty initiating voluntary movement. However, it can cause a wide spectrum of other
symptoms, including dementia, abnormal speech,
sleep disturbances, swallowing problems, sexual
dysfunction, and depression.
UNDERSTANDING PARKINSON’S DISEASE
• Parkinson’s 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.
• Using genetics to understand Parkinson’s disease:
Although most people do not inherit Parkinson’s
disease, studying the genes responsible for the inherited
cases is advancing our understanding of both common
and familial Parkinson’s disease. Identifying genes that
can cause Parkinson’s 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 Parkinson’s disease. Beyond single
genes, we must unravel the complex interactions
between genetic predisposition and environmental
influences that cause most cases of Parkinson’s disease.
• Epidemiology to determine entvironmental risk
factors for parkinson’s disease: Epidemiological
investigations can provide essential clues to what
causes Parkinson’s 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
Parkinson’s 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
Parkinson’s disease and provide other needed
epidemiological information. It would be highly
efficient in such a study to include other disorders.
• Life and death of neurons involved in Parkinson’s
disease: Parkinson’s disease selectively kills only
certain types of brain cells. Understanding the normal
biology of neurons susceptible to Parkinson’s 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
Parkinson’s 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 Parkinson’s
disease.
• Neural circuits and systems in Parkinson’s 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 brain’s movement control
stystems. Moreover, we do not understand how
Parkinson’s 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.
DEVELOPING NEW TREATMENTS FOR
PARKINSON’S DISEASE
• Developing therapies to prevent Parkinson’s disease, to
suppress symptoms, to halt disease progression, and to
repair damage are all fundamental goals. Available drugs
suppress symptoms early in Parkinson’s 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.
• 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 Parkinson’s 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 Parkinson’s disease.
Delaying or preventing Parkinson’s 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 Parkinson’s disease, are likely to be more
efficient.
• Deep brain stimulation and other surgical
approaches: Neurosurgical approaches are
becoming increasingly important in the treatment
of Parkinson’s 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.
• Cell implantation: Restoration of Function is critical
for people who now have Parkinson’s 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 Parkinson’s disease.
• Gene therapy: In the long run gene therapy offers
potential for Parkinson’s 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
Parkinson’s disease: NIH can work with other
appropriate government agencies and private sector
organizations to use “evidence based” methods to
develop recommendations for treating Parkinson’s
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.
CREATING NEW RESEARCH CAPABILITIES
Several resources and tools must be provided to
promote research on Parkinson’s 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 Parkinson’s disease must
apply these methods to understand at the
molecular level the causes and progression of
disease and the responses of neurons to treatment.
• Models of Parkinson’s disease: Non-human
models of Parkinson’s 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 Parkinson’s disease, the
gradual cell loss, or the destruction of nondopamine 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.
• Biomarkers: Better biomarkers, that is, reliable
indicators of risk, disease state, and disease
progression, would accelerate research on the
causes and progression of Parkinson’s 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 Parkinson’s 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.
• High throughput drug screening for Parkinson’s
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 Parkinson’s 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 Parkinson’s
disease.
ENHANCING THE RESEARCH PROCESS
• Ethical issues in research involving persons with
Parkinson’s disease: NIH is committed to being a
leader not only in basic and clinical research on
Parkinson’s 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 Parkinson’s 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.
• Public-Private
partnerships:
Private
organizations play a critical role in Parkinson’s
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.
CONCLUSION
• This document will inform Congress about the
exceptional opportunities for making progress
against Parkinson’s disease. The professional
budget estimate highlights approximately $ 70
million of new spending for FY2001,
approximately a 40% increase over NIH projected
spending levels for Parkinson’s 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.
• The task of finding a cure for Parkinson’s 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 Parkinson’s disease,
would immediately apply to other disorders. For
others there is substantial, though not complete,
overlap. While this document is properly focused
on Parkinson’s disease research, the relevance of
this research agenda for other diseases should be
noted. Parkinson’s disease research and lead the
way in the fight against all forms of
neurodegeneration.