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 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.

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 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.

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.