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Citing Progress and Charting Prospects: The New NIH Parkinson's Research Plan
By Robin Elliott
Six years ago, the National Institutes of Health (NIH) issued the PD Research Agenda, its first comprehensive "plan" for Parkinson's research. That report, drawing on the expertise of dozens of leading PD scientists, identified multiple pathways to exploring the disease and placed a price-tag on the work - over five years - of about $1 billion.
Today, people are asking: How far have we come on our path to finding the causes of the disease and its cure? Where is PD research headed?
These are the questions that government research administrators wrestle with in the 2006 Parkinson's Research Plan. The 34-page document is based on recommendations from a PD Summit that was organized by the National Institute of Neurological Disorders and Stroke (NINDS) in June 2005. Attendees included leading academic and industry clinicians, scientists, patient advocacy groups and NIH representatives. The plan is a comprehensive overview of the progress of investments in PD research by government and other agencies from 2000 to 2004. It also aims to identify promising directions for future research.
While the report does not attempt to pinpoint just where we are in our drive to beat Parkinson's, the authors note with pride the number and range of scientific studies that have been sponsored since the earlier report in 2000. They also point to gains that have been achieved in "accelerating therapeutics discovery and translational research" - that is, over and above the "basic" research that remains the core of the work that is supported by the NIH. This strengthened emphasis on translational research has been a major priority of the PD community in recent years.
Improving our understanding of PD
Of all the areas of basic Parkinson's science, none has shown more progress than genetics. Since 1997, when the link was discovered between certain cases of PD and a mutation in the gene for a protein called alpha-synuclein, five additional genes have been linked to Parkinson's and "evidence suggests the existence of additional, as yet unidentified genes." These advances "provide a direct window into the cellular causes of disease, not only for individuals with hereditary disease, but for those [the vast majority] with sporadic [i.e., non-genetic] disease."
The authors urge further work on gene discovery, with a focus on the interaction between genes and the environment. Two areas in particular are targeted for highest priority. One is genetic studies of people with Parkinson's (along with their family members who do not have the disease but may be carriers of genetic mutations). The other is to survey people who do not have Parkinson's but whose genetic make-up could provide clues as to what causes PD.
Translating discoveries into treatments
Noting that PD research "appears to be at the stage when translational research is an important next step towards goals for feasible new drug treatments," the NIH report highlights two areas in particular as "most important for focused translation." These are gene therapy and cell implantation.
Gene therapy is a process by which scientists strip the patient's DNA of the genes that produce certain bad proteins, and then replace them with genes producing good proteins. The good proteins are then sent off to repair damaged brain cells using a viral delivery system. Two "good" proteins singled out by the NIH team are GDNF and neurturin.
In 2004, Amgen (the company that holds the patent to a specific delivery system of GDNF) halted clinical trials of the product, saying the treatment was not effective and might be dangerous. Work on GDNF continues at other study sites.
As for the other protein, neurturin, the Ceregene company has recently released promising results from a Phase I clinical trial, concluding that the participants experienced no significant negative side-effects. The study also suggests some preliminary evidence that the treatment may work - something that will be tested in a forthcoming Phase II trial (see News In Brief).
Cell implantation (or cell replacement) involves replacing damaged dopamine-producing brain cells with healthy cells from such sources as stem cells - both embryonic and adult. The history of this approach, including two major NINDS-funded trials involving the transplantation of fetal brain tissue, has been clouded by findings that some of the participants experienced unrestrained cell growth following implantation, leading to serious dyskinesias (violent involuntary movements). The authors recommend further research on this approach.
Traditionally, the development of new treatments has been left to the pharmaceutical industry, building on a platform created by university scientists. In this report, the NIH authors see universities as becoming increasingly more involved in drug development - especially in the process known as "high-throughput screening," in which thousands of drugs are run through a computer program to test for relevance to specific diseases, including Parkinson's.
The authors see this change in role as helpful in advancing new treatments in two ways. One is identifying potential new compounds for investigation and development by industry. The other is helping to identify new roles for old medicines - treatments that have already been found to be safe and effective for one medical condition, and may have relevance also for Parkinson's.
Looking to the future of NIH's involvement in drug discovery, the authors give high priority to the development of new animal models for Parkinson's. They also recommend greater involvement of pharmaceutical companies as advisors to NIH and greater commitment by NIH in translational research, including validating drug targets and conducting studies of drug toxicity.
Finding better ways to treat Parkinson's
Noting that current treatments for Parkinson's are primarily limited to easing the symptoms of the disease, the authors urge research into treatments that may be "neuroprotective and disease modifying."
One major NIH initiative to this end is NET-PD, a large set of clinical trials that are designed to assess interventions that may slow the progression of Parkinson's. Trials of two of these interventions - creatine and coenzyme Q10, both dietary supplements - are scheduled to begin over the next several months.
The authors also urged that scientists pay greater attention to developing treatments for people with early-stage Parkinson's, and to finding new "biomarkers" that will track the progression of the disease and responses to treatment.
Another subject addressed was deep brain stimulation (DBS), where the authors point to the need for long-term follow-up of trial participants. They urge the exploration of technical improvements and assessments of the importance of DBS for non-motor symptoms of PD, such as mood and speech.
A clear difference between this report and the last one is the increased attention to the non-motor symptoms of Parkinson's. It recommends additional research on such non-motor impairments in Parkinson's as sleep and fatigue; behavioral and cognitive impairments; and anxiety, depression and psychosis.
To accomplish this task, the report recommends such measures as getting non-motor manifestations of Parkinson's disease better represented in clinical trials, improving ways of measuring them and developing new animal models to test the safety and efficacy of treatments for non-motor symptoms.
Another marked change from the 2000 report is a shift in focus from strictly medical issues towards those that fall into the area known as "quality of life."
Noting the attention given to such areas as exercise, music and creativity at the recent World Parkinson Congress (in which PDF played a leadership role), the authors say that such "non-invasive approaches to quality of life are extremely important to individuals living with PD."
Improving research tools and resources
The report notes significant gains since 2000 in the core research infrastructure available to Parkinson's scientists. Notable are improvements in shared resources (e.g., animal models and human tissue banks) and in integrating and enhancing clinical studies of Parkinson's at the 13 universities designated by NIH as Morris K. Udall Centers of Excellence for Parkinson's Disease Research.
Looking to the future
What now? Six years after the first plan, where are we? Does the new "plan" keep us on track?
Some observers have noted that the document is not so much a "plan," with a set of action points to follow, as it is a comprehensive, authoritative and accessible review of Parkinson's science. By identifying the most promising areas in PD science, this document can be used by the research community in planning focal points for studies to find the cause(s) of and a cure for Parkinson's.
Leaders in the Parkinson's community also commend Dr. Story Landis, Director of NINDS, and her team for their forthright response to changes both in the medical and sociological definitions of Parkinson's and the pointers to its management. This includes recognizing the potential role of the NIH in translational research and drug development and being open to redefinitions of PD that take better account of non-motor symptoms.
For the full document, visit http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm.
Robin Elliott is Executive Director of the Parkinson's Disease Foundation.