107th Congress

Testimony on Parkinson’s Disease Research

Audrey Penn
Acting Director, National Institute of Neurological Disorders and Stroke
May 22, 2002

Mr. Chairman and Members of the Committee, I am Dr. Audrey Penn, Acting Director of the National Institute of Neurological Disorders and Stroke (NINDS). NINDS has a long history of supporting critical research in Parkinson’s disease (PD), and we are currently leading the National Institutes of Health (NIH) effort to implement the Parkinson’s Disease Research Agenda. We have exciting progress to report, and I am pleased to present some of the highlights of this work to you today.

Background

Parkinson’s disease, as many of you are aware, is a devastating and debilitating neurological disorder caused by the progressive loss of nerve cells that control movement. These cells produce the neurotransmitter dopamine, and their disappearance from the brain leads to tremors, rigidity, and slowing of movement. Other disabling effects can also occur, including speech problems and, in some individuals, difficulties with thinking, sleep, and depression. Parkinson’s affects more than 500,000 Americans at any given time, and its severity varies from person to person. For some, the disease is marked by a rapidly debilitating physical deterioration, while in others, the disease can be managed for years with available medical therapies. Most people are diagnosed with the disease after the age of 50, although this disorder is not uncommon in younger people. All of these individuals need treatments that can control their disease and eventually a cure, and we are committed to continuing an intensified and coordinated effort to bring research to bear on this need.

For more than three decades, NINDS has been heavily invested in PD research. We have supported early studies of L-dopa, fundamental research on the brain circuitry affected by PD, the development of critical animal models, and important advances in understanding the genetic basis of parkinsonism. In the late 1990s, NINDS expanded these efforts by establishing the Morris K. Udall Centers of Excellence for Parkinson’s Disease Research. Selected through a competitive review process, these Centers have proven to be a sound investment. Over the past several years, they have developed essential collaborations and have contributed to a wide range of research investigations, from the genetics of PD and cellular dysfunction of neurons in the disorder, to studies of brain circuitry, neuropathology, and preclinical testing of therapies.

As requested by Congress, and in light of the numerous opportunities in Parkinson’s research, NINDS took its commitment to this field one step further, by leading the development of a multi-year scientific research plan for PD. As part of this effort, all components of the PD community came together to evaluate progress, re-examine plans and priorities, and identify critical research needs and new approaches with significant promise. NIH submitted this plan, the Parkinson’s Disease Research Agenda, to Congress in March 2000. Although we are all optimistic that the Agenda will serve as a useful road map to developing and integrating treatments for PD, it is not possible to predict a precise time line for major breakthroughs or a cure for this disorder - even in a time of great scientific progress.

We believe that one of the most important results of developing the Agenda was that it highlighted the promise of many ongoing areas, as well as new opportunities in PD research, and the importance of accelerating progress in all of them simultaneously. To address these needs, NINDS and NIH staff have developed numerous grant and contract solicitations, consortia, and workshops that complement the investigator-initiated awards that make up the core of our grant programs. The number of NINDS-initiated PD research activities undertaken since the inception of the Agenda has far exceeded that for any other disease in the history of the Institute, and the number of NINDS staff working on PD has been expanded beyond that for other disorders within the Institute’s mission. The scientific community has responded enthusiastically to these actions, and several significant research efforts have resulted, including the initiation of major clinical trials that we believe will have a significant impact on the treatment of Parkinson’s - both in individuals who have just recently been diagnosed, and in those in the later stages of the disease.

Drug Therapy

For several decades, replacement of the neurotransmitter dopamine has been the mainstay of PD therapy. The delivery of the dopamine precursor L-dopa, as well as other drugs that stimulate the brain’s dopamine receptors, has given many people symptomatic relief, enabling some to continue working and enjoying recreational activities for several years after their diagnosis. However, these treatments can come at a price – their effectiveness can diminish over time; they can cause uncontrolled movements and other debilitating side effects; and perhaps most importantly, they do not stop the continuing loss of nerve cells.

The identification of a therapy that could preserve dopamine neurons – a true neuroprotective agent – would be a watershed event in PD research. NINDS has now taken an important step towards addressing this urgent need, building on years of research to understand the disease at the molecular level. In September 2001, NINDS awarded funds to develop the design and infrastructure for a large trial of drug therapies believed to have the potential for slowing the loss of dopamine-producing nerve cells. In order to identify the most promising compounds for testing, NINDS solicited recommendations from academic and industry researchers, as well as from members of the advocacy community. Many drugs were suggested for consideration, and extramural experts, the trial organizers, and the scientific staff of NINDS developed detailed, objective criteria, in order to permit an unbiased evaluation of all suggestions. NINDS asked the committee to use this approach so that the selection of compounds for further testing would be based solely on their scientific promise. Following the initial pilot studies to determine proper dosing, safety, tolerability, and any preliminary evidence of benefit in Parkinson’s patients, the most appropriate compound, or compounds, will be selected to proceed into definitive Phase III controlled trials. These studies are expected to enroll approximately 3000 subjects at 42 testing centers. The results from the pilot phase of the project are expected within the next two years, but preliminary results from the Phase III trial are not anticipated until approximately 2010-11. This effort represents a significant commitment on the part of NINDS – one that will require an investment of approximately $40 million.

Surgical Therapy

Even with the promise of new and improved drug treatments for Parkinson’s, critical attention is also being focused on surgical therapies, especially for advanced PD. The U.S. Food and Drug Administration has recently approved deep brain stimulation (DBS) – the passage of electrical current through electrodes that are surgically-implanted in very specific brain regions, critical to motor control – for the treatment of advanced Parkinson’s, and interest in this option is growing steadily. NINDS’ commitment to the exploration of DBS as a therapy for PD goes back several years, and includes solicitations targeted to several technical aspects of DBS therapy. The Institute has now funded a number of investigators to study many basic questions about DBS, and we have assembled these researchers into a consortium that will meet for the first time in June 2002. In addition, NINDS is collaborating with the Department of Veterans Affairs (VA) on the largest clinical trial ever of DBS to treat PD. In this study, which will enroll approximately 300 subjects at six VA sites and affiliated academic institutions, researchers will compare stimulation of one of two different brain regions to best medical management of Parkinson’s. If DBS is shown to be the more effective approach, subjects on medical management will also receive DBS – and the effects of the two different stimulation strategies will be compared. The results of the trial will address questions of critical importance to those affected by PD now, and NINDS support of the academic sites in this trial will enable the appropriate enrollment of both women and minorities in the study.

Cell and Tissue Transplantation

For people with advanced PD, who have already lost many of their dopamine-producing nerve cells, replacement cell or tissue therapy is another promising strategy. Studies of fetal tissue transplantation have already demonstrated that this approach is feasible in the treatment of PD, and advances in stem cell biology have made this therapy a future possibility as well. NINDS has long supported research on animal embryonic stem cells and adult stem cells, and some of this work has demonstrated success in reversing motor impairments in animal models of PD. We are committed, within the criteria of the President’s stem cell policy, to expanding these studies further, and to aggressively exploring the potential of human embryonic stem cells in treating this disorder.

Research Agenda Implementation and Scientific Advances

These examples illustrate the types of targeted program activities that have already contributed to the implementation of the PD Research Agenda. Grant solicitations and workshops in areas such as gene therapy, stem cells, the cellular basis of PD, environmental and genetic risk factors, drug screening, and surgical therapies have encouraged investigators to apply their knowledge to the field of PD research, and numerous new grants have been awarded. Although NINDS has initiated a number of these activities, many other NIH Institutes and Centers (ICs) have also developed programs that are directly responsive to the needs identified in the Agenda. For example, the National Institute of Environmental Health Sciences (NIEHS) is currently developing a Consortium Centers Program that will operate as a highly interactive national network engaged in research to understand the potential environmental influences in the causation of PD. In addition, multiple ICs participated in a joint exploratory grant program with several private PD research funding organizations.

While the initiation of these actions has been a critical part of our implementation effort, we recognize that it is ultimately the scientific output of the Agenda that will make a difference in the lives of people with Parkinson’s. To that end, we have progress to report on a number of fronts:

• NINDS-supported stem cell researchers and their collaborators have found that mouse embryonic stem cells can develop into dopamine neurons in a rodent model of Parkinson’s and help reverse impairments in motor function. Importantly, these cells exhibit their plasticity without any manipulation beyond implantation into the motor control regions of the brain. This work builds upon studies of the factors that can induce cells to become dopaminergic neurons, conducted over many years by NINDS intramural investigators and others, and it emphasizes the need to pursue stem cell applications within the federal policy.


• Although several genes that are involved in inherited forms of Parkinson’s disease have been identified, the influence of particular genes on the more common forms of the disease is not fully understood. However, researchers have now conducted large-scale screening of the human genome and have identified several chromosomal regions that may be involved in PD. In particular, one study has identified small differences in the tau gene – which codes for a protein known to play a role in Alzheimer’s disease and other neurodegenerative disorders – as a possible susceptibility factor for Parkinson’s.


• While the influence of inherited genes on the development of PD has not been completely characterized, gene therapy is emerging as a promising technique for restoring function in animal models of this disorder. This work took a dramatic step forward two years ago, when NINDS-funded investigators found that the delivery of specific growth factors to primates with a parkinsonian condition, using a genetically-modified virus, could have dramatic reparative effects. Now a separate group of researchers has added to this armamentarium, demonstrating that a different virus – engineered to deliver enzymes critical for the production of L-dopa – can have similarly impressive effects in a rat model of the disorder. As researchers accumulate more information about the safety and efficacy of different delivery systems and treatment compounds, translational research on gene therapy for PD can move forward.


• NINDS and the National Institute on Aging have supported research that demonstrates exposure of rodents to the pesticide rotenone can cause the development of anatomic and behavioral changes that mimic those seen in PD. In addition, work supported by NIEHS has shown that other agricultural compounds can also produce abnormalities in cells that are similar to those produced by PD. This mounting evidence strongly implicates environmental toxicants in the development of PD, and along with the genetic contributions to the disease, establishes a framework for more extensive studies of risk factors and their cellular effects.


• Last month, intramural researchers at NINDS published a study showing widespread effects of PD on the sympathetic nervous system. This system controls functions such as blood pressure and heart rate – those we think of as automatic. Until this work was completed, researchers did not appreciate the extent to which the disease damages these nerves. Individuals with PD often experience symptoms such as orthostatic hypotension, or a drop in blood pressure upon standing, and the loss of sympathetic nerves observed in this study may help to explain why this occurs.

Despite the progress made by NIH-supported investigators, the task of implementing the Agenda will require our continued attention. A great deal of basic science research is still needed, and much of what is known must be moved along, so it can advance into the clinic. Our Institute is acutely aware of this need, and we are taking steps to facilitate translational studies across all areas of disease. We expect these plans will have a very positive impact on PD research, since many researchers in this community are poised to move their work into preclinical studies, and thus could take immediate advantage of such a program.

Future Plans

The most valuable outcome of the Agenda has been its use as a scientific planning tool. For the past two years, we have used the Agenda, along with the feedback we have received from the external scientific community through workshops and conferences, to guide our efforts. Since the start of the PD Research Agenda, NINDS has organized four meetings on different aspects of Parkinson’s, and other NIH ICs have supported at least six others. The January 2002 Consortium meeting held at the request of Congress offered an additional opportunity for the research, advocacy, and NIH communities to engage in specific discussions about evolving needs in PD research. Among a wide range of suggestions offered by the clinical and basic science discussants, six emerged as priority areas from both groups:

• Participants encouraged NIH to strengthen translational, or bench-to-bedside, research. Translational projects are often quite different from research grants that test straightforward hypotheses about disease causation and treatment, and are at varying points of development along the basic to clinical research spectrum. For several months, NINDS has been developing a new grant program that will attract proposals that bridge basic studies with model development and preclinical evaluation of therapies, and will develop a framework in which these applications can compete more effectively for funding. We expect this program to be initiated in early FY 2003.


• Participants also encouraged NIH to increase our understanding of how PD affects the dopamine systems of the brain. For years, NINDS-funded researchers and our own intramural scientists have been engaged in this work, primarily through basic science approaches to understanding the fundamental malfunctions in dopamine neurons that lead to their degeneration. We will continue to support this research, through investigator-initiated awards, as well as special solicitations and workshops, as critical new areas of biology are identified.


• To complement these efforts, participants recommended further expansion of research beyond the dopamine systems of the brain. This would include other brain systems and circuits that may be affected by PD, the effects of PD throughout the body, and the resulting non-motor complications of PD – which can range from depression and sleep disturbances to speech problems. NINDS is committed to supporting many aspects of this research, including continued exploration of the damage to sympathetic neurons caused by PD. An expansion of this work in all relevant research areas will likely require a trans-NIH effort.


• Despite the wide use of validated scales to assess outcomes, both NINDS and PD researchers in general have recognized the need for better biomarkers – biological indicators/tests of disease susceptibility, progression, or response to treatment. Certainly, our continued focus on the genetics of PD will lead to new ways to assess individual disease risk. However, early biomarkers of this risk and later markers of progression may be much more difficult to develop. NINDS will continue to fund improvements in imaging and other currently used techniques; however, the central problem in identifying new markers is our incomplete understanding of the disease process at the cellular level. For example, researchers in the Alzheimer’s disease community understand how specific molecules are broken down in affected neurons – this offers hope for finding some of these molecules in the spinal fluid or blood. However, researchers have not fully characterized the degradation processes that take place in neurons affected by PD, and thus, we do not know if evidence of these processes can be detected peripherally. NINDS staff is acutely aware of these difficulties, and will continue to evaluate mechanisms that can enhance and accelerate this research.


• Participants also recommended NIH support for preclinical studies of gene therapy, so that this research can move forward into clinical testing. We have already solicited applications on this therapy, and we expect that our efforts in encouraging translational research will also help in this regard. Further, once clinical studies are developed, we anticipate that the framework we have already developed in our clinical trials program, and our enhanced communications with the FDA, will facilitate the development of gene therapy approaches in PD.


• Lastly, the group recommended that NIH support improvements in animal models of PD, including small animals and non-human primates. We are already deeply invested in this work, and NIH- funded investigators have developed new animal models of PD since the start of the Agenda. However, we are committed to improvements in these models, and as a first step in the process, we have already engaged the extramural research community in discussions of how to facilitate the sharing of models that are currently available.

In the past two years, we have been successful in using the PD Research Agenda to guide our support of Parkinson's research, and this strategy has helped us to achieve the balance of investments outlined in the original Agenda. NIH estimates that PD research funding will be approximately $199 million in FY 2002 and $215 million in FY 2003. We believe that sufficient resources will be available to support the PD Agenda during this period, while NIH also attends to its many competing priorities. We will use both the recommendations from the original Agenda and those identified at the January and subsequent consortia meetings to guide the allocation of our resources in different areas of PD research.

We recognize that the Congress and the Parkinson’s community have concerns about the level of funding that NIH has been providing for the implementation of the Agenda. Appropriations for NIH and its individual ICs have been extremely generous in past years, and Parkinson’s research has clearly benefitted from this generosity. As a result, NINDS invested more of its FY 2001 funds on PD research than on any other disorder except stroke, which has an incidence at least ten-fold higher than that of PD. However, workshops and planning efforts increasingly indicate that opportunities for research advances against problems such as stroke, epilepsy, multiple sclerosis, brain tumors, autism, spinal cord injury, muscular dystrophy and health disparities are abundant. Maintaining an appropriate balance among the many disorders within the NINDS mission is a challenge as the Institute moves toward the future. One hopeful note is that basic research applies to many disorders, and even research focused on a particular disease, has a bearing on many others. NINDS must capitalize on these synergies to most effectively carry out its mission in the coming years.

In closing, we are extremely proud of the progress we have made in accelerating research in Parkinson’s disease, and we are grateful for the support of the Congress in these efforts. We do not have a cure yet, but we are initiating clinical trials that we believe will be critical to improving the treatment and quality of life of individuals with PD; we are developing a framework so that basic research can be effectively translated into treatments; and we continue to invest in essential basic science research – the foundation for all progress in medical science. We are not alone in these efforts. Many other ICs at NIH are involved in the implementation of the PD Research Agenda, and several voluntary organizations have expressed an interest in further collaborations. We will continue to work with other ICs through the NIH Parkinson’s Disease Coordinating Committee, and with our external advisors and colleagues from the research and voluntary communities through the Parkinson’s Disease Implementation Committee. With all NIH ICs and voluntary organizations working together, this undertaking can and will be successful.

Thank you, Mr. Chairman, for the opportunity to speak with you today. I would be happy to answer any questions.