May 19-20 in Gaithersburg, MD
Sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Diseases (ORD) at NIH along with the NBIA Disorders Association.
Scientists, new collaborators from around the world meet to advance research into NBIA
On May 19 and 20, 2005, 50 physicians, scientists and NBIA family members met in Gaithersburg Maryland for the Second Scientific Workshop on NBIA. The Workshop was sponsored by two units of the NIH, the National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Diseases, and by the NBIA Disorders Association. Drs. Danilo Tagle and Susan Hayflick planned and organized the meeting.
The goals were to review the state of knowledge about the NBIA group of disorders, discuss resources that are needed to advance research in this area, and formulate a plan for future studies. Since many of the attending scientists are not currently studying NBIA but have research interests that complement this area of investigation, an important additional goal of the Workshop was to stimulate new research on NBIA by attracting new investigators and nurturing collaborations between scientists currently working on NBIA.
The Workshop drew scientists from the US, France, Great Britain, Germany, and Israel and included general sessions, a poster discussion forum and an exchange of ideas and information between family members and scientists. The sessions focused on the following: brain iron and neurodegeneration, overview information about NBIA, pantothenate kinase proteins, animal models of PKAN, strategies for therapy, mechanisms of disease, and research resources needed to move the field forward. Since this was the first scientific meeting devoted to NBIA since the discovery of the PANK2 gene and its role in disease, much of the meeting focused on advances made in PKAN.
The meeting began with a broad discussion of the role of iron in normal brain function and in other neurodegenerative disorders, including Parkinson disease, Friedreich ataxia, restless legs syndrome and aceruolplasminemia. The advances made in understanding how iron participates in these disease processes may help to direct studies in NBIA. One key question that remains unanswered is why iron is normally regionally distributed in brain. The area most severely affected in NBIA (the globus pallidus) also has the highest concentration of iron under normal conditions. Therefore, discovering the reason for this normal process may shed light on what goes awry in the diseased brain.
In order to assure that all attendees were fully informed about the NBIA group of disorders, a session was devoted to reviewing their features and updating the group on new discoveries in this area. Work done by the OHSU/UCSF team led to the identification of a new eye feature in PKAN of altered pupillary function without affecting vision. This observation may pinpoint previously unrecognized brain regions affected by the disease.
Other work by Kotzbauer and colleagues at the University of Pennsylvania identified brain changes in NBIA patients that are similar to those seen in Parkinson disease. Recent advances made in understanding the Parkinson disease process may also improve understanding of NBIA through their shared features. These studies need to be confirmed in brain samples that have been properly preserved for state-of-the-art analyses from individuals whose disease has been fully characterized. Through the commitments of a growing number of NBIA families, these valuable tissue samples are becoming available for study.
Since the gene for one form of NBIA has been identified, an entire Workshop session was devoted to discussing the group of pantothenate kinase proteins and their role in metabolism, with an emphasis on the PANK2 gene and protein. This session highlighted important work done to help explain why the loss of PANK2 compromises health. Even the most basic biochemical effects of deficient PANK2 are uncertain and difficult to measure. Competing scientific views included decreased energy production, impaired defenses from oxidative stress, altered lipid metabolism and a combination of these. Experiments were proposed to help clarify these points, and the group was unanimous in their agreement of the importance of answering this central question.
In a lead up to discussions of current therapies for NBIA, features of a mouse with Pank2 deficiency developed by the UCSF/OHSU team were presented. Though this mouse does not have obvious dystonia, it does show other changes similar to those seen in humans with PKAN. These include changes in the retina, testes and general growth pattern. The mouse was developed in order to study the PKAN disease process and test new therapies. Though it does not show some of the neurological problems that affect humans, these Pank2 gene “knock-out” mice are clearly valuable to the entire NBIA scientific community. They have been offered as a research resource to any scientist who requests them.
A session that was especially well attended by NBIA family members examined therapeutic strategies. Discussions included the benefits and limitations of deep brain stimulation (DBS), new drug therapies, and efforts to replace the PANK2 protein by either gene replacement therapy or stem cell therapy. Whereas DBS has clear benefits in some patients and remains a promising treatment for NBIA symptoms, it is an invasive procedure that does not alter the disease process. Nevertheless, early studies in PKAN indicate limited benefits with some relief of symptoms. From these and larger studies of DBS in more common neurological disorders, it is clear that one of the most important factors to maximize the benefits and minimize the risks is the experience of the DBS team, which includes a neurologist, neurosurgeon and anesthesiologist.
The participants discussed ideas of new drug or nutritional therapies based on the current understanding of PKAN biochemistry, some of which are being studied in mouse and fruitfly models.
For the general problem of high brain iron that plagues all individuals affected by NBIA, new chelators to help rid the body of iron were discussed and may show promise. While the field of gene therapy continues to advance, it is still premature for human trials of neurological disorders. In NBIA, the challenges of gene therapy are compounded by the need to deliver the correct gene across the blood-brain barrier and into the brain. Parallel challenges exist for stem cell therapy, in which there remains much work to uncover the process by which a stem cell differentiates into the needed cell type to correct the NBIA disease process. Since the NBIAs are a group of distinct but related disorders, each form may require the replacement of a different cell type. Clearly, research is needed to identify the types of cells that are damaged in each form of NBIA.
The Workshop concluded with a frank discussion of key research questions that need to be addressed and essential resources needed to advance research in NBIA. There was strong agreement that the basic biochemical effect of deficient PANK2 must be delineated. Once this is identified, its subsequent effects on cell function will need to be determined. This will begin to describe the cascade of changes that lead from an altered gene to the full disease process. In turn, this understanding will help pinpoint steps in the disease process that can be targeted by drugs or other therapies.
In order to begin to advance understanding of the other forms of NBIA, their genes must be identified. Work on new NBIA gene discovery is currently underway by the OHSU/UCSF team with funding from the NBIA Disorders Association and NORD. The group was enthusiastic to learn of the availability of a mouse and fly model for PKAN. Additional mouse mutants may be needed, as well.
Since new ideas for treatment strategies do not need to wait for us to understand the entire disease process, there was high enthusiasm for organizing families to participate in studies of promising therapies. In partnership with families, this initiative will move forward.
Finally, the Workshop participants strongly endorsed the need to direct more funding and national research resources to NBIA. Unique resources supported by NINDS, including the microarray core facility and small molecule screening programs are available to NBIA investigators. In addition to their support for the Workshop, NINDS may be open to targeted funding to address key questions of iron in normal and diseased brain.
The Workshop ended with an open exchange between scientists and NBIA families that was followed by an informal opportunity for continued discussions over wine and cheese. These lively interactions were marked by new understanding of both the science of NBIA and the human toll taken by these diseases.
