Second Scientific Workshop on Neurodegeneration with Brain Iron Accumulation

May 19-20, 2005
Washingtonian Marriott
Gaithersburg, MD

Overview

The National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Diseases (ORD) at NIH along with the NBIA Disorders Association co-sponsored this workshop. This scientific workshop was organized by Dr. Danilo A. Tagle (NINDS), and Dr. Susan Hayflick (Oregon Health and Science University).

The goals of the workshop include:

• To review the state of knowledge about the NBIA group of disorders
• To define specific scientific questions on NBIA that need to be addressed
• To identify resources that are needed to advance research in this area

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 of the NBIA Disorders Association and scientists. The sessions focused on the following: brain iron and neurodegeneration, overview information about NBIA, pantothenate kinase proteins, animal models of pantothenate kinase-associated neurodegeneration (PKAN), mechanisms of disease, strategies for therapy, 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, understanding the 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 ocular feature in PKAN of altered pupillary function (Adie's pupil) that may indicate the involvement of previously unrecognized brain regions in this 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 against 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 PKAN pathogenesis and test new therapies. Despite the limited murine phenotype, these Pank2 knock-out mice are valuable for studying PKAN pathogenesis and testing new therapies and are available to the scientific community.

Discussions of therapeutic strategies included the benefits and limitations of deep brain stimulation (DBS), new drug therapies including chelators, 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 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, with much work still needed to define the process by which a stem cell differentiates into the needed cell type in order 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, state-of-the-art studies are needed to identify the types of cells that are damaged in each form of NBIA.

Recommendations

The workshop concluded with a discussion of key research questions that need to be addressed and essential resources needed in order 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 and may make possible the development of cell models to investigate PKAN. Cybrids may be useful for exploring mitochondrial factors contributing to disease. Neuronal cell cultures from the Pank2 KO mice may be of value as well as new congenic strains with defective Pank2 for investigating pathogenesis. These investigations may 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, the causative genes or other etiologic factors 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 the National Organization for Rare Disorders (NORD).

Since new ideas for treatment 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. This effort will require the development of a clinical database or patient registry through the NBIA Disorders Association. To facilitate testing of new drugs, inquiries should be made to the FDA to define endpoints and acceptable surrogate markers for new therapies. Finally, NBIA investigators should access the unique resources supported by NINDS, including the microarray core facilities and small molecule screening programs which are available to NBIA investigators.

Second Scientific Workshop on
Neurodegeneration with Brain Iron Accumulation

May 19-20, 2005
Washingtonian Marriott
Gaithersburg, MD

Meeting Organizers: Dr. Susan Hayflick and Dr. Danilo A. Tagle

Thursday, May 19, 2005

7:30-8:00 a.m. Registration/Continental Breakfast

8:00-8:15 a.m. Welcome/Introduction from NINDS and ORD: Meeting Organizers

Welcome from NINDS and ORD: Drs. Story Landis and Steve Groft

Statement of workshop goals: Meeting Organizers

8:15-10:15 a.m. Session I: Brain Iron and Neurodegeneration
Susan Hayflick, M.D.,Session Chair

Brain iron and neurodegeneration in mouse models and humans
Sharon Cooperman, M.D., Ph.D., NICHD, NIH

Cellular management of iron in the brain
Torben Moos, M.D., Ph.D.s, University of Copenhagen

Metal accumulation in globus pallidus
Michael Aschner, Ph.D., Vanderbilt University

Mitochondrial dysfunction in neurodegeneration
Anthony Schapira, D.Sc., M.D., F.R., Royal Free Hospita

Lipid metabolism and neurodegeneration
Robert Nussbaum, M.D., NHGRI, NIH

General discussion

10:15-10:30 a.m. Break

10:30-12:00 a.m. Iron in FRDA, PD, AD, RLS and aceruloplasminemia

Friedreich Alaxia
Rob Wilson, M.D., Ph.D, University of Pennsylvannia

Parkinson's Disease, Iron and Multifunctional Monoamine Oxidase Inhibitor-Iron Chelator Drugs
Moussa Youdim, Ph.D., Technion-Rappaport

The Role of Iron Overload in Age-Related Macular Degeneration
Joshua Dunaief, M.D., Ph.D., University of Pennsylvannia

Iron and the Function and Translation of the Alzheimer's Amyloid Precursor Protein
Jack T. Rogers, Ph.D., Massachusetts General Hospital

RLS
Anthony Schapira, D.Sc., M.D., F.R., Royal Free Hospital

Aceruloplasminemia
Zena Leah Harris, M.D., Johns Hopkins University

General discussion

12:00-1:00 p.m. Lunch (Sponsored by: NBIA Disorders Association)

1:00-2:45 p.m. Session II: Overview of NBIA
Jane Gitschier, Ph.D., Session Chair

Clinical features and genetics
Susan Hayflick, M.D., Oregon Health & Science University- (general)
Penelope Hogarth, M.D., Oregon Health & Science University- (neuro)
Robert Egan, M.D.,Oregon Health & Science University- (neuro-ophtho)
Howard Rowley, M.D., University of Wisconsin- (radiology)
Paul Kotzbauer, M.D., Ph.D., University of Pennsylvania- (Neuropathological features of NBIA)

General Discussion

2:45-3:00 p.m. Coffee Break

3:00-4:30 p.m. Session III: Panthothenate Kinases
Jane Gitschier, Ph.D., Session Chair

PANK in Cellular metabolism: Roles and Regulation
Suzanne Jackowski, Ph.D., St. Jude's Children's Research Hospital

PANK2: Gene Structure
Shawn Westaway, Ph.D., Oregon Health & Science University

Altered stability and catalytic function of mutant PanK2 protein
Paul Kotzbauer, M.D., Ph.D.,University of Pennsylvania

General Discussion

4:30-5:30 p.m. Poster Session

Friday, May 20, 2005

8:00-8:30 a.m. Registration/Continental Breakfast

8:30-9:30 a.m. Session IV: Animal Models of PKAN
Paul Kotzbauer, M.D., Ph.D., Session Chair

Mouse Pank2-Characterization of the PANK2 Knock-Out Mouse
Yien Ming Kuo, Ph.D., University of California, San Francisco

General Discussion

9:30-11:30 a.m. Session VII: Therapeutic Strategies
Robert Nussbaum, M.D., Session Chair

Deep Brain Stimulation
Pierre Castelnau, M.D., Ph.D., Tours University

Rational Pharmacologic Therapies
Susan Hayflick, M.D., Oregon Health & Science University

What Causes Selective SN Iron Increase in PD? Towards Logical Therapeutics
Julie Anderson, Ph.D., Buck Institute

Cellular Therapy
Lorenz Studer, M.D., Sloan Kettering Institute

Gene Therapy for the CNS
John Wolfe, V.M.D., Ph.D., Children's Hospital of Philadelphia

General Discussion

11:40-1:00 p.m. Working Lunch (Sponsored by: NBIA Disorders Association)

Hypotheses of Pathogenesis (Panel Discussion)
Jane Gitschier, Ph.D. (Chair), Rob Wilson, M.D., Ph.D., Paul Kotzbauer, M.D., Ph.D., Susan Jackowski, Ph.D., Anthony Schapira, D.Sc., M.D., F.R.

1:00-2:30 p.m. Summary and Future Directions
Discussants: Susan Hayflick, M.D., Patricia Wood and Danilo Tagle, Ph.D.

• Pathogenic Mechanisms
• Animal Models
• Treatment Strategies
• Future Research Priorities and Research Collaborations
• Funding Strategies

3:00-5:00 pm Scientists Meet with Families from NBIA Disorders Association
Discuss Research Progress and Plans
Questions & Answers

5:00-6:00 p.m. Happy Hour for Scientists and NBIA families (sponsored by: NBIA Disorders Association) - opportunity to meet NBIA children and discuss research in depth with interested families

PARTICIPANTS LIST

Julie Andersen, Ph.D.
Buck Institute

Michael Aschner, Ph.D.
Department of Physiology and Pharmacology
Vanderbilt University

Pierre Castelnau, M.D. Ph.D.
Pediatric Neurology Unit
Clocheville Children's Hospital
Tours University, France

Chuang Chiueh, Ph.D.
NIMH, NIH

Sharon Cooperman, M.D., Ph.D.
NICHD, NIH

Jeffr Doerner, M.B.A.
NBIA Disorders Association

Joshua Dunaief, M.D., Ph.D.
Department. of Opthalmology
University of Pennsylvania

Monika Ebhardt, M.D.
GSF-Research Centre
Institute of Human Genetics, Germany

Robert Egan, M.D.
Oregon Health Sciences University

Jane Gitschier, Ph.D.
University of California, San Francisco

Steve Groft, Pharm. D.
ORD, NIH

Valery Gurinovich
Institute of Biochemistry, Belarus

Katrina Gwinn-Hardy, M.D.
NINDS, NIH

Zena Leah Harris, M.D.
Johns Hopkins University

Susan Hayflick, M.D.
Oregon Health Sciences University

Penelope Hogarth, M.D.
Oregon Health Sciences University

Suzanne Jackowski, Ph.D.
St. Jude Children's Research Hospital

David Jett, Ph.D.
NINDS, NIH

Paul Kotzbauer, M.D.
University of Pennsylvania

Yien-Ming Kuo, Ph.D.
University of California San Francisco

Story Landis, Ph.D.
NINDS, NIH

Torben Moos, M.D., Ph.D.
The Panum Institute
University of Copenhagen

Lynn Morin
NINDS, NIH

Robert Nussbaum, M.D.
NHGRI, NIH

Sokhon Pin, M.S.
Johns Hopkins University

Brenda Polster
Oregon Health and Science University

Jack T. Rogers, Ph.D.
Massachusetts General Hospital

Howard Rowley, M.D.
University of Wisconsin Medical School

Danish Saleheen
Aga Khan University

Terrence Sanger, M.D., Ph.D.
Stanford University Medical Center

Anthony Schapira, D.Sc., M.D., F.R.
Royal Free Hospital

Giovanna Spinella, M.D.
ORD, NIH

Lorenz Studer, M.D.
Sloan-Kettering Institute

Danilo A. Tagle, Ph.D.
NINDS, NIH

Richard Weleber, M.D.
Oregon Health and Science University

Shawn Westaway, Ph.D.
Oregon Health and Science University

Rob Wilson, M.D., Ph.D.
University of Pennsylvania

John H. Wolfe, V.M.D., Ph.D.
University of Pennsylvania

Patricia Wood
NBIA Disorders Association

Xueying Xue, M.D.
Johns Hopkins University

Moussa Youdim, Ph.D.
Technion-Rappaport University

Yong-Mei Zhang, Ph.D.
St. Jude Children's Research Hospital