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2004 Bone Marrow Transplant Scientific Meeting

Bone Marrow Transplant Scientific Meeting:

Forging Ahead by Exploring Potential Treatments

April 25-26, 2004 at the National Institutes of Health in Bethesda, Maryland

The Progeria Research Foundation, in partnership with the National Human Genome Research Institute and the National Heart, Lung and Blood Institute, sponsored an exciting meeting: “Exploring the Potential for Stem Cell Transplantation in Hutchinson-Gilford Progeria Syndrome”. This meeting brought together physicians and scientists with expertise in fields that are essential for a comprehensive assessment of the potential for stem cell and bone marrow transplantation strategies to treat children with Progeria. Pulling together 22 scientific experts in various fields essential to exploring this innovative research direction, this third PRF co-sponsored workshop was successful in addressing this challenging topic. Here is some background information on this topic and the results of the meeting:

What are bone marrow and stem cells?

In the center of our bones, we have marrow that contains special cells known as stem cells. Stem cells can divide to form more stem cells, or they can mature into cell types found in all of the organs of our bodies, such as those cells making up our blood vessels.

What is bone marrow transplantation?

Bone marrow transplantation (BMT) is a procedure in which a child’s own bone marrow cells are replaced with new bone marrow stem cells (a transplant) from a healthy donor. While the ideal donor is an identical twin, Progeria children could potentially receive transplants from a relative with a close match to their own cells, or even someone who is unrelated.

For cancer treatment, doctors use radiation and chemotherapy before bone marrow transplantation. Would that be a part of this treatment for Progeria?

For cancer, this type of “pretreatment” is needed to kill off as many of the cancer cells as possible. We do not need to get rid of the Progeria cells, so we would not expect to use the same type of pretreatment for BMT in Progeria. However, there would be a milder form of pretreatment to help the child with Progeria to receive cells from the donor without reacting against them. Therefore, there is some risk involved in this type of treatment. That is why it is very important to do as much research as possible before potentially moving to treatment in Progeria children.

Are we moving forward with bone marrow transplantation in children with Progeria, or are we going to work in animal models first? Here’s what the experts at our meeting recommended:

The first step for safe and effective treatment is to perform BMT in animals, such as mice, that have been created to mimic the disease process in Progeria as closely as possible. Many laboratories in the scientific community are working hard to create these animal models (some of which are funded by PRF.) The experts who attended this meeting all agreed that PRF needs to move as quickly as possible to test BMT as a treatment in Progeria mice. This will help to answer two key questions: 1) Is this procedure safe? and 2) Will the bone marrow/stem cells go to the organs in which they are most needed – the blood vessels, heart, fat stores, etc. – to replace unhealthy cells? In the coming months, PRF will promote the research that is essential to understanding whether BMT will improve the lives of children with Progeria. This workshop provided a great starting point.

Workshop Agenda & Speakers

Session One: Clinical and Genetic Aspects of HGPS

Chair: Leslie B. Gordon, MD, PhD

Clinical overview of HGPS and longitudinal assessment strategies: How will we know if the treatments are improving disease?

Leslie Gordon, MD, PhD
Medical Director,The Progeria Research Foundation;
Assistant Professor,Tufts University School of Medicine, Boston, MA;
Assistant Professor of Pediatrics, University School of Medicine, Brown University, Providence, RI

Elizabeth Nabel, MD
Scientific Director of Clinical Research and Head of Vascular
Biology Branch, National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD

The HGPS gene defect and what it means: Putativedisease mechanism and senescence characteristics

Francis Collins, MD, PhD
Director of the National Human Genome Research Institute,
Bethesda, MD

Session Two:Why Might BMT Work for HGPS?Learning from BMT in Other Diseases

Chair: Jennifer M. Puck, MD
Senior Investigator and Chief, Genetics and Molecular Biology
Branch,National Human Genome Research Institute, Bethesda,MD

Metabolic correction of Mucopolysaccharidosis Disorders by bone marrow transplantation and gene therapy

Chester B.Whitley, MD, PhD
Professor, Gene Therapy Center, Department of Pediatrics and Professor,
Institute of Human Genetics, University of Minnesota, Minneapolis, MN

BMT strategies in osteogenesis imperfecta: Clinical trials and lessons learned

Edwin Horwitz, MD, PhD
Associate Member, Department of Hematology–Oncology,
Divisions of Stem Cell Transplantation and Experimental
Hematology, St. Jude’s Children’s Research Hospital,

Transplantation experiences with storage diseases that may apply to HGPS

William Krivit, MD, PhD
Emeritus Professor, Department of Pediatrics, University of
Minnesota, Minneapolis, MN

Session Three: Evidence For / Against Vascular Repopulation Leading to Clinical Improvement

Chairs: Elizabeth Nabel, MD and Donald Orlic, PhD
Associate Investigator, Genetics and Molecular Biology Branch,
NHLBI, Bethesda, MD

Vascular wall cell recruitment and BMT: How might transplant affect vascular plaques?

Richard Mitchell, MD, PhD
Associate Professor of Pathology, Harvard Medical School,
Staff Pathologist, Brigham & Women’s Hospital, Boston, MA

Potential for cardiovascular repopulation with BMT in Progeria – evidence from human and mouse studies

Richard Cannon, MD
Clinical Director of the Division of Intramural Research,
NHLBI, Bethesda, MD

The state of funding for Hutchinson-Gilford Progeria Syndrome from the National Institute on Aging

Huber Warner, PhD
Director, Biology of Aging Program, National Institute on Aging,
National Institutes of Health, Bethesda, MD

Session Four: Complications and Assessment of Risks and Benefits

Chair:William A. Gahl, MD, PhD
Clinical Director, National Human Genome Research Institute,
Bethesda, MD

Early and late risks of hematopoietic cell transplants vs disease control

Armand Keating, MD
Chief of Medical Services, Epstein Professor and Head of
Department of Medical Oncology and Hematology, Princess
Margaret Hospital/Ontario Cancer Institute,Toronto, Ontario, Canada

What can we learn from stem cell transplants to correct other genetic disorders?

John Barrett, MD
Director, Bone Marrow Transplantation Unit of Hematology
Branch, NHLBI, Bethesda, MD

Umbilical cord blood transplantation; results from prior studies and assessment of this strategy for Progeria

John Wagner, MD
Scientific Director of Clinical Research Blood and Marrow
Transplant Program, Department of Pediatrics, Division of Bone
Marrow Transplantation, University of Minnesota School of
Medicine, Minneapolis, MN

Gene therapy for HGPS: Strategies, targets, and timeline

Cynthia Dunbar, MD
Head of the Molecular Hematopoiesis Section,
Hematology Branch, NHLBI, Bethesda, MD

Additional BMT Workshop Attendees

Scott D. Berns, MD, MPH, FAAP
Vice President, Chapter Programs, March of Dimes, White Plains, NY

Fabio Candotti, MD
Genetics and Molecular Biology Branch, National Human
Genome Research Institute, Bethesda, MD

Michael Erdos, PhD
Staff Scientist in the laboratory of Dr. Francis Collins,
National Human Genome Research Institute, Bethesda, MD

Audrey Gordon, Esq.
President,The Progeria Research Foundation

Monica Kleinman, MD
Senior Associate of Critical Care Medicine,
Medical-Surgical Intensive Care Unit, Medical
Director of the Transport Program & Associate in Anesthesia
Children’s Hospital, Boston, MA

Felipe Sierra, PhD
Head of the Extramural Portfolio on Cell Structure and
Function of the Biology of Aging Program at the National
Institute on Aging, Bethesda, MD

Lino Tessarollo, PhD
Head, Neural Development Group and Gene Targeting
Facility, Mouse Cancer Genetics Program
National Cancer Institute, Frederick, MD

Rene Varga, PhD
Post-doctoral candidate in the laboratory of Dr. Francis Collins
National Human Genome Research Institute, Bethesda, MD

Selected Participant Comments:

A very impressive group of experts was assembled, and the quality of the scientific discussion was very high. I learned a lot about the pros and cons of bone marrow transplantation for other genetic disorders, and how that experience might extrapolate to Hutchinson-Gilford Progeria Syndrome.

Francis Collins, MD, PhD, Director of the
National Human Genome Research Institute

I thoroughly enjoyed participating in this workshop. The greatest strength was that the diverse group enabled us to address most aspects of Progeria in a concise and informative manner. My congratulations for assembling such an outstanding group.

Edwin Horwitz, MD, PhD
St. Jude’s Children’s Research Hospital