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The Mucopolysaccharidoses: Therapeutic Strategies for the Central Nervous System


 

The Mucopolysaccharidoses: Therapeutic Strategies for the Central Nervous System

National Institute of Neurological Disorders and Stroke

Bethesda Marriott Hotel
Bethesda, Maryland
September 24-25, 2002

Table of Contents

 

Overview

The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), the National Institute of Child Health and Human Development (NICHD), and the Office of Rare Diseases (ORD) along with the National MPS Society co-sponsored this workshop. This workshop was organized by Dr. Danilo A. Tagle (NINDS), Dr. Elizabeth Neufeld (UCLA), Dr. Richard Proia (NIDDK) and members of the MPS Society Scientific Advisory Board. The workshop addressed several research and clinical issues related to MPS and other lysosomal storage disorders, including obstacles to therapeutics into the brain and how to facilitate the exchange and integration of ideas, information and technologies from experts in the fields of imaging, gene therapy, drug delivery, and stem cells (see Meeting Agenda). The goals of this workshop were to identify the major problems in delivering therapeutics across the blood-brain-barrier, to determine therapeutic strategies and delivery methods with the greatest potential for overcoming these problems, to determine how animal models can facilitate therapy development, and to determine efficacy and outcome measures of treatment. The speakers were tasked to consider these areas in their presentations and to engage the participants in a meaningful and productive discussion after each session topic.

Mucopolysaccharidosis (MPS) is a group of genetic, progressive disorders that result in excessive intra-lysosomal accumulation of mucopolysaccharides (glycosaminoglycans) in various tissues. Mucopolysaccharides are long chains of sugar molecules used to build connective tissues and organs in the body. When mutations occur in the genes for the enzymes involved in the normal turnover of mucopolysaccharides, excess amounts of them are stored in the body, causing progressive damage and, in most cases, early death. Clinical features include organomegaly, corneal clouding, thickening of skin, coarse facial hairs, mental retardation, growth deficiency, skeletal dysplasias, hernias and joint contractures. Several subtypes of (MPS) have been identified. Examples of these disorders are: Hunter's syndrome, Hurler's syndrome, Scheie's syndrome, Sanfilippo syndrome, Maroteaux-Lamy syndrome, and Morquio's disease. There are no current cures for the mucopolysaccharidosis. Bone marrow transplantations have given various degrees of success. Enzyme replacement trials are under investigation and hold promise, but treatments for skeletal and CNS abnormalities remain intractable due to preferential uptake of the enzyme(s) by the liver and the blood brain barrier.

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Introduction to the MPS

Since the workshop consisted of scientists from diverse research areas, this session serves to introduce and review MPS to others who are not in the field.

Joseph Muenzer from the University of North Carolina provided an overview of the clinical manifestations in MPS and the current status of therapy. There are 11 different enzyme deficiencies that comprise 7 different clinical types with the hallmark being excessive storage of glycoaminoglycans, each being different for each clinical form. Clinical symptoms are as described above in the overview. MPS I, II and III are the most common forms and show the most pronounced neurological involvement. Clinical severity is quite heterogeneous and there is no predictive diagnosis available. Genes and mutations have been identified for most of the MPS but there is no clear genotype to phenotype correlation. Clinical diagnosis is often confirmed with a urine enzyme analysis. There is no current clear definitive treatment for MPS. However an important perspective in developing treatment strategies for MPS is that even one or two percent of residual enzyme activity might be able to correct glycosaminoglycan (GAG) metabolism. Stem cell transplants (from bone marrow or cord blood) in MPS patients show clear clinical improvements though the neurologic outcomes varies widely. Enzyme replacement therapy is in various stages of clinical trials, but in general results in reduction of urinary GAG excretion and decrease size of the enlarged liver and spleen.

Mark Haskins from the University of Pennsylvania gave a comprehensive overview of the animal models of MPS. Though rodent models of MPS exist, much of the presentation was on large animals models, such as dogs and cats, and to more exotic models, such as emu and goat. These animal models are faithful clinical and pathological representations of the disease and show neurologic signs and shortened lifespan, though mental function especially higher cortical functions is difficult to assess in animals. Retroviral gene therapy approaches on neonatal dog models of MPSVII show promising outcomes though insertional mutagenesis may become an issue in the long run.

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Pathology of the MPS brain

Arthur Lander indicated the importance of proteoglycans in the CNS. There is evidence that proteoglycans of the extracellular matrix play a role in the growth and guidance of axons, and in synaptic formation and structure. On the other hand, cell-surface proteoglycans appear to be involved in neurogenesis, in axon guidance, in synaptic structure and function. For MPS, it may be useful to look at proteoglycan function as an early marker of disease and as targets for therapy.

Steve Walkley talked about the direct and indirect consequences of GAG storage and abnormalities in proteoglycan metabolism. Other storage diseases but not MPS have prominent pathological features like demyelination, neuronal axonal dystrophy and axonal spheroid formation. Materials that accumulate in neurons of individuals with MPS includes heparin sulfate, GM2 and GM3 gangliosides, cholesterol, and autofluorescent materials. Abnormal accumulation of GM2 has been correlated with re-growth of primary dendrites.

Evidence for inflammatory reaction, at least in MPS III brain was presented by Elizabeth Neufeld. There are many other studies of microglial activation in neurodegenerative disorders, like Alzheimer's disease, Parkinson's, multiple sclerosis, traumatic brain injury, and HIV-AIDS dementia. Bone marrow transplantation in mouse models for Sandhoff disease results in significant increase in lifespan despite no decrease in storage of GM2 ganglioside presumably due to replacement of GM2 gangliosidosis microglia with normal microglia.An antibody against macrophages, MOMA-2, show positive immunostaining in cortex of MPS I mice at 14 months of age but much earlier at 6 months in MPS IIIB. Another marker for activated microglia, CD-68, is found in MPS I and IIIB and appears much earlier than MOMA-2.

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The blood-brain barrier: a major obstacle to therapy

Lester Drewes gave a crash course on the cerebral vascular biology. He began by showing a picture of the vasculature of the brain and telling about its microvessels, which are an array of capillaries about 5 microns in diameter. The brain's blood vessels are lined with endothelial cells, which are tightly connected to one another, leaving no gaps for extracellular diffusion among cells. The luminal and abluminal sides of the vessels have different features. At the molecular level, the microvessels have tight junction proteins, which are a critical obstacle in bypassing the blood-brain barrier. There are several nutrient transporters on the luminal (blood) side. Nutrients that can be transported on this side include glucose, amino acids, fatty acids, creatine, choline and water. On the other hand, lipophilic substances with molecular weight less than 500, such as ethanol, can get into the brain by simple diffusion into the lipid bilayer. Higher molecular weight lipid-soluble compounds are transported by energy-dependent carriers, such as P-glycoproteins. Drewes and his colleagues recently conducted an experiment using rat brain microvessels as a source of RNA for gene expression analysis. Using serial analysis of gene expression (SAGE), they compared the microvessels to hippocampus cells to find out the functions of the microvessels. Genes expressed in the microvessels are transporters, receptors, vesicle trafficking and signal transduction. They did another experiment in which they compared lactate expression in the luminal membranes of young suckling animals with levels in non-suckling animals. They found 25 times more lactate expression in the luminal membrane cells of suckling animals. Drewes briefly discussed protein drug delivery to the CNS. He mentioned the following: viral vectors, osmotic opening, cell trafficking, intranasal, receptor-mediated transcytosis.

William Pardridge gave a talk on "Receptor-mediated targeting of recombinant proteins and therapeutic genes through the blood-brain barrier". He indicated that 98 percent of small molecule drugs do not cross the blood-brain barrier (BBB). 100 percent of large molecule drugs do not cross the BBB. Zero percent of drug companies have a BBB drug delivery program. The problem is that drug companies are still using the "small-molecule business model." Epilepsy, depression and a few other diseases respond well to medications, but bypassing the BBB is the rate-limiting step in clinically effective therapeutics for most brain-related diseases. Dr. Partridge also went into great detail about carrier-mediated transport systems and chimeric peptide hypothesis. In the latter, drugs may be delivered to the brain by conjugation of the drug to BBB transport vectors, or species-specific "Trojan horses." Using a rodent model for ischemia, Partridge and colleagues made a chimeric peptide with brain-derived neuroprotective factor (BDNF). The chimeric peptide reduced stroke volume by 65 % for up to two hours after stroke. Possibilities for gene medicines include trans-cellular delivery system for brain gene therapy, artificial virus gene delivery system, and global non-viral gene transfer with IV administration.

Todd Zankel and his colleagues at BioMarin are in the midst of a study to see if they can modify lysosomal enzymes for transcytosis. Basically, they're combining a lysosomal enzyme and a carrier protein to try to get it across the BBB. The carrier must be able to do the following to be used for this purpose: 1) transcytose across the BBB, 2) be endocytosed by parenchymal cells, 3) be transported to the lysosome, and 4) have no effect on enzyme function or diminish its half-life.

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Gene transfer approaches

The presentations largely centered on adeno-associated virus (AAV), in part because large body of toxicology data on this vector and its relevance for use in targeting the CNS. Mark Sands reviewed both intravenous and direct (intrathecal and intraocular) routes to get into the brain of MPS mouse models. Current data suggest that systemic approach will only be marginally effective. On the other hand, direct injection into the CNS would indicate high level of expression that is relatively stable. Unlike the adenoviral vector studies, AAV vector studies showed that enzyme diffused a significant distance from the injection site, there is widespread reduction of lysosomal storage, and functional correction in mice. Similarly lentiviral vectors, which include human immunodeficiency and feline immunodeficiency virus (FIV), show minimal to no acute toxicity and persistent high level expression. A potential advantage of lentiviral vectors over AAV is that they can be very easily pseudotyped or different envelope proteins incorporated to allow broader tropism.

John Wolfe also reviewed some AAV and other work, talking about the difficulties and accomplishments with widespread distribution of vector itself within the brain, the tropism of different AAV serotypes, and the idea even that multiple vectors might be used to transduce the pathologically-relevant parts of the brain. He commented about the CMV promoter being apparently shut down, whereas the human GUSB promoter provided more durable expression, and the fact that neural pathways can be exploited to transport vector into some parts of the brain, but also perhaps not all of them.

Gianvito Martino talked about multiple sclerosis, impressing the importance of finding clinically applicable means of delivering gene therapy. Probably very few patients will go along with the idea of having holes bored in their head and injecting needles, but he showed that the intrathecal route, doing a spinal tap basically, might be an alternate way of delivering vector. Beverly Davidson talked about some limitations and advances with various types of AAV vectors. She also described her work using FIV vector which also show robust expression of b-glucouronidase and focal transduction primarily of neurons. She pointed out that correction of lysosomal storage was achieved not only on the injected side of the brain but also in the contralateral cortex and striatum. She emphasized the diffusion of the enzyme once it's expressed in the brain also extends the volume of distribution or the area of metabolic correction. She also touched on the ability of AAV-5 to spread within the parenchyma of the brain more so than AAV-2 and AAV-4. Davidson also discussed on what seems to be a great deal of plasticity in the seemingly injured MPS brain, and that one can test correction of disease manifestations, both behavioral and electrophysiologic function. She also described work in modifying the enzyme to improve biodistribution. She modified the GUSB protein intending to make it distribute further and actually accomplished that by interfering with the normal mannose-6-phosphate pathway uptake method.

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Stem cells as therapeutic agents

Eva Mezey addressed her concerns about the functional relevance of transplanted stromal and hematopoietic cells: We know that bone marrow cells can differentiate into neurons. What we don't know is whether those new neurons can become functional. Bone marrow cells differentiate into functional neurons in vitro. Post-mortem data from female patients who received male bone marrow transplants shows that many glial cells do contain Y-chromosomes, indicating successful differentiation. But, how are the cells brought into the brain and how do they differentiate? This is what we need to study more.

Edward Schuchman talked about his work on intra-cerebral mesenchymal stem cell transplantation in the Type A Niemann Pick disease (NPD) mice. NPD knockout mice exhibit tremors, Purkinge cell loss, abnormal gait, and a shortened lifespan. Possible treatments include transgene, enzyme and bone marrow treatments. The bottom line of their experiments is that low ASM levels have had a profound effect on NPD symptoms in these mice. Therefore, there is a low therapeutic threshold. Mesenchymal stem cells are easy to obtain. They can be transduced to over express; they survive and migrate where needed. The same cell source can be used to treat CNS and visceral organ diseases. Schuchman and his colleagues did the following experiment where donor MSC were transduced with human ASM retroviral vector. The results showed up to 8-month survival (doubled lifespan), about 20 percent of GFP+ cells differentiated into neural types, decreased sphingomyelin storage, Purkinge cells survival decreased as the distance from the injection site increased. Thus MSC transplants can lead to significant but incomplete improvement. How can we improve the results? Possibly by decrease immune response, injecting more cells earlier, or simultaneous treatment with transduced cells to produce a synergistic effect. Results from a combined MSC Gene Therapy approach into more than 20 animals at 3 weeks of age showed 80% survival at 8 months, lifespan extended to one year, normal Purkinge cell morphology, and a gradual drop-off of clinical effect.

Greg Stewart described their work on adult-derived neural stem cells from mouse and rats. Rat NSC stain for markers for neurons, such as NeuN. Prior to engraftment, cells are pre-labeled with bromodeoxyuridine in order to track the cell's migration. Typically 105 cells are injected, with widespread distribution seen in 4 weeks. Cells differentiate into oligodendrocytes but are rather refractory to becoming neurons. Mouse NSC were similarly characterized and these cells do not show the same migratory capability as the rat NSC. Stewart showed that the age of implanted cells and the site of injection can have dramatic effect on cell distribution. Overall goal is to use stem cells as drug delivery vehicles. These cells must be able to release enzyme and show cross-correction in mouse models.

Joanne Kurtzberg spoke on their work on the clinical use of unrelated umbilical cord stem cells to treat inborn errors of metabolism. Cord blood stem cells are capable of multilineage differentiation, and also capable of rescuing bone marrow after myelo-ablative therapy. They also have the advantage of being immunologically more tolerant and therefore can be transplanted across partial HLA mismatches. This means that it is easier to find a cord blood donor than a bone marrow donor for a patient in need of a transplant. Like bone marrow, cord blood can transdifferentiate into cells of non-hematopoietic lineages. There are public banks in the US that have almost 30,000 available units for transplantation. Cord blood are uniquely suited for pediatric patients with inborn errors of metabolism: readily available, >95% chance of finding a donor match, CMV-negative, and donors with high enzyme expression can be selected. Summary of their work is as follows:

  • Hurler Syndrome
    • The dose is 10 times less than needed for a bone marrow transplant
    • Supportive care is complicated and expensive: antibiotics, prophylactic antivirals, antifungals, etc., nutrition, transfusions, low-dose heparin, pain control (parental control apparatus).
    • 89% event-free survival
    • Recover normal immune function
    • Cognitive development at normal pace one year post-transplant
    • CD-4 safe at 8 months

  • Krabbe Disease
    • Pre-symptomatic treatment - 100% survival
    • Post-symptomatic treatment - 40% survival
    • Mortality risk for the procedure is about 10 percent
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Imaging to follow the course of disease and progress of therapy

Afonso Silva spoke on the advantages of magnetic resonance imaging (MRI) for biomedical applications, particularly because it is a noninvasive procedure, high spatial and temporal resolution. When applied to animal models, MRI has the additional advantage of being able to perform experiments at higher magnetic fields that can translate into higher signal to noise ratio which can be traded for higher spatial resolution compared to what clinical human research can obtain. Measurements of brain function can be obtained using arterial spin labeling technique which measures regional blood flow. Moreover there is the capability to use MRI in the context of high throughput screens for drug effects by parallel MRI scanning.

William Ball described his work in functional imaging in the MPS and its difficulties due to the tremendous amount of overlap between phenotypes. In this group of disorders, there is a mixed involvement of grey and white matter, varying degrees of CSF spaces, and prominent perivascular spaces. In end stage MPS, there is often widening of the extra-axial fluid spaces, prominence of the ventricular system, and hypomyelination. It points to a spectrum of conditions that can be present in MPS and the inadequacy of natural history studies for MPS. Spectroscopic studies for metabolites in MPS show a pattern of decreased NAA ( a marker of neuronal integrity/synaptic density), normal to increased choline (a membrane marker of turnover within the brain), elevated myoinositol (a glial marker), and an elevation of proteolipids, particularly in Hurler's disease which may represent either an inability to myelinate or a breakdown in existing myelin. Future studies should involve assessing cognitive function in MPS, such as language development over time. Diffusion tensor imaging which allows the evaluation of tracts of white matter within the brain may also be useful in assessing function and plasticity in MPS.

Harley Kornblum described the applicability of positron emission tomography (PET) in rodent models. PET is capable of imaging rodent brain glucose metabolism at relatively high resolution in a fully quantitative fashion. Images can be obtained with the animals in an awake, conscious state during tracer uptake, which may provide an advantage over some other imaging modalities. Micro-PET can be used to study the loss and recovery of function following lesion. It may also serve as a useful platform to test pharmacological and other therapeutic interventions. The major limitation is that the resolution is insufficient to accurately depict structures within the mouse brain unless highly specific tracers are used, such as dopamine D2 receptor probe.

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Recommendations

Workshop participants raised several issues and made recommendations to facilitate research in the MPS and possibly other lysosomal storage diseases. The issues and scientific questions that were raised are as follows:

  • Concern whether the reorganization in study sections in CSR, particularly the Medical Biochemistry IRG may have an impact in the review of applications from this group
  • Will the somatic problems in MPS interfere with the treatment of the brain? Effective therapy argues for multiple different approaches. How would regulating bodies like FDA or RAC or even IRB look at such a multi-step approach to treatment?Lessons from multiple treatment modalities in cancer.
  • Support for collaborations and translational research
  • Need to form an interdisciplinary network of investigators who would do clinical trial design, correlative studies, develop measures for outcome, identify surrogate clinical endpoints, develop centralized screening and diagnostic technology, etc..

The future research priorities that were identified and discussed by the group are:

  • Additional strategies to get enzymes in the brain
  • Improved gene delivery methods into the brain
  • Cell-mediated therapy that get across the blood-brain-barrier
  • Other avenues, such as receptor-mediated transcytosis and melanotransferin, to get across the blood-brain-barrier
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Agenda

The Mucopolysaccharidoses: Therapeutic Strategies for the Central Nervous System
September 24-25, 2002
Bethesda Marriott Hotel
5151 Pooks Hill Rd.
Bethesda, MD
(301) 564-5096

Co-chairs - Elizabeth Neufeld (UCLA) and Richard Proia (NIH)

September 24

8:00 - 8:30 AM
Continental Breakfast

8:30 AM
Connie Atwell: Welcome Remarks
Danilo A.Tagle - Statement of workshop goals

8:45 - 10:00 AM
Session 1 - Introduction to the MPS (Chair - Elizabeth Neufeld, UCLA)

  • 8:45-9:10 Joseph Muenzer (UNC) - Clinical manifestations the MPS; current status of therapy
  • 9:10-9:30 Mark Haskins (U Penn) - Animal models of MPS
  • 9:30-10:00 Discussion

10:00 - 10:30 AM COFFEE BREAK

10:30 - 12:00 PM
Session 2 - Pathology of the brain (Chair - Richard Proia, NIH)

  • 10:30-10:50 Arthur Lander (UC Irvine) - Normal functions of nervous system proteoglycans
  • 10:50-11:10 Steve Walkley (Albert Einstein NY) - Neuronal pathology in human and animal MPS
  • 11:10-11:30 Elizabeth Neufeld (UCLA)- Activated microglia in mouse models of MPS I and IIIB.
  • 11:30-12:00 Discussion

12:00 - 1:00 PM LUNCH

1:00 - 2:30 PM
Session 3 - The blood-brain barrier: a major obstacle to therapy (Chair - John Hopwood, U Adelaide)

  • 1:00-1:25 Lester Drewes (U Minnesota) - What is the blood-brain barrier? A molecular perspective
  • 1:25-1:45 William Pardridge (UCLA) - Receptor-mediated targeting of recombinant proteins and therapeutic genes through the blood-brain barrier
  • 1:45-2:00 Todd Zankel (BioMarin) - Melanotransferrin (p97) as vehicle for ferrying enzymes across the blood-brain barrier
  • 2:00-2:30 Discussion

2:30 - 3:00 PM BREAK

3:00 - 4:45 PM
Session 4 - Gene transfer approaches to getting enzyme into the brain (Chair - Chester Whitley, U Minnesota)

  • 3:00-3:20 Mark Sands (Washington U) - Overall review of gene therapy in animal models of MPS
  • 3:20-3:40 John Wolfe (U Penn) - Mechanisms for distributing therapeutic gene and gene product
  • 3:40-4:00 Gianvito Martino (Milan U) - Ependymal-leptomeningeal route of delivery for gene therapy
  • 4:00-4:20 Beverly Davidson (U Iowa) - Improving enzyme and vector distribution in brain
  • 4:20-4:45 Discussion

4:45 - 6:20 PM Poster session

6:30 - 8:30 PM RECEPTION - Hosted by The National MPS Society
Remarks by Les Sheaffer, Chairman, Committee on Federal Legislation and MPS Parent

September 25

8:00 - 8:30 AM Continental Breakfast

8:30 - 10:15 AM
Session 5 - Stems cells as therapeutic agents (Chair - Jane Barker, Jackson Lab)

  • 8:30-8:50 Eva Mezey (NIH) -Turning blood into brain
  • 8:50-9:10 Edward Schuchman (Mt Sinai NY) - Intra-cerebral mesenchymal stem cell transplantation in the Type A Niemann Pick disease mouse.
  • 9:10-9:25 Greg Stewart (Genzyme) - Neural stem cells and neurometabolic disease
  • 9:25-9:50 Joanne Kurtzberg (Duke) - Correction of lysosomal storage diseases with cord blood transplantation - a clinical perspective
  • 9:50-10:15 Discussion

10:15 - 10:45 AM COFFEE BREAK

10:45 - 12:00 PM
Session 6 - Imaging to follow the course of disease and progress of therapy (Chair - Mark Sands)

  • 10:45 - 11:05 Afonso Silva (NIH) - MRI in animal models
  • 11:05 - 11:25 William Ball (U Cincinnati) - Advances in neurochemistry and functional imaging
  • 11:25 - 11:45 Harley Kornblum (UCLA) - Positron emission tomography for non-invasive imaging of neuroplasticity, repair and gene therapy in rodents
  • 11:45-12:10 Discussion

12:10 - 1:00 PM LUNCH

1:00 - 3:00 PM
Final Session - Recommendations (Discussion leader - William Sly, St. Louis U)

  • Future research priorities
  • Potential collaborations
  • Funding strategies

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Speakers and Participants

Speakers and Session Chairs

Connie Atwell, Ph.D.
Director
Division of Extramural Research
National Institute of Neurological Disorders and Stroke
National Institutes of Health

William S. Ball, M.D.
Professor
Departments of Radiology and Pediatrics
Interim Chairman
Department of Biomedical Engineering
Children's Hospital Medical Center
University of Cincinnati

Jane E. Barker, Ph.D.
Senior Staff Scientist
Jackson Laboratory

Beverly L. Davidson, Ph.D.
Professor
Department of Internal Medicine
School of Medicine
University of Iowa

Lester R. Drewes, Ph.D.
Professor and Head
Department of Biochemistry and Molecular Biology
School of Medicine
University of Minnesota

Mark Haskins, V.M.D., Ph.D.
Professor
Department of Pathobiology
School of Veterinary Medicine
University of Pennsylvania

John J. Hopwood, Ph.D.
Professor
Department of Chemical Pathology
Women's and Children's Hospital

Harley Kornblum, M.D., Ph.D.
Associate Professor
Departments of Pharmacology and Pediatrics
School of Medicine
University of California, Los Angeles

Joanne Kurtzberg, M.D.
Director
Pediatric Bone Marrow Transplant and Stem Cell Program
Department of Pediatrics
Duke University Medical Center

Arthur Lander, M.D., Ph.D.
Professor and Chair
Department of Developmental and Cell Biology
University of California, Irvine

Gianvito Martino, M.D.
Head, Neuroimmunology Unit
Department of Neuroscience
San Raffaele Scientific Institute - DIBIT
Via Oglettina 58
20132 Milan Italy
Phone: 39 02 2643 4867
Fax: 39 02 2643 4855
E-mail: gmartino@hsr.it

Eva Mezey, M.D., Ph.D.
Staff Scientist
In Situ Hybridization Facility
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Joseph Muenzer, M.D., Ph.D.
Associate Professor
Division of Genetics and Metabolism
Department of Pediatrics
University of North Carolina

Elizabeth F. Neufeld, Ph.D.
Professor and Chair
Department of Biological Chemistry
The David Geffen School of Medicine
University of California, Los Angeles

William M. Pardridge, M.D.
Professor
Department of Medicine
The David Geffen School of Medicine
University of California, Los Angeles

Richard L. Proia, Ph.D.
Chief
Genetics of Development and Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health

Mark S. Sands, Ph.D.
Associate Professor
Departments of Internal Medicine and Genetics
Washington University School of Medicine

Edward H. Schuchman, Ph.D.
Professor and Vice-Chairman for Research
Department of Human Genetics
Mount Sinai School of Medicine, NY

Afonso C. Silva, Ph.D.
Staff Scientist
Laboratory of Functional and Molecular Imaging
National Institute of Neurological Disorders and Stroke
National Institutes of Health

William S. Sly, M.D.
Professor and Chairman
Edward A. Doisy Department of Biochemistry and Molecular Biology
St. Louis University School of Medicine

Gregory R. Stewart, Ph.D.
Director of Neuroscience
Genzyme Corporation

Danilo A. Tagle, Ph.D.
Program Director
Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Steven U. Walkley, D.V.M., Ph.D.
Professor
Department of Neuroscience
Albert Einstein College of Medicine

Chester B. Whitley, M.D., Ph.D.
Professor
Gene Therapy Center
Department of Pediatrics
University of Minnesota

John H. Wolfe, V.M.D., Ph.D.
Professor
Department of Pathology
School of Veterinary Medicine
Professor
Department of Pediatrics
School of Medicine
University of Pennsylvania

Todd C. Zankel, Ph.D.
Director
Cellular Genetics
BioMarin Pharmaceutical, Inc.

Participants

Bruce Anthony, Ph.D.
Postdoctoral Fellow
Jackson Laboratory

Elena Aronovich, Ph.D.
Research Associate
Gene Therapy Program
Institute of Human Genetics
Department of Pediatrics
University of Minnesota

Gavin D. Arthur, Ph.D.
Team Leader
In Vivo Drug Assessment
BioMarin Pharmaceutical, Inc.

Bruce R. Blazar, M.D.
Professor
Division of Hematology, Oncology and Blood and Bone Marrow Transplant
Department of Pediatrics
University of Minnesota

Roscoe O. Brady, M.D.
Chief
Developmental and Metabolic Neurology Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Alessandra d'Azzo, Ph.D.
Professor
Department of Genetics
St. Jude Children's Research Hospital

Mary Demory
Senior Analyst
Office of Rare Diseases
Office of Disease Prevention
Office of the Director
National Institutes of Health

Samuel V. Dunkell, M.D.
New York, NY

N. Matthew Ellinwood, D.V.M, Ph.D.
Postdoctoral Fellow
Department of Pathobiology
School of Veterinary Medicine
University of Pennsylvania

Bradley E. Enerson
Graduate Research Assistant
Department of Biochemistry and Molecular Biology
School of Medicine
University of Minnesota

Carol Feld
Director
Office of Science Program and Policy Analysis
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health

Nigel W. Fraser, Ph.D.
Professor
Department of Microbiology
University of Pennsylvania Medical School

Haiyan Fu, Ph.D.
Research Assistant Professor
Division of Biochemical Genetics and Metabolism
Department of Pediatrics
University of North Carolina at Chapel Hill

Roberto Furlan, M.D., Ph.D.
Researcher
Neuroimmunology Unit
Department of Neuroscience
San Raffaele Scientific Institute - DIBIT

William A. Gahl, M.D., Ph.D.
Clinical Director
National Human Genome Research Institute
National Institutes of Health

Svitlana Garbuzova-Davis, Ph.D., D.Sc.
Assistant Professor
Department of Neurosurgery
University of South Florida

David S. Greenberg, Ph.D.
Research Associate
Department of Biological Chemistry
The David Geffen School of Medicine
University of California, Los Angeles

Franziska B. Grieder, D.V.M., Ph.D.
Director
Laboratory Animal Science
Division of Comparative Medicine
National Center for Research Resources
National Institutes of Health

Pankaj Gupta, M.D.
Assistant Professor
Division of Hematology/Oncology/Transplantation
Department of Medicine
University of Minnesota Medical School
VA Medical Center

Jennifer G. Hall, M.D.
Surgical Research Fellow
Department of General Surgery
Duke University Medical Center

James W. Hanson, M.D.
Chief
Mental Retardation and Developmental Disabilities Branch
National Institute of Child Health and Human Development
National Institutes of Health

Anne K. Hennig, Ph.D.
Postdoctoral Research Associate
Division of Stem Cell Biology
Department of Internal Medicine
Washington University School of Medicine

Henrietta D. Hyatt-Knorr
Senior Advisor
Office of Rare Diseases
National Institutes of Health

Heekyung Jin, D.V.M., Ph.D.
Postdoctoral Fellow
Department of Human Genetics
Mount Sinai School of Medicine

Emil D. Kakkis, M.D., Ph.D.
Senior Vice President, Scientific Affairs
BioMarin Pharmaceutical, Inc.

Hiroshi Kobayashi, M.D.
Research Fellow
Division of Research Immunology/Bone Marrow Transplantation
Children's Hospital Los Angeles
School of Medicine

Robert McGlynn
Research Technician
Department of Neuroscience
Albert Einstein College of Medicine

Catherine McKeon, Ph.D.
Senior Advisor for Genetic Research
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health

Stephanie J. Mihalik, Ph.D.
Senior Research Scientist
Neo Gen Screening

Alan M. Miller, Ph.D.
Director, Genetics
Transkaryotic Therapies, Inc.

Rachel Myerowitz, Ph.D.
Associate Professor
Department of Biology
St. Mary's College of Maryland

Dan Oppenheimer, Ph.D.
Manager
Business Development
BioMarin Pharmaceutical, Inc.

Koji Orii, M.D., Ph.D.
Assistant Research Professor
Department of Biochemistry and Molecular Biology
St. Louis University

Mary Oster-Granite, Ph.D.
Health Scientist Administrator
Mental Retardation and Developmental Disabilities Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
National Institutes of Health

Dao Pan, Ph.D.
Research Associate
Gene Therapy Program
Institute of Human Genetics
Department of Pediatrics
University of Minnesota

Thomas J. Sferra, M.D.
Associate Professor
Center for Gene Therapy
Department of Pediatrics
Ohio State University
Columbus Children's Research Institute

Lamya S. Shihabuddin, Ph.D.
Staff Scientist
Department of Neuroscience/Cell Biology and Protein Therapeutics
Genzyme Corporation

Brian W. Soper, Ph.D.
Research Scientist
The Jackson Laboratory

Giovanna Spinella, M.D.
Program Director
Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Susan L. Staba, M.D.
Fellow
Pediatric Hematology/Oncology
Department of Pediatrics
Duke University Medical Center

Colleen S. Stein, Ph.D.
Research Investigator
Department of Internal Medicine
School of Medicine
University of Iowa

Cynthia J. Tifft, M.D., Ph.D.
Senior Staff Clinician
Genetics of Development and Disease Branch
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health

Charles H. Vite, D.V.M.
Research Associate
Section of Neurology
School of Veterinary Medicine
University of Pennsylvania

Gordon L. Watson, Ph.D.
Scientist
Children's Hospital Oakland Research Institute

Yun-Ping Wu, M.D., Ph.D.
Research Fellow
Genetics of Development and Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health

Robert K. Yu, Ph.D, Med.Sci.D.
Professor and Director
Institute of Molecular Medicine and Genetics
Medical College of Georgia

Ke-Wei Zhao, Ph.D.
Assistant Research Scientist
Department of Biological Chemistry
University of California, Los Angeles

MPS Board Members

Denise Dengel
Board of Directors
The National MPS Society, Inc.

Debbie Dummann
Board of Directors
The National MPS Society, Inc.

Ernie Dummann
Vice President
The National MPS Society, Inc.

Amy Fisher
Board of Directors
The National MPS Society, Inc.

Joyce Fox, M.D.
Board of Directors
The National MPS Society, Inc.
Division of Human Genetics
Department of Pediatrics
Long Island Jewish Hospital

Amy Holland
Board of Directors
The National MPS Society, Inc.

Steve Holland
Treasurer
The National MPS Society, Inc.

Larry Kirch
Board of Directors
The National MPS Society, Inc.

Mark Kristensen
Board of Directors
The National MPS Society, Inc.

Sissi Langford
Board of Directors
The National MPS Society, Inc.

Sue Rattman
Board of Directors
The National MPS Society, Inc.

Les Sheaffer
Board of Directors
The National MPS Society, Inc.

Linda Shine
President
The National MPS Society, Inc.

Barbara Wedehase
Executive Director
The National MPS Society, Inc.

MPS Parents and Friends

Melvyn A. Anhalt, M.D.
MPS Type II Grandparent

Wayne B. Bardsley, J.D.
MPS Type II Parent
President
Government Scientific Source, Inc.

Laura J. Collins
Physical Therapist
MPS Type II Family Member

Mark A. Dant
Executive Director
The Ryan Foundation for MPS Children

Andy Dopheide
Treasurer
The Sanfilippo Syndrome Medical Research Foundation

Alice M. Horne

Rick Jitla
MPS Type VI Child Family Member

Maureen E. Lon
MPS Type II Parent

Rajan and Shruti Misra
MPS Type VI Parents

Doug and Tracie Nicoll
MPS Type IIIA Parents

Teri Sheaffer
MPS Type IIIA Parent

Rex Wang, Ph.D., and Sharon Wang
MPS III Type A Parents

Bradford and Susan Wilson
Co-Founders
The Children's Medical Research Foundation

Gordon Wingate
MPS Type IIIA Parent

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Last updated April 8, 2011