Address:
Division of Oncology
Mail Stop 8007-0066-05
Washington University
660 South Euclid Avenue
St. Louis, MO 63110
Room 5509, 4444 Forest Park (office)
Room 5510, 4444 Forest Park (lab)
Ph: 314-362-5496 (lab)
- Lysosomal storage diseases
- Neurodegenerative disorders
- Gene therapy
- Enzyme replacement
- Hematopoiesis
- Bone marrow transplantation
Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that encompass greater than 50 distinct diseases. Individually, these disorders are rare but as a group they occur with a frequency of approximately 1 in 5,000 live births, making them one of the most common childhood inherited diseases. These diseases usually result from a deficiency in one of the many acid hydrolases localized within the lysosome. Since most lysosomal enzymes are ubiquitously expressed, their absence affects most cell types and consequently results in a broad spectrum of clinical signs.
These include organomegally, skeletal dysplasia, auditory deficits, retinal degeneration, cardiac insufficiency, and cognitive impairment. One goal of our laboratory is to better understand the underlying pathophysiology associated with these disorders. To accomplish this goal we use murine models of several of these disorders. We have characterized the cognitive deficits using a battery of behavioral assays, the seizure frequency using electroencephalography, the retinal dysfunction using electroretinography and the hearing deficits using auditory-evoked brain stem responses. We are also pursuing several recent observations that these mouse models of LSD have immune deficits, suffer from chronic inflammation and have profound secondary metabolic abnormalities. Finally, we recently discovered, and are pursuing a link between lysosomal enzyme gene defects and adult-onset neurological diseases.
Another goal of our lab is to develop effective therapies for this class of disease. We showed previously that bone marrow transplantation, enzyme replacement and systemic adeno-associated viral (AAV)-mediated gene therapy can prevent many of the biochemical, histological and clinical signs of disease in mice with mucopolysaccharidosis type VII (MPSVII). We also showed that CNS-directed AAV-mediated gene therapy can correct some of the cognitive deficits associated with MPSVII and several other disorders. Injection of an AAV vector directly into the vitreous of the eye can also improve retinal function. Interestingly, the therapeutic enzyme was transported axonally from the eye into the CNS correcting the disease in specific areas of the brain. We created a xenotransplantation model of MPSVII and performed a pre-clinical experiment using an HIV-based gene transfer vector in hematopoietic stem cells from an affected patient. This approach formed the basis of similar human gene therapy clinical trial.
Our hope is that an increased understanding of the disease process along with improved gene transfer techniques will allow us to effectively treat this class of inherited metabolic disease.
Biosketch
Education
- 1990: PhD, State University of New York at Stony Brook
- 1980: BS, Rochester Institute of Technology, Rochester, NY
Post-Graduate Training
- 1994-1993: Postdoctoral Fellow, The University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA
- 1993-1990: Postdoctoral Fellow, The Jackson Laboratory, Bar Harbor, ME
Academic Positions
- present-2007: Professor, Departments of Medicine and Genetics, Washington University, St. Louis, MO
- 2007-2001: Associate Professor, Departments of Medicine and Genetics, Washington University, St. Louis, MO
- 2001-1994: Assistant Professor, Departments of Medicine and Genetics, Washington University, St. Louis, MO
- 1984-1980: Research Technologist, Department of Radiology, University of Rochester School of Medicine, Rochester, NY
University Appointments & Committees
- present-2015: Senior Scientific Advisor, Intellectual and Developmental Disabilities Research Center (ICCRC), Washington University School of Medicine
- present-2009: Radiation Safety Committee, Increased Controls Subcommittee
- present-1994: Stem Cell Biology Recruitment Committee
- 2014-2005: Institutional Biosafety Committee
- 2011-2006: Co-Director, Viral Gene Vector Laboratory, Department of Neurology
- 2009-2004: Admissions Committee, Division of Biology and Biomedical Sciences
- 2007-2004: Scientific Director, Lysosomal Storage Disease Center
Honors & Awards
- 2018: Distinguished Educator Award, Washington University School of Medicine, St. Louis, MO
- 2015: Krivit Lecture, University of Minnesota School of Medicine, Minneapolis, MN
- 2002: Guest Lecturer, Roscoe Brady Symposium, Washington, DC
- 2000: Extramural Guest Lecturer, XVIII International Complement Workshop, Salt Lake City, UT
- 1999: International Guest Lecturer, Kumamoto University, National Center of Neurology and Psychiatry, National Children’s Medical Research Center, Japan
Editorial Boards
- present-2012: Editorial Board, Journal of Clinical Medicine
- 2016: Guest Editor, Pediatric Endocrinology Reviews, Vol. 14, Supplement 1, Part Three: Therapy for Lysosomal Storage Disorders: How Therapies are Being Developed for Orphan Diseases
- 2014: Guest Editor, Pediatric Endocrinology Reviews, Vol. 12, Supplement 1, Part Two: Some Diseases With Current Therapies or/in Clinical Trials
Professional Societies & Organizations
- American Society of Hematology
- American Society of Gene and Cell Therapy
- American Society for Microbiology
- American Association for the Advancement of Science
- Society for Neuroscience
- Batten Disease Support and Research Association
- Scientific Advisory Board, present-2002
- Mucopolysaccharidosis Society
- Scientific Advisory Board, present-2001
- Chairman, 2009-2006
- ASGCT
- Genetic Diseases Committee, 2010-2007
- Chairman, 2009-2008
- Global Organization for Lysosomal Storage Diseases
- Council Member, 2009-2008
- Hunter’s Hope Foundation
- Scientific Advisory Board, 2001-1999