WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that encompass greater than 45 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.

Another goal of our lab is to develop effective therapies for this class of disease. We showed previously that syngeneic bone marrow transplantation (see below) and direct protein replacement can prevent many of the clinical signs of disease in MPS VII mice. More recently we showed that injection of an adeno-associated viral (AAV) gene transfer vector directly into the brain can correct some of the cognitive deficits associated with several of these diseases. We showed that injection of an AAV vector directly into the vitreous of the eye can improve retinal function. Interestingly, the therapeutic enzyme was also transported axonally from the eye into the CNS and corrected the disease in specific areas of the brain. Finally, encouraging results from a pre-clinical experiment using a human immunodeficiency virus (HIV)-based gene transfer vector in hematopoietic stem cells from an MPS VII patient have led to a pending clinical trial for this disease.

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.

The mouse on the left (dwarfed, blunted nose, short limbs) is an untreated mouse with MPS VII. The mouse on the right (normal phenotype) is a littermate that also has MPS VII but received BMT the day it was born. In addition to the phenotypic improvement, BMT increases the life span, improves hearing and improves retinal function. Similar phenotypic and functional improvements can be achieved with gene therapy and enzyme replacement approaches. We are currently testing other novel therapeutic approaches in the MPS VII mouse and extending these studies to other models of lysosomal storage diseases.

Education

1980	B.S., Rochester Institute of Technology, Rochester, NY
1990	Ph.D., State University of New York at Stony Brook

Post-graduate Training

1990-1993	Postdoctoral Fellow, The Jackson Laboratory, Bar Harbor, ME
1993-1994	Postdoctoral Fellow, The University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA

Academic Positions

1994-2001	Assistant Professor, Depts. of Internal Medicine and Genetics, Washington University, St. Louis, MO
2001-2007	Associate Professor, Depts. of Internal Medicine and Genetics, Washington University, St. Louis, MO
2007-present	Professor, Depts. of Internal Medicine and Genetics, Washington University, St. Louis, MO

University Appointments & Committees

1994-present	Stem Cell Biology Recruitment Committee
2004-2007	Scientific Director, Lysosomal Storage Disease Center
2004-2009	Admissions Committee, Division of Biology and Biomedical Sciences
2005-present	Institutional Biosafety Committee
2006-2011	Co-Director, Viral Gene Vector Laboratory, Department of Neurology
2009-present	Increased Radiation Controls Subcommittee
	Stem Cell Strategic Subcommittee

Editorial Boards

2012-present

Editorial Board, Journal of Clinical Medicine

Professional Activities & 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
	Hunter’s Hope Foundation    Scientific Advisory Board, 1999-2001
	Mucopolysaccharidosis Society    Scientific Advisory Board, 2001-present    Chairman, 2006-2009
	Batten Disease Support and Research Association    Scientific Advisory Board, 2002-present
	ASGCT    Genetic Diseases Committee, 2007-present    Chairman, 2008-2009
	Global Organization for Lysosomal Storage Diseases    Council Member, 2008-2009

• Updated: February 8, 2012
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