Faculty
Oncology Division
Sands.jpg

Mark S. Sands, PhD

Professor
Department of Medicine
Oncology Division
Stem Cell Biology
Department of Genetics

Research Interests

  • Lysosomal storage diseases
  • Neurodegenerative disorders
  • Gene therapy
  • Enzyme replacement
  • Hematopoiesis
  • Bone marrow transplantation

Contact

  • 314-362-5494 (office)
  • 314-362-5496 (lab)
  • 314-747-5770 (fax)
  • Room 5509, 4444 Forest Park (office)
  • Room 5510, 4444 Forest Park (lab)
  • Division of Oncology
    Section of Stem Cell Biology
    Washington University Medical School
    660 South Euclid Avenue - Box 8007
    St. Louis, MO 63110

Research

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.

 

Mice The animal on the left is a normal mouse. The middle mouse is an untreated, age-matched MPSVII animal (dwarfed, blunted nose, short limbs). The normal-appearing mouse on the right also has MPSVII but received a single intravenous injection of an AAV gene transfer vector the day it was born. In addition to the improved skeletal development, systemic AAV increased the life span and improved hearing, retinal and cardiac functions. We are currently testing other novel therapeutic approaches in the MPS VII mouse and extending these studies to other models of LSD.