Upregulation of Iduronidase Enzyme in MPSI Disease

Project: Research project

Description

? DESCRIPTION (provided by applicant) Mucopolysaccharidosis I (MPSI, Hurler-Scheie Disease) is an autosomal recessive genetic disorder in which the alpha-L-iduronidase (IDUA) enzyme is depleted or absent from the affected individual. Such individuals have a limited capacity to process glycosaminoglycans (GAGs) causing lysosomal buildup leading to cell and organ failure and eventually death at a young age. The prevalence of this disease is approximately 1:100,000. Allogenic hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy (ERT) are currently the best options for MPSI patients, however HSCT carries a significant patient risk profile and ERT remains inefficient and costly (~$400,000 per year). There remains a significant need for additional MPSI treatments, both for reduction of peripheral and also brain GAGs, and to supplement ERT. We engaged in a high throughput screen to identify novel compounds to upregulate IDUA expression. We discovered that stilbene family of generally regarded as safe (GRAS) compounds (e.g. piceatannol, resveratrol) significantly increase in IDUA expression and activity. In this current application, we aim to develop stilbene related compounds to validate their activity in MPSI models, with a view toward eventual clinical translation. To do this we will first validate our findings within the compound family and identify and characterize natural product analogs that have potentially better in vitro and in vivo activity. We will validate our findings in additional patient derived samples, to identify the patient cohorts best suited to treatment, and identify those that do not respond. We aim to show that the brain penetrant compounds upregulate IDUA in vivo and improve both GAG clearance and behavioral outcomes (locomotion, cognitive ability, etc.). Finally, we will work to uncover the clinical potential of te compounds in order to enable translation for MPSI disease. As preliminary evidence to support this work, we identified one compound, piceatannol, that after one month of daily dosing showed a small, but statistically significant increase (~25%; p500%; p
StatusActive
Effective start/end date4/1/163/31/21

Funding

  • National Institutes of Health: $335,781.00
  • National Institutes of Health: $335,781.00
  • National Institutes of Health: $335,781.00
  • National Institutes of Health: $335,781.00

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Iduronidase
Enzyme Replacement Therapy
Up-Regulation
Glycosaminoglycans
Mucopolysaccharidosis I
Stilbenes
Enzymes
Hematopoietic Stem Cells
Transplants
Inborn Genetic Diseases
Aptitude
Brain
Locomotion
Biological Products
Therapeutics