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%; p<0.05) in brain IDUA enzymatic activity and a considerable increase in plasma IDUA enzymatic activity (>500%; p<0.05) in wild type mice. These findings will need to be replicated in validated disease specific animal models, specifically the W402X-synologous mouse. This mouse model replicates the mutations found in the patient derived cells that were used for HTS and initial identification of piceatannol. The W402X premature stop codon mutation is found in some 40% of MPSI patients. We also show that piceatannol treatment of additional patient derived fibroblasts results in increased IDUA activity suggesting broader application of these compounds in MPSI patients. The underlying premise of this application is that upregulation of IDUA enzyme levels, even with enzymes that are inefficient due to mutation, will result in beneficial reduction of GAG levels in the periphery and possibly also in the brain that could translate to clinically meaningful outcomes in patients.

Public Health Relevance

Mucopolysaccharidosis I (MPSI) is an autosomal recessive genetic disorder in which the alpha-L-iduronidase (IDUA) enzyme is depleted or absent from the affected individual. In the current application, we will work to develop natural product compounds and that we identified for their ability to upregulate IDUA activity in the periphery and possibly also in the brain. The approach that we propose here could lead to an inexpensive and meaningful method to treat MPSI patients to supplement current therapeutic approaches.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Morris, Jill A
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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