Abstract
Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.
Original language | English (US) |
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Pages (from-to) | 178-187 |
Number of pages | 10 |
Journal | Molecular Therapy |
Volume | 27 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2 2019 |
Bibliographical note
Funding Information:The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics .
Funding Information:
The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics.
Publisher Copyright:
© 2018 The Author(s)
Keywords
- gene editing
- gene therapy
- lysosomal diseases
- Zinc Finger Nucleases/genetics
- Enzyme Replacement Therapy
- Genetic Therapy/methods
- Male
- Mucopolysaccharidosis I/drug therapy
- Gene Editing/methods
- Lysosomal Storage Diseases/drug therapy
- Animals
- Female
- Glycosaminoglycans/metabolism
- Mice
- Iduronidase/metabolism
- Disease Models, Animal
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article