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.
Highlights
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of the enzyme a-L-iduronidase (IDUA), which is required for the lysosomal degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate.[1]
Insertion of human IDUA (hIDUA) at the Albumin Locus and Expression in Hepatocytes The proposed strategy is outlined in Figure 1A, in which a pair of zinc finger nucleases (ZFNs) driven by a liver-specific promoter-enhancer induce the targeted insertion of a promoterless, partial hIDUA cDNA with the signal peptide removed
The data shown here demonstrate that in vivo ZFN-mediated insertion of a therapeutic hIDUA transgene at the albumin locus in hepatocytes drives the expression of hIDUA in the liver, secretion of hIDUA into the bloodstream in an active form, and uptake by secondary tissues at levels sufficient for the reduction of GAG storage material
Summary
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of the enzyme a-L-iduronidase (IDUA), which is required for the lysosomal degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate.[1]. The current standard of care for infants with Hurler syndrome is hematopoietic stem cell transplantation (HSCT), which carries a significant risk of mortality (10%–15%) and severe morbidity; if such allogeneic transplant is successful, children may survive into adulthood but still suffer persistent and progressive skeletal deformity and require ongoing surgical interventions. Those affected with more attenuated phenotypes (Hurler-Scheie syndrome and Scheie syndrome) may receive palliative enzyme replacement therapy (ERT).[2,4] despite weekly life-long ERT infusions, affected individuals still incur devastating systemic problems requiring multiple surgical interventions (i.e., hip replacement, cornea transplantation) and suffer a poor quality of life. ERT has negligible neurological impact limited by the blood-brain barrier (BBB) and has little therapeutic effect on cardiac valve disease or skeletal abnormalities.[2]
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