Abstract
Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB [MPS IIIB]) is a lysosomal storage disorder primarily affecting the brain that is caused by a deficiency in the enzyme α-N-acetylglucosaminidase (NAGLU), leading to intralysosomal accumulation of heparan sulfate. There are currently no treatments for this disorder. Here we report that, ex vivo, lentiviral correction of Naglu−/− neural stem cells derived from Naglu−/− mice (iNSCs) corrected their lysosomal pathology and allowed them to secrete a functional NAGLU enzyme that could be taken up by deficient cells. Following long-term transplantation of these corrected iNSCs into Naglu−/− mice, we detected NAGLU activity in the majority of engrafted animals. Successfully transplanted Naglu−/− mice showed a significant decrease in storage material, a reduction in astrocyte activation, and complete prevention of microglial activation within the area of engrafted cells and neighboring regions, with beneficial effects extending partway along the rostrocaudal axis of the brain. Our results demonstrate long-term engraftment of iNSCs in the brain that are capable of cross-correcting pathology in Naglu−/− mice. Our findings suggest that genetically engineered iNSCs could potentially be used to deliver enzymes and treat MPS IIIB.
Highlights
Mucopolysaccharidosis type IIIB (MPS IIIB), an inherited lysosomal disorder, is a sub-type of MPS III caused by deficiency of a-N-acetylglucosaminidase (EC 3.2.1.50 [NAGLU]), a lysosomal acid hydrolase that normally degrades heparan sulfate.[1]
Morphology, alkaline phosphatase staining, and immunofluorescence for Oct[4] were used to confirm their pluripotency (Figure 1A). induced pluripotent stem cells (iPSCs) clones were differentiated to neural stem cells (NSCs) as described previously,[19] and Nestin was expressed at the mRNA and protein levels (Figures 1B and 1C)
The iPSC clones were differentiated to NSCs (iNSCs) were further differentiated into neurons, astrocytes, and oligodendrocytes to show their neural and glial lineage potential (Figures 1D–1F)
Summary
Mucopolysaccharidosis type IIIB (MPS IIIB), an inherited lysosomal disorder, is a sub-type of MPS III caused by deficiency of a-N-acetylglucosaminidase (EC 3.2.1.50 [NAGLU]), a lysosomal acid hydrolase that normally degrades heparan sulfate.[1]. Systemic ERT has been successful in treating some types of MPS with extensive somatic involvement (MPS I,4 II,[5] IVA,[6] and VI7), but this approach is not feasible for MPS IIIB because of the inability of the NAGLU enzyme to cross the blood-brain barrier and alleviate the neurological deficits associated with MPS IIIB. This problem could potentially be solved if the missing enzyme could be delivered to the brain via the cerebrospinal fluid (CSF), life-long repeated administration would still be required.[8]
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