Abstract
Mucopolysaccharidosis type IIIA (MPS-IIIA) is a lysosomal storage disorder (LSD) caused by inherited defect of sulfamidase, a lysosomal sulfatase. MPS-IIIA is one of the most common and severe forms of LSDs with CNS involvement. Presently there is no cure. Here we have developed a new gene delivery approach for the treatment of MPS-IIIA based on the use of a modified version of sulfamidase expression cassette. This cassette encodes both a chimeric sulfamidase containing an alternative signal peptide (sp) to improve enzyme secretion and sulfatase-modifying factor 1 (SUMF1) to increase sulfamidase post-translational activation rate. We demonstrate that improved secretion and increased activation of sulfamidase act synergistically to enhance enzyme biodistribution in wild-type (WT) pigs upon intrathecal adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Translating such gene delivery strategy to a mouse model of MPS-IIIA results in a rescue of brain pathology, including memory deficit, as well as improvement in somatic tissues. These data may pave the way for developing effective gene delivery replacement protocols for the treatment of MPS-IIIA patients.
Highlights
Mucopolysaccharidosis type IIIA (MPS-IIIA) is one of the most common and severe forms of neurodegenerative lysosomal storage disorders (LSDs).[1,2] It is caused by inherited defect of the sulfamidase (SGSH), a soluble lysosomal enzyme belonging to the family of sulfatases,[3] and leads to the accumulation of heparan sulfate in cell, within the CNS
To evaluate the potential for therapeutic effectiveness of intra-cerebrospinal fluid (CSF) associated virus serotype 9 (AAV9)-mediated delivery of IDSspSGSH-IRES-sulfatase-modifying factor 1 (SUMF1), we used the B6Cg-Sgsh(mps3a/PstJ) mouse (SgshÀ/À), a spontaneous MPS-IIIA mouse model largely used in preclinical studies of this disease.[24]
We found a significant increase in SGSH activity in brain sections from the IDSspSGSH-injected MPS-IIIA mice and a further significant increase in enzymatic activity upon the administration of AAV9-IDSspSGSHIRES-SUMF1 (Figure S1)
Summary
Mucopolysaccharidosis type IIIA (MPS-IIIA) is one of the most common and severe forms of neurodegenerative lysosomal storage disorders (LSDs).[1,2] It is caused by inherited defect of the sulfamidase (SGSH), a soluble lysosomal enzyme belonging to the family of sulfatases,[3] and leads to the accumulation of heparan sulfate in cell, within the CNS. There are no treatments available to treat the CNS in MPS-IIIA patients. Gene delivery aimed at correcting defective hydrolytic lysosomal defects represents the most promising replacement strategy for the CNS treatment of MPS-IIIA, as well as other MPSs with similar causes, because of its potential for a onetime treatment.[4]. Among viral vectors used for gene transfer, adeno-associated viral (AAV) vectors are most commonly utilized for in vivo gene transfer because they are safe, provide significantly long transgene expression, a major medical need in the clinical care of MPS-III patients is to overcome these limitations and develop safe and minimally invasive gene transfer approaches with improved CNS transduction.
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