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.