Ana Sergijenko*, Alexander Langford-Smith*, Ai Yin Liao, Claire E Pickford, John McDermott, Gabriel Nowinski, Kia J Langford-Smith, Catherine LR Merry, Simon A Jones, JE Wraith, Robert F Wynn, Fiona L Wilkinson, Brian W Bigger
*These authors contributed equally to this work
Molecular Therapy
https://doi.org/10.1038/mt.2013.141
Abstract
Mucopolysaccharidosistype IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosaminesulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments.We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LV) overexpressing SGSH in wild type (WT) hematopoietic stem cell transplants (LV-HSCT), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LV in autologous MPSIIIA HSC transplants.To improve brain expression via monocyte/microglial specificity, LV expressing eGFP under ubiquitous PGK, or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice.Eight months after HSCT, LV-PGK-coSGSH vectors produced similar bone marrow SGSH (576% normal activity) to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11% vs 7%), demonstrating improved brain specificity. LV-CD11b- coSGSHnormalized MPSIIIA behavior, brain heparan sulfate, GM2ganglioside and neuroinflammation to WT levels, whilst LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.