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Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in Mucopolysaccharidosis IIIA mice

journal contribution
posted on 2023-05-17, 13:29 authored by Langford-Smith, A, Wilkinson, FL, Langford-Smith, KJ, Holley, RJ, Sergijenko, A, Howe, SJ, William BennettWilliam Bennett, Jones, SA, Wraith, JE, Merry, CLR, Wynn, RF, Bigger, BW
Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.

History

Publication title

Molecular Therapy

Volume

20

Issue

8

Pagination

1610-1621

ISSN

1525-0016

Department/School

Menzies Institute for Medical Research

Publisher

Nature

Place of publication

525 B St, Ste 1900, San Diego, USA, Ca, 92101-4495

Rights statement

Copyright 2012 The American Society of Gene & Cell Therapy

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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