Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade.

Journal Article (Journal Article)

Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease.

Full Text

Duke Authors

Cited Authors

  • Han, S-O; Li, S; Brooks, ED; Masat, E; Leborgne, C; Banugaria, S; Bird, A; Mingozzi, F; Waldmann, H; Koeberl, D

Published Date

  • January 2015

Published In

Volume / Issue

  • 26 / 1

Start / End Page

  • 26 - 35

PubMed ID

  • 25382056

Pubmed Central ID

  • PMC4303018

Electronic International Standard Serial Number (EISSN)

  • 1557-7422

Digital Object Identifier (DOI)

  • 10.1089/hum.2014.115


  • eng

Conference Location

  • United States