Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade

Hum Gene Ther. 2015 Jan;26(1):26-35. doi: 10.1089/hum.2014.115.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / genetics*
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antibodies, Viral / immunology
  • CD4 Antigens / immunology
  • Capsid Proteins / immunology
  • Cell Line
  • Cross Reactions / immunology
  • Dependovirus / genetics*
  • Dependovirus / immunology
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Glycogen Storage Disease Type II / genetics*
  • Glycogen Storage Disease Type II / therapy*
  • Humans
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Sex Factors
  • Transduction, Genetic
  • Transgenes
  • alpha-Glucosidases / genetics*
  • alpha-Glucosidases / immunology
  • alpha-Glucosidases / metabolism


  • Antibodies
  • Antibodies, Monoclonal
  • Antibodies, Viral
  • CD4 Antigens
  • Capsid Proteins
  • alpha-Glucosidases