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

Abstract

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.

• Authors: Sang-oh Han, Songtao Li, Elizabeth D Brooks, Elisa Masat, Christian Leborgne, Suhrad Banugaria, Andrew Bird, Federico Mingozzi, Herman Waldmann, Dwight Koeberl
• Journal: Human gene therapy (Hum Gene Ther) Vol. 26 Issue 1 Pg. 26-35 (Jan 2015) ISSN: 1557-7422 [Electronic] United States
• PMID: 25382056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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