Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Pompe disease is a lysosomal storage disorder treated with enzyme replacement therapy (ERT).
• ERT efficacy is limited by antibody formation against recombinant human acid α-glucosidase (GAA).
• Gene therapy using adeno-associated virus (AAV) vectors also faces immune challenges, with antibodies targeting both the vector and the GAA transgene product.

Purpose of the Study:

• To investigate the efficacy of a nondepleting anti-CD4 monoclonal antibody (mAb) in suppressing immune responses to AAV vector-mediated gene therapy for Pompe disease.
• To assess the impact of anti-CD4 mAb treatment on GAA transgene expression, enzyme activity, and therapeutic outcomes in a mouse model of Pompe disease.

Main Methods:

• Mice with Pompe disease were treated with an adeno-associated virus serotype 9 (AAV2/9) vector encoding GAA, preceded by intravenous administration of a nondepleting anti-CD4 mAb.
• Humoral immune responses, including anti-GAA immunoglobulins (IgG1, IgG2a, IgG2b, IgG2c, IgG3), were measured.
• Transduction efficiency of a subsequent AAV2/8 vector was evaluated.
• GAA enzyme activity and glycogen accumulation in heart and skeletal muscles were assessed.

Main Results:

• Administration of anti-CD4 mAb significantly reduced anti-GAA immunoglobulins.
• The anti-CD4 mAb treatment improved transduction efficiency with a subsequent AAV vector, indicating a broader immune control.
• GAA activity was significantly increased in cardiac and skeletal muscles, accompanied by a significant reduction in glycogen accumulation.

Conclusions:

• Combining nondepleting anti-CD4 mAb with AAV gene therapy effectively controls humoral immune responses to both the vector and the GAA transgene.
• This immunomodulatory strategy leads to enhanced therapeutic benefit in a mouse model of Pompe disease, addressing key limitations of current treatments.