Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade.
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.
1 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center , Durham, NC 27710.
Sang-oh
SO
Han
Songtao
S
Li
Elizabeth D
ED
Brooks
Elisa
E
Masat
Christian
C
Leborgne
Suhrad
S
Banugaria
Andrew
A
Bird
Federico
F
Mingozzi
Herman
H
Waldmann
Dwight
D
Koeberl
D000818:Animals; D000906:Antibodies / Q000235:genetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012737:Sex Factors; D014161:Transduction, Genetic; D019076:Transgenes; D000520:alpha-Glucosidases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D036022:Capsid Proteins; D000520:alpha-Glucosidases