Evasion of Immune Responses to Introduced Human Acid α-Glucosidase by Liver-Restricted Expression in Glycogen Storage Disease Type II

Abstract

Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4+/CD8+ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.

Pompe disease diagnosis and management guideline

“…Studies demonstrate that expression of the acid alpha glucosidase gene within muscle cells or in some cases secretion of GAA from liver leads to a reduction of the glycogen storage abnormality in the mice. Moreover, these studies showed that the immune response to the expressed enzyme in AAV-treated Pompe mice treated can be reduced in some cases117,121 or be influenced by tissue specific expression 118,119…”

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…Therefore, responses are generally dose dependent 43 and can be avoided by a more restricted expression, for example by using tissuespecific promoters as opposed to systemic general promoters. [44][45][46] Independent from these findings, evidence is accumulating that targeting AAV vectors specifically to the liver seems to induce tolerance to the transgene product. 13,47,48 Tolerance induction in liver: the role of regulatory T cells…”

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

“…34 TfR2 and HFE are capable of forming a complex, 35,36 suggesting that the complex is involved in hepcidin regulation. 37 In this study, we used a recombinant serotype 2 adenoassociated virus vector pseudotyped with serotype 8 capsid (AAV2/8) and carrying a hepatic-specific promoter 38 to express either Hfe or Tfr2 in mice to test the role of the HFE/TfR2 complex in the regulation of hepcidin. Our results indicate that the virally encoded Hfe and Tfr2 are expressed in mouse livers.…”