Fully Deleted Adenovirus Persistently Expressing GAA Accomplishes Long-Term Skeletal Muscle Glycogen Correction in Tolerant and Nontolerant GSD-II Mice

Abstract

Glycogen storage disease type II (GSD-II) patients manifest symptoms of muscular dystrophy secondary to abnormal glycogen storage in cardiac and skeletal muscles. For GSD-II, we hypothesized that a fully deleted adenovirus (FDAd) vector expressing hGAA via nonviral regulatory elements (PEPCK promoter/ApoE enhancer) would facilitate long-term efficacy and decrease propensity to generate anti-hGAA antibody responses against hepatically secreted hGAA. Intravenous delivery of FDAdhGAA into GAA-tolerant or nontolerant GAA-KO mice resulted in long-term hepatic secretion of hGAA. Specifically, nontolerant mice achieved complete reversal of cardiac glycogen storage and near-complete skeletal glycogen correction for at least 180 days and tolerant mice for minimally 300 days coupled with the preservation of muscle strength. Anti-hGAA antibody levels in both mouse strains were significantly less relative to those previously generated by CMV-driven hGAA expression in nontolerant GAA-KO mice. However, plasma GAA levels decreased in nontolerant GAA-KO mice despite long-term intrahepatic GAA expression from the persistent vector. This intriguing result is discussed in light of other examples of "tolerance" induction by gene-transfer-based approaches.

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

“…For example, intravenous injection of HDAd expressing the canine coagulation factor IX in hemophilia B dogs resulted in sustained phenotypic improvement of the bleeding diathesis for the duration of the experiment of over 1 year after vector administration. 3 These, as well as other recent studies, [4][5][6][7][8][9][10][11][12][13] provide compelling evidence for using HDAd to treat genetic disorders.…”

Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors

“…8,11,12 Furthermore, we have recently shown that several rapid immune responses, typically noted after systemic Ad vector injections into Ad-naive mice, are also significantly impacted upon by the presence of a fully functional complement system. 12,18 For example, multiple cytokines and chemokines, noted to rise to significant levels in the plasma of Ad-injected wild-type (WT) mice, do so in a C3-dependent manner in vivo. 12 More dramatically, we have shown that the utilization of rAds both in vitro and in vivo results in a rapid and profound change in the cellular transcriptome, with a high percentage of these genes being rapidly induced (or repressed) by Ads in a C3-dependent manner.…”

Pompe's Disease in Childhood: A Metabolic Myopathy

“…Glucose tetrasacchride has been used as a biomarker for monitoring the therapeutic response to ERT in Pompe's disease [17]. The enzyme is present in fibroblasts grown from amniotic fluid cells and can be utilized for prenatal diagnosis as well [18,19]. Gene encoding of acid alpha-glucosidase has been localized to band 17q23 and gene therapy is in the early stages of preclinical investigation.…”