Enhanced Response to Enzyme Replacement Therapy in Pompe Disease after the Induction of Immune Tolerance

Abstract

Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid alpha -glucosidase (GAA) (also called "acid maltase"), causes death in early childhood related to glycogen accumulation in striated muscle and an accompanying infantile-onset cardiomyopathy. The efficacy of enzyme replacement therapy (ERT) with recombinant human GAA was demonstrated during clinical trials that prolonged subjects' overall survival, prolonged ventilator-free survival, and also improved cardiomyopathy, which led to broad-label approval by the U.S. Food and Drug Administration. Patients who lack any residual GAA expression and are deemed negative for cross-reacting immunologic material (CRIM) have a poor response to ERT. We previously showed that gene therapy with an adeno-associated virus (AAV) vector containing a liver-specific promoter elevated the GAA activity in plasma and prevented anti-GAA antibody formation in immunocompetent GAA-knockout mice for 18 wk, predicting that liver-specific expression of human GAA with the AAV vector would induce immune tolerance and enhance the efficacy of ERT. In this study, a very low number of AAV vector particles was administered before initiation of ERT, to prevent the antibody response in GAA-knockout mice. A robust antibody response was provoked in naive GAA-knockout mice by 6 wk after a challenge with human GAA and Freund's adjuvant; in contrast, administration of the AAV vector before the GAA challenge prevented the antibody response. Most compellingly, the antibody response was prevented by AAV vector administration during the 12 wk of ERT, and the efficacy of ERT was thereby enhanced. Thus, AAV vector-mediated gene therapy induced a tolerance to introduced GAA, and this strategy could enhance the efficacy of ERT in CRIM-negative patients with Pompe disease and in patients with other lysosomal storage diseases.

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

“…48 These studies highlight the importance of regulatory T cells in maintaining tolerance to the transgene product. Furthermore, immune tolerance induction through AAV-mediated liver-directed gene transfer has enabled supplementary therapies such as enzyme replacement therapy 55 or muscle-directed gene transfer. 56 How AAV liver-directed gene transfer leads to the development of tolerance and the induction of regulatory T cells is not clear.…”

Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

“…Induced Tregs were capable of suppressing cytotoxic T lymphocyte and antibody responses against F.IX, and were required for tolerance induction (Dobrzynski et al, 2006;Cao et al, 2007a). Once tolerance has been established, supplementary gene transfer to other organs or systemic therapeutic protein delivery can be safely applied (Hoffman et al, 2007;Passini et al, 2007;Sun et al, 2007;Luth et al, 2008). Tolerance induction by liver-restricted transgene expression has been documented for several different transgene products and vectors (Herzog, 2005;Brown et al, 2007;Cerullo et al, 2007).…”

Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

“…6,7 However, to achieve clearance of glycogen in skeletal muscle, high enzyme level is required, which can also elicit antibody responses. 7,23 The impaired efficacy of ERT for other lysosomal storage diseases 24 and of gene therapy for glycogen storage disease type II 25 due to neutralizing antibodies was already described, and efforts have been made to render immunotolerance to hGAA therapeutics. 12,23,26,27 Thus, to overcome this hurdle, neonatal gene transfer can be a useful therapeutic approach for this and other related lysosomal storage diseases.…”