REVISED 3/21/2009 - Newborn screening for Pompe disease is available and enzyme replacement therapy (ERT) with human acid alpha glucosidase (hGAA) is effective, ifERT is started early and immune tolerance is present. Knowledge of the mechanisms for immune tolerance to hGAA in Pompe disease will guide the design of future clinical trials for Pompe disease and other lysosomal storage disorders.Wepropose to use an innovative strategy to express hGAA in the liver that simultaneously leads to immune tolerance to hGAA and long lasting efficacy from ERT in Pompe disease mice. Using these model systems, we will investigate the immunologic mechanisms required to induce immune tolerance in GAA-null mice, and evaluate the impact of immune tolerance on efficacy of ERT or gene therapy. This strategy can be translated to clinical applications very readily, because unlike other gene therapy approaches the vector dose is very low, risks are similarly low, and potential benefits are great.General Hypothesis: Liver-specific expression of hGAA will induce immune tolerance and enhance the efficacy of replacement therapy (ERT and/or gene therapy) in Pompe disease.
Specific Aim 1 will evaluate mechanisms responsible for the induction of immune tolerance to hGAA by Pompe disease. Liver-specific expression of hGAA with a tolerogenic AAV vector will establish immune tolerance in GAA-null mice. Immune tolerance to hGAA will be demonstrated via challenges with recombinant hGAA and adjuvant. The role of key players of the adaptive immune response, including Treg cells and NKT cells, will be examined in the presence or absence of immune tolerance. Treg cell depletion will prevent immune tolerance to hGAA.
Specific Aim 2 will demonstrate that efficacy of the hGAA therapy can be improved by modulating the immune response to hGAA. A dose reduction experiment with tolerogenic vector will determine a lower threshold for achieving immune tolerance to hGAA. Long-term efficacy from ERT will be enhanced by immune tolerance, because adaptive immune responses will be abrogated by the less immunogenic transgene. The benefit of immune tolerance to hGAA will be demonstrated by evaluating ERT in GAA-null mice that received low-dose tolerogenic vector. We will evaluate an innovative approach to immunodulatory gene therapy, consisting of desensitization to the hGAA protein by the administration of low-dose tolerogenic vector to mice that previously formed antibodies to hGAA. Desensitization prevents mortality from anaphylaxis during ERT in antibody-positive GAA-null mice. These comparisons will guide preclinical experiments to further immunomodulatory gene therapy in Pompe disease and other lysosomal storage disorders.

Public Health Relevance

BENEFITS: Newborn screening for Pompe disease is available and enzyme replacement therapy is effective, if therapy is started early and immune tolerance is present. We will develop treatment strategies to achieve tolerance in Pompe disease, thus providing a public health benefit through early detection and treatment.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD054795-02
Application #
7911737
Study Section
Special Emphasis Panel (ZHD1-MRG-C (21))
Program Officer
Urv, Tiina K
Project Start
2009-08-12
Project End
2011-08-31
Budget Start
2010-08-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$459,578
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Bond, J E; Kishnani, P S; Koeberl, D D (2017) Immunomodulatory, liver depot gene therapy for Pompe disease. Cell Immunol :
Wang, Gensheng; Young, Sarah P; Bali, Deeksha et al. (2014) Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Mol Ther Methods Clin Dev 1:14018
Zhang, Ping; Luo, Xiaoyan; Bird, Andrew et al. (2012) Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease. Biores Open Access 1:109-14
Zhang, Ping; Sun, Baodong; Osada, Takuya et al. (2012) Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. Hum Gene Ther 23:460-72
Sun, Baodong; Li, Songtao; Bird, Andrew et al. (2010) Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease. J Gene Med 12:881-91
Sun, B; Li, S; Bird, A et al. (2010) Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease. Gene Ther 17:1500-5
Koeberl, Dwight D; Kishnani, Priya S (2009) Immunomodulatory gene therapy in lysosomal storage disorders. Curr Gene Ther 9:503-10