Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in... more Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-limb muscles from liver-directed delivery of recombinant adeno-associated virus (rAAV)5- and rAAV8-GAA vectors. GAA(-/-) mice receiving 1 x 10(12) vector genomes of rAAV5- or rAAV8-DHBV-hGAA were analyzed for anti-GAA antibody response, GAA levels, glycogen reduction, and contractile function. We demonstrate that restoration of GAA to the affected muscles is dependent on the presence or absence of the antibody response. Immune-tolerant mice had significantly increased enzyme levels in the heart and skeletal muscles, whereas immune-responsive mice had background levels of GAA in all tissues except the diaphragm. The increased levels of activity in immune-tolerant mice correlated with reduced glycogen in the heart and diaphragm and, overall, contractile function of the soleus muscle was significantly improved. These findings highlight the importance of the immune response to rAAV-encoded GAA in correcting GSDII and provide additional understanding of the approach to treatment of GSDII.
Deficiencies in one or several of the numerous degradative enzymes that reside in the lysosome of... more Deficiencies in one or several of the numerous degradative enzymes that reside in the lysosome often result in one of many clinically severe diseases, almost all of which have no currently available therapy. Although bone marrow transplantation, enzyme replacement and substrate inhibition therapies are being considered, gene therapy represents an increasingly attractive approach, particularly for those lysosomal storage diseases with neurological manifestations. This review summarizes the most recent advances in developing gene therapies for this large and heterogeneous group of disorders.
Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in... more Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-limb muscles from liver-directed delivery of recombinant adeno-associated virus (rAAV)5- and rAAV8-GAA vectors. GAA(-/-) mice receiving 1 x 10(12) vector genomes of rAAV5- or rAAV8-DHBV-hGAA were analyzed for anti-GAA antibody response, GAA levels, glycogen reduction, and contractile function. We demonstrate that restoration of GAA to the affected muscles is dependent on the presence or absence of the antibody response. Immune-tolerant mice had significantly increased enzyme levels in the heart and skeletal muscles, whereas immune-responsive mice had background levels of GAA in all tissues except the diaphragm. The increased levels of activity in immune-tolerant mice correlated with reduced glycogen in the heart and diaphragm and, overall, contractile function of the soleus muscle was significantly improved. These findings highlight the importance of the immune response to rAAV-encoded GAA in correcting GSDII and provide additional understanding of the approach to treatment of GSDII.
Deficiencies in one or several of the numerous degradative enzymes that reside in the lysosome of... more Deficiencies in one or several of the numerous degradative enzymes that reside in the lysosome often result in one of many clinically severe diseases, almost all of which have no currently available therapy. Although bone marrow transplantation, enzyme replacement and substrate inhibition therapies are being considered, gene therapy represents an increasingly attractive approach, particularly for those lysosomal storage diseases with neurological manifestations. This review summarizes the most recent advances in developing gene therapies for this large and heterogeneous group of disorders.
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