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Chou J.Y.,U.S. National Institutes of Health | Mansfield B.C.,U.S. National Institutes of Health | Mansfield B.C.,Correlogic Systems Inc.
Expert Opinion on Biological Therapy | Year: 2011

Introduction: Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy. Areas covered: A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression. Expert opinion: rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains as to whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-pronged approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney and hematopoietic stem cells is required for treating GSD-I. © 2011 Informa UK, Ltd.


Chou J.Y.,U.S. National Institutes of Health | Jun H.S.,U.S. National Institutes of Health | Mansfield B.C.,U.S. National Institutes of Health | Mansfield B.C.,Correlogic Systems Inc.
Current Opinion in Hematology | Year: 2010

Purpose of review: Glycogen storage disease type Ib, characterized by disturbed glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in a ubiquitously expressed glucose-6-phosphate transporter (G6PT). G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the endoplasmic reticulum, in which it is hydrolyzed to glucose either by a liver/kidney/intestine-restricted glucose-6-phosphatase- α (G6Pase-α) or by a ubiquitously expressed G6Pase-β. The role of the G6PT/G6Pase-α complex is well established and readily explains why G6PT disruptions disturb interprandial blood glucose homeostasis. However, the basis for neutropenia and neutrophil dysfunction in glycogen storage disease type Ib is poorly understood. Recent studies that are now starting to unveil the mechanisms are presented in this review. Recent findings: Characterization of G6Pase-β and generation of mice lacking either G6PT or G6Pase-β have shown that neutrophils express the G6PT/G6Pase-β complex capable of producing endogenous glucose. Loss of G6PT activity leads to enhanced endoplasmic reticulum stress, oxidative stress, and apoptosis that underlie neutropenia and neutrophil dysfunction in glycogen storage disease type Ib. Summary: Neutrophil function is intimately linked to the regulation of glucose and G6P metabolism by the G6PT/G6Pase-β complex. Understanding the molecular mechanisms that govern energy homeostasis in neutrophils has revealed a previously unrecognized pathway of intracellular G6P metabolism in neutrophils. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Trademark
Correlogic Systems Inc. | Date: 2003-09-16

Computer software, namely, pattern recognition and pattern discovery, computer programs for analyzing biological data, including but not limited to, protein expressions, for early disease detection and diagnosis, toxicity assessment and diagnosis, and therapeutic efficacy.


Trademark
Correlogic Systems Inc. | Date: 2001-04-06

Computer software, namely, pattern recognition and pattern discovery, computer programs for analyzing biological data, including but not limited to, protein expressions, for early disease detection and diagnosis, toxicity assessment and diagnosis, and therapeutic efficacy.


Trademark
Correlogic Systems Inc. | Date: 2003-12-23

Computer software, namely, pattern recognition and pattern discovery, computer programs for analyzing biological data, including but not limited to, protein expressions, for early disease detection and diagnosis, toxicity assessment and diagnosis, and therapeutic efficacy.

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