Recombinant AAV-directed gene therapy for type I glycogen storage diseases

Abstract

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.

Figure 1

The G6Pase-α/G6PT complex maintains interprandial glucose homeostasis. G6Pase-α and G6PT are shown anchored in the membrane of the ER in contact with both the cytoplasm and ER lumen. The catalytic site of G6Pase-α lies in the ER lumen and the amino acids participating in G6Pase-α catalysis are highlighted. The spatial representations are illustrative only, for the complexes to be active, G6Pase-α must couple functionally with G6PT.

Figure 2

GSD-Ia and GSD-Ib manifest overlapping, yet distinct, phenotypes.