Gene therapy for mucopolysaccharidosis

Abstract

Mucopolysaccharidoses (MPS) are due to deficiencies in activities of lysosomal enzymes that degrade glycosaminoglycans. Some attempts at gene therapy for MPS in animal models have involved intravenous injection of vectors derived from an adeno-associated virus (AAV), adenovirus, retrovirus or a plasmid, which primarily results in expression in liver and secretion of the relevant enzyme into blood. Most vectors can correct disease in liver and spleen, although correction in other organs including the brain requires high enzyme activity in the blood. Alternative approaches are to transduce hematopoietic stem cells, or to inject a vector locally into difficult-to-reach sites such as the brain. Gene therapy holds great promise for providing a long-lasting therapeutic effect for MPS if safety issues can be resolved.

Figure 1. Long-term expression of GUSB in MPS VII dogs after neonatal retroviral vector-mediated gene therapy

Newborn MPS VII dogs were injected i.v. with 3 × 10⁹ transducing units/kg of a retroviral vector with the human α₁-antitrypsin promoter upstream of the canine GUSB cDNA [29], Serum GUSB activity is shown on a semilog plot versus the age years after retroviral vector transduction. The enzyme activity prior to gene therapy was < 1 U/ml, as indicated by the initial data point. The serum activity in normal dogs Is indicated by the shaded region. GUSB: Serum β-glucuronidase; MPS: Mucopolysaccharidosis.