CNS-directed gene therapy for lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders usually caused by deficient activity of a single lysosomal enzyme. As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems, including the central nervous system (CNS). At least 75% of all LSDs have a significant CNS component. Approaches such as bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) can effectively treat the systemic disease associated with LSDs in some patients. However, CNS disease remains a major challenge. Gene therapy represents a promising approach for the treatment of CNS disease as it has the potential to provide a permanent source of the deficient enzyme. Direct intracranial injection of viral gene transfer vectors has resulted in reduced lysosomal storage and functional improvement in certain small (rodent) and large (canine and feline) animal models of LSDs. The addition of protein transduction domains (PTDs) to the recombinant enzymes increased the distribution of enzyme and the extent of correction. Therapeutic levels of lysosomal enzymes can also be delivered to distant sites in the brain by anterograde and retrograde axonal transport. Finally, combining disparate approaches such as BMT and CNS-directed gene therapy can increase treatment efficacy in LSDs with severe CNS disease that are refractory to more conventional approaches.

Conclusion: The development of gene transfer vectors that mediate persistent expression in vivo, the addition of PTDs, a better understanding of lysosomal enzyme trafficking and combining different therapies provide hope that the CNS component of LSDs can be effectively treated.

Figure 1

Anterograde axonal transport of β-glucuronidase (GUSB) in canine mucopolysaccharidosis type VII (MPS VII). One-month-old dogs with MPS VII were injected intravitreally with approximately 7 × 10⁸ infectious units of the same AAV2 vector expressing human GUSB (AAV-GUSB) that was used in previous experiments (58). The animal shown received a single injection in the left eye and was examined 6 months post injection. Robust GUSB expression was observed in the retina of the injected animal (data not shown). Coronal sections (5–8 mm thick) of the brain from rostral (A) to caudal (H) were stained histochemically (13) for GUSB activity. GUSB activity (red stain, blue arrows) was observed in the optic nerve (C) and through the visual tracts of the brain (sections D–G).