Blood–Brain Barrier Targeting of Therapeutic Lysosomal Enzymes

Abstract

There are over 50 lysosomal storage disorders (LSDs) for which the main therapy is enzyme replacement therapy (ERT) with the recombinant enzyme. Although 75 % of the LSDs affect the central nervous system (CNS), the replacement enzymes are large molecules that do not cross the blood–brain barrier (BBB), and, thus, ERT is not an effective therapy for the CNS manifestations of the disease. The brain and spinal cord can be treated if the enzyme is re-engineered as an IgG-enzyme fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) that targets an endogenous receptor-mediated transport system on the BBB such as the insulin or transferrin receptor. The receptor-specific IgG domain of the fusion protein acts as a molecular Trojan horse to ferry the fused lysosomal enzyme across the BBB. Mucopolysaccharidosis (MPS) Type I is caused by defects in the iduronidase (IDUA) lysosomal enzyme, and MPS Type II is caused by mutations in the iduronate 2-sulfatase (IDS) lysosomal enzyme. Both of these diseases have prominent CNS manifestations. This chapter describes biobetter forms of these recombinant enzymes, and the drug development of IgG-IDUA and IgG-IDS fusion proteins for the treatment of the CNS in MPS Type I and Type II.