Non-clinical evaluation of a blood-brain barrier-penetrating enzyme for the treatment of mucopolysaccharidosis type I

Abstract

Treatment of central nervous system (CNS) disorders in patients with lysosomal storage diseases by intravenous enzyme replacement therapy is still challenging because the blood-brain barrier (BBB) interferes the drug delivery to the brain. We have developed JR-141, a fusion protein consisting of anti-human transferrin receptor antibody (named J-Brain Cargo) and iduronate-2-sulfatase, which can cross the BBB utilizing receptor-mediated transcytosis of transferrin, and are currently conducting clinical trials for Mucopolysaccharidosis II (MPS II). Here we report a non-clinical evaluation of JR-171, another J-Brain Cargo-applied enzyme for the treatment of MPS I. MPS I is caused by deficiency of a lysosomal enzyme α-L-iduronidase (IDUA) and characterized by pathological accumulation of heparan sulfate (HS) and dermatan sulfate (DS) in cells throughout the body, resulting in a broad spectrum of somatic and CNS symptoms. We prepared JR-171, a fusion protein consisting of J-Brain Cargo and IDUA, and examined its biodistribution in cynomolgus monkeys. JR-171 was detected in the brain as well as in peripheral tissues of monkeys after intravenous administration, indicating its penetration of the BBB. We then evaluated the efficacy of repetitive intravenous administration of JR-171 in the reduction of accumulated HS and DS in peripheral tissues and the brain using human transferrin receptor knock-in mice lacking Idua gene as an animal model of MPS I. The intact IDUA decreased HS and DS concentrations in peripheral tissues but failed to reduce the substrates in the brain of the mice. In contrast, JR-171 markedly reduced HS and DS concentrations in the brain as well. These results demonstrate that the J-Brain Cargo-applied IDUA distributes to the brain by crossing the BBB when administered intravenously, and suggest that JR-171 has a potential to exert therapeutic effects on CNS disorders as well as somatic symptoms in MPS I.