Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I.

摘要: Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing in many tissues ameliorating clinical disease. However, intravenous ERT does not adequately treat disease the central nervous system (CNS), presumably due to effects of blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate brain meninges. An initial dose-response study showed that doses 0.46-4.14 mg IT rhIDU successfully penetrated normal dogs reached tissue levels 5.6 18.9-fold overall 2.7 5.9-fold deep sections lacking CSF contact. assess efficacy safety treating disease, four weekly approximately 1 were administered MPS I-affected resulting a mean 23- 300-fold iduronidase total meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis treatment reduced GAG achieved 57% reduction meningeal accompanied by histologic improvement all cell types. The did develop dose-dependent immune response against protein lymphocytic/plasmacytic infiltrate. route administration may be an way CNS applicable other disorders.