Enzyme replacement therapy for CLN1 batten disease that crosses the blood-brain-barrier

Abstract

CLN1 Batten disease is caused by mutations in the CLN1 gene which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1). Disease progression is marked by intellectual and motor deterioration, seizures, vision loss, and early mortality. There are no approved treatments for this severe pediatric condition. We describe the development and characterization of recombinant human PPT1 (rhPPT1) suitable for use as a clinical enzyme replacement therapy in CLN1 Batten patients. rhPPT1 displays similar mannose-6-phosphate receptor (M6PR)-dependent uptake kinetics in neuronal cell lines from human, rat and non-human primate but not in mouse cells. rhPPT1 crosses the blood-brain-barrier (BBB) in adult mice which is uncommon for unmodified lysosomal enzymes, and is independent of the M6PR and sialic acid receptors even though analytical characterization of rhPPT1 shows complex M6P and sialic acid containing glycans. Our findings suggest for the first time that intravenous dosing of rhPPT1 may be complementary to other dosing strategies in CLN1 patients and may expand its use for other applications.