A Hitchhiker's Guide to the Blood–brain Barrier: In Trans Delivery of a Therapeutic Enzyme

Abstract

Enzyme replacement therapy (ERT) for the systemic disease associated with lysosomal storage disorders (LSDs) has been an unequivocal success.1 Unfortunately, similar success has not been realized for the central nervous system (CNS) pathology associated with LSDs—in large part because the intravenously administered lysosomal enzymes are unable to cross the blood–brain barrier (BBB). In this issue of Molecular Therapy, Meng et al. report their achievement of supraphysiological levels of the lysosomal enzyme tripeptidyl peptidase I (TPP1) in the brains of young adult mice with the neurodegenerative LSD known as late infantile neuronal ceroid lipofuscinosis (LINCL; late infantile Batten disease).2 Remarkably, therapeutic levels of activity in the brain were achieved following an intravenous injection in young adult animals with an intact BBB. This was accomplished via coinjection of TPP1 and a carrier peptide capable of crossing the BBB.3 The enzyme and carrier peptide were not covalently linked, suggesting that this approach could be useful for a wide range of CNS disorders. Although both the safety and applicability of this approach to other systems must be determined, it could represent an important step forward for the delivery of large molecules across the BBB.