Intracerebroventricular alpha-N-acetylglucosaminidase Delivery to the Brain - PROJECT SUMMARY
MPS IIIB is lysosomal storage disease; a disease in which a key enzyme, alpha-N-acetylglucosaminidase
(NAGLU) is missing in cells, resulting in the toxic accumulation of complex sugars called glycosaminoglycans,
principally in the central nervous system (CNS). A primary approach for treating related types of disorders
involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy
resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the
CNS. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and
its application to MPS IIIB, a disease with severe neurodegenerative symptoms but no current therapies due to
poor transport across the blood-brain barrier. We have tested our approach on a similar disease, MPSI; which
is missing a different key enzyme called iduronidase (IDUA). Using iduronidase (IDUA) conjugated to
guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to
cells derived from MPS I patients and that intranasal administration of small amounts of the conjugated
enzyme were sufficient to reduce pathological glycosaminoglycans in the brain. The purpose of this grant is
conjugate NAGLU with GNeo (GNeo-NAGLU) and assess the effectiveness of enzyme replacement therapy
delivered directly to the central nervous system in the MPS IIIB mouse model using intracerebroventricular
administration. Dose-dependent biodistribution of GNeo-NAGLU and effects on biochemical and histological
pathology, and behavior will be evaluated. Efficacy and safety will be assessed in single dose and 2-week
dosing studies. The results will provide the preclinical information needed to proceed towards a novel
treatment of the disease in humans.
