Intranasal Enzyme Replacement Therapy for the Brain

PI: Jeffrey Esko, PhD

Institution: University Of California, San Diego

MPS Statistics

Institutions Awarded


Countries Awarded


# of Awards


Total Amount


Iduronidase (IDUA)-deficient mice accumulate glycosamino-

glycans in cells and tissues and exhibit many of the same neuro-

pathological symptoms of patients suffering from Mucopoly-

saccharidosis I. Intravenous enzyme-replacement therapy

for Mucopolysaccharidosis I ameliorates glycosaminoglycan

storage and many of the somatic aspects of the disease but fails

to treat neurological symptoms due to poor transport across

the blood-brain barrier. In this study, we examined the delivery

of IDUA conjugated to guanidinoneomycin (GNeo), a molecu-

lar transporter. GNeo-IDUA and IDUA injected intravenously

resulted in reduced hepatic glycosaminoglycan accumulation

but had no effect in the brain due to fast clearance from the cir-

culation. In contrast, intranasally administered GNeo-IDUA

entered the brain rapidly. Repetitive intranasal treatment

with GNeo-IDUA reduced glycosaminoglycan storage, lyso-

some size and number, and neurodegenerative astrogliosis in

the olfactory bulb and primary somatosensory cortex, whereas

IDUA was less effective. The enhanced efficacy of GNeo-IDUA

was not the result of increased nose-to-brain delivery or

enzyme stability, but rather due to more efficient uptake into

neurons and astrocytes. GNeo conjugation also enhanced

glycosaminoglycan clearance by intranasally delivered sulfami-

dase to the brain of sulfamidase-deficient mice, a model of

Mucopolysaccharidosis IIIA. These findings suggest the gen-

eral utility of the guanidinoglycoside-based delivery system

for restoring missing lysosomal enzymes in the brain.