TY - JOUR
T1 - Biochemical evaluation of intracerebroventricular rhNAGLU-IGF2 enzyme replacement therapy in neonatal mice with Sanfilippo B syndrome
AU - Kan, Shih hsin
AU - Elsharkawi, Ibrahim
AU - Le, Steven Q.
AU - Prill, Heather
AU - Mangini, Linley
AU - Cooper, Jonathan D.
AU - Lawrence, Roger
AU - Sands, Mark S.
AU - Crawford, Brett E.
AU - Dickson, Patricia I.
N1 - Funding Information:
The rhNAGLU-IGF2 used in this study is a research form and was kindly provided by BioMarin Pharmaceutical Inc. This project was supported by National Institutes of Health R01 NS088766, R61 NS111079-01 (P.I.D.), and T32 training grant GM8432-27/28 (S-h.K.).
Funding Information:
The rhNAGLU-IGF2 used in this study is a research form and was kindly provided by BioMarin Pharmaceutical Inc. This project was supported by National Institutes of Health R01 NS088766 , R61 NS111079-01 (P.I.D.), and T32 training grant GM8432-27 /28 (S-h.K.).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/6
Y1 - 2021/6
N2 - Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency in α-N-acetylglucosaminidase (NAGLU) activity, which leads to the accumulation of heparan sulfate (HS). MPS IIIB causes progressive neurological decline, with affected patients having an expected lifespan of approximately 20 years. No effective treatment is available. Recent pre-clinical studies have shown that intracerebroventricular (ICV) ERT with a fusion protein of rhNAGLU-IGF2 is a feasible treatment for MPS IIIB in both canine and mouse models. In this study, we evaluated the biochemical efficacy of a single dose of rhNAGLU-IGF2 via ICV-ERT in brain and liver tissue from Naglu−/− neonatal mice. Twelve weeks after treatment, NAGLU activity levels in brain were 0.75-fold those of controls. HS and β-hexosaminidase activity, which are elevated in MPS IIIB, decreased to normal levels. This effect persisted for at least 4 weeks after treatment. Elevated NAGLU and reduced β-hexosaminidase activity levels were detected in liver; these effects persisted for up to 4 weeks after treatment. The overall therapeutic effects of single dose ICV-ERT with rhNAGLU-IGF2 in Naglu−/− neonatal mice were long-lasting. These results suggest a potential benefit of early treatment, followed by less-frequent ICV-ERT dosing, in patients diagnosed with MPS IIIB.
AB - Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency in α-N-acetylglucosaminidase (NAGLU) activity, which leads to the accumulation of heparan sulfate (HS). MPS IIIB causes progressive neurological decline, with affected patients having an expected lifespan of approximately 20 years. No effective treatment is available. Recent pre-clinical studies have shown that intracerebroventricular (ICV) ERT with a fusion protein of rhNAGLU-IGF2 is a feasible treatment for MPS IIIB in both canine and mouse models. In this study, we evaluated the biochemical efficacy of a single dose of rhNAGLU-IGF2 via ICV-ERT in brain and liver tissue from Naglu−/− neonatal mice. Twelve weeks after treatment, NAGLU activity levels in brain were 0.75-fold those of controls. HS and β-hexosaminidase activity, which are elevated in MPS IIIB, decreased to normal levels. This effect persisted for at least 4 weeks after treatment. Elevated NAGLU and reduced β-hexosaminidase activity levels were detected in liver; these effects persisted for up to 4 weeks after treatment. The overall therapeutic effects of single dose ICV-ERT with rhNAGLU-IGF2 in Naglu−/− neonatal mice were long-lasting. These results suggest a potential benefit of early treatment, followed by less-frequent ICV-ERT dosing, in patients diagnosed with MPS IIIB.
KW - Heparan sulfate
KW - Intracerebroventricular enzyme replacement therapy (ICV-ERT)
KW - Mucopolysaccharidosis IIIB
KW - Neonatal mice
KW - Sanfilippo syndrome type B
UR - http://www.scopus.com/inward/record.url?scp=85103924576&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2021.03.013
DO - 10.1016/j.ymgme.2021.03.013
M3 - Article
C2 - 33839004
AN - SCOPUS:85103924576
SN - 1096-7192
VL - 133
SP - 185
EP - 192
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -