Department of Pediatrics, The Lundquist Institute (formally Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, CA 90502, United States of America; CHOC Research Institute, Orange, CA 92868, United States of America.
Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States of America.
Mol Genet Metab. 2021 Jun;133(2):185-192. doi: 10.1016/j.ymgme.2021.03.013. Epub 2021 Mar 31.
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.
黏多糖贮积症 IIIB 型（MPS IIIB，Sanfilippo 综合征 B 型）是由α-N-乙酰氨基葡萄糖苷酶（NAGLU）活性缺乏引起的，导致硫酸乙酰肝素（HS）积累。MPS IIIB 导致进行性神经功能下降，受影响的患者预期寿命约为 20 年。目前尚无有效的治疗方法。最近的临床前研究表明，脑室内（ICV）给予 rhNAGLU-IGF2 融合蛋白的 ERT 是犬和鼠模型中 MPS IIIB 的一种可行治疗方法。在这项研究中，我们评估了单次脑室内 rhNAGLU-IGF2 通过 ERT 给药在 Naglu 新生小鼠脑和肝组织中的生化疗效。治疗后 12 周，脑内 NAGLU 活性水平为对照组的 0.75 倍。在 MPS IIIB 中升高的 HS 和β-己糖胺酶活性降低至正常水平。这种效应在治疗后至少持续 4 周。在肝脏中检测到升高的 NAGLU 和降低的β-己糖胺酶活性水平；这些作用在治疗后持续了长达 4 周。单次脑室内 rhNAGLU-IGF2 ERT 在 Naglu 新生小鼠中的整体治疗效果持久。这些结果表明，在诊断为 MPS IIIB 的患者中，早期治疗后，采用较少频率的脑室内 ERT 给药可能具有潜在益处。
