背景:粘多糖贮积症(MPS)IIIB,也被称为Sanfilippo综合症B,是一种毁灭性的儿童疾病。不幸的是,目前尚无MPSIIIB患者的可用治疗方法.然而,溶酶体贮积病的动物模型是确定有希望的治疗途径的有价值的工具。酶替代疗法,基因治疗,和骨髓移植在MPSIIIB模型系统中均显示出功效。在溶酶体贮积病的啮齿动物模型中普遍存在的发现是,最佳治疗结果是在症状发作之前进行干预。因此,本研究的目的是在MPSIIIB小鼠模型中鉴定疾病的早期标志物,并检查该模型中尚未探索的临床相关行为领域.
方法:使用MPSIIIB小鼠模型,我们探索了沟通和步态的早期发展轨迹,以及后来的社会行为,与恐惧有关的惊吓和条件反射,和视觉能力。此外,我们通过磁共振成像和弥散张量成像检查了大脑结构和功能。
结果:我们观察到MPSIIIB小鼠中母体隔离引起的超声发声相对于对照组减少,以及许多光谱特征的中断。MPSIIIB在出生后的前两周也表现出体温调节中断,体重没有任何差异。步态的发育轨迹基本正常。在成年早期,我们观察到完整的视力和社交能力,但更顺从的表型,攻击行为增加,和减少社会嗅探相对于控制。MPSIIIB小鼠对一种pretone的反应表现出更大的惊吓抑制作用,总体惊吓反应降低,提示恐惧记忆降低。MPSIIIB在整个成年期的体重也明显高于对照组,并且通过磁共振和扩散张量成像测量显示更大的全脑体积和具有完整组织完整性的标准化区域体积。分别。
结论:一起,这些结果表明,在该模型中,疾病标志物早在出生后的前两周就存在。Further,这个模型概括了社会,感觉和恐惧相关的临床特征。我们使用MPSIIIB小鼠模型的研究提供了必要的基线信息,这些信息将在未来对潜在治疗的评估中有用。
BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model.
METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging.
RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively.
CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.