Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Gene Ther. 2013 Sep;20(9):913-21. doi: 10.1038/gt.2013.14. Epub 2013 Mar 28.
Mucopolysaccharidosis type IIIB (MPS IIIB) or Sanfilippo Syndrome type B is a lysosomal storage disease resulting from the deficiency of N-acetyl glucosaminidase (NAGLU) activity. We previously showed that intracranial adeno-associated virus (AAV)-based gene therapy results in partial improvements of several aspects of the disease. In an attempt to further correct the disease, MPS IIIB mice were treated at 2-4 days of age with intracranial AAV2/5-NAGLU (IC-AAV), intravenous lentiviral-NAGLU (IV-LENTI) or the combination of both (BOTH). The BOTH group had the most complete biochemical and histological improvements of any treatment group. Compared with untreated MPS IIIB animals, all treatments resulted in significant improvements in motor function (rotarod) and hearing (auditory-evoked brainstem response). In addition, each treatment group had a significantly increased median life span compared with the untreated group (322 days). The combination arm had the greatest increase (612 days), followed by IC-AAV (463 days) and IV-LENTI (358 days). Finally, the BOTH group had nearly normal circadian rhythm measures with improvement in time to activity onset. In summary, targeting both the systemic and central nervous system disease of MPS IIIB early in life appears to be the most efficacious approach for this inherited metabolic disorder.
黏多糖贮积症 IIIB 型（MPS IIIB）或 Sanfilippo 综合征 B 型是一种溶酶体贮积病，由 N-乙酰氨基葡萄糖苷酶（NAGLU）活性缺乏引起。我们之前的研究表明，基于腺相关病毒（AAV）的颅内基因治疗可使疾病的多个方面得到部分改善。为了进一步纠正该疾病，我们在 MPS IIIB 小鼠 2-4 天大时采用颅内 AAV2/5-NAGLU（IC-AAV）、静脉内慢病毒-NAGLU（IV-LENTI）或两者联合（BOTH）进行治疗。与未治疗的 MPS IIIB 动物相比，BOTH 组在生化和组织学方面的改善最全面。与未治疗的 MPS IIIB 动物相比，所有治疗组的运动功能（转棒）和听力（听觉诱发电位脑反应）均有显著改善。此外，与未治疗组相比，每个治疗组的中位生存期都显著延长（322 天）。联合治疗组的生存期延长幅度最大（612 天），其次是 IC-AAV（463 天）和 IV-LENTI（358 天）。最后，BOTH 组的昼夜节律测量几乎恢复正常，活动开始时间也有所改善。总之，在生命早期针对 MPS IIIB 的全身性和中枢神经系统疾病进行靶向治疗似乎是治疗这种遗传性代谢疾病最有效的方法。
