Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice.
Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice.
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作者：
血脑屏障（BBB）的存在是粘多糖沉积症（MPS）IIIB治疗开发中最关键的挑战，该疾病是一种溶酶体贮积病，由于α-N-乙酰氨基葡萄糖苷酶（NaGlu）缺乏而具有严重的神经系统表现。早些时候，我们显示了一个全球中枢神经系统（CNS）的转导小鼠通过甘露醇促进进入静脉（IV）交付的重组腺相关病毒血清型2（rAAV 2）载体。在这项研究中，我们优化了方法，并表明当rAAV 2载体在甘露醇给药后8分钟静脉注射时，CNS中的最大转导发生，并且比甘露醇输注后5或10分钟静脉注射载体的效率高约10倍。使用该最佳（8分钟）方案，rAAV 2-CMV-hNaGlu载体的单次IV输注对于治疗成年小鼠中MPS IIIB的CNS疾病是治疗有益的，具有显著延长的存活、改善的行为表现和减少的脑溶酶体贮积病理。治疗益处与最大递送至CNS相关，但与外周组织无关。这一里程碑式的数据显示了第一个有效的基因递送通过BBB来治疗CNS疾病。载体递送和甘露醇输注的关键时机突出了这种预处理对成功干预的重要贡献，并且甘露醇在患者中安全使用的悠久历史预示着其在CNS基因治疗中的应用。
The presence of the blood–brain barrier (BBB) presents the most critical challenge in therapeutic development for mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological manifestation, because of α-N-acetylglucosaminidase (NaGlu) deficiency. Earlier, we showed a global central nervous system (CNS) transduction in mice by mannitol-facilitated entry of intravenous (IV)-delivered recombinant adeno-associated viral serotype 2 (rAAV2) vector. In this study, we optimized the approach and showed that the maximal transduction in the CNS occurred when the rAAV2 vector was IV injected at 8 min after mannitol administration, and was approximately 10-fold more efficient than IV delivery of the vector at 5 or 10 min after mannitol infusion. Using this optimal (8 min) regimen, a single IV infusion of rAAV2-CMV-hNaGlu vector is therapeutically beneficial for treating the CNS disease of MPS IIIB in adult mice, with significantly extended survival, improved behavioral performance, and reduction of brain lysosomal storage pathology. The therapeutic benefit correlated with maximal delivery to the CNS, but not peripheral tissues. This milestone data shows the first effective gene delivery across the BBB to treat CNS disease. The critical timing of vector delivery and mannitol infusion highlights the important contribution of this pretreatment to successful intervention, and the long history of safe use of mannitol in patients bodes well for its application in CNS gene therapy.
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影响因子：
30.8
作者：
KAPLITT, MG;LEONE, P;DURING, MJ
通讯作者：
DURING, MJ
DOI：
10.1073/pnas.96.5.2296
发表时间：
1999-03-02
影响因子：
11.1
作者：
Daly, TM;Vogler, C;Sands, MS
通讯作者：
Sands, MS
影响因子：
11.2
作者：
Heuer, GG;Passini, MA;Wolfe, JH
通讯作者：
Wolfe, JH
影响因子：
168.9
作者：
Kaplitt, Michael G.;Feigin, Andrew;During, Matthew J.
通讯作者：
During, Matthew J.
影响因子：
2.4
作者：
Chen, Y.;Dalwadi, G.;Benson, H. A. E.
通讯作者：
Benson, H. A. E.