Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice.
Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice.
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双ISOOFORM HUBE3A基因转移改善了Angelman综合征模型小鼠的行为和癫痫发作结果。
DOI：
10.1172/jci.insight.144712
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发表时间：
2021-10-22
期刊：
影响因子：
8
通讯作者：
Philpot BD
中科院分区：
文献类型：
--
作者：
Judson MC;Shyng C;Simon JM;Davis CR;Punt AM;Salmon MT;Miller NW;Ritola KD;Elgersma Y;Amaral DG;Gray SJ;Philpot BD
母体 UBE3A 等位基因的缺失会导致 Angelman 综合征 (AS)，这是一种使人衰弱的神经发育障碍。在这里，我们设计了一种基于恢复发育中大脑中人类 UBE3A (hUBE3A) 双亚型表达的 AS 治疗策略。我们的密码子优化载体 (hUBE3Aopt) 的 Kozak 序列工程能够以接近内源的 3:1（短/长）比例翻译短和长 hUBE3A 蛋白亚型，这一特征有助于支持最佳治疗结果。为了模拟 hUBE3A 表达的广泛脑分娩和产后早期发作，我们将 hUBE3Aopt 载体包装到 PHP.B 衣壳中，并在新生儿中进行脑室内注射。这种治疗显着改善了 AS 小鼠的运动学习和先天行为，并使它们能够抵抗癫痫发作和由癫痫发作引起的相关海马神经病理学。 hUBE3A 过度表达经常发生在海马体中，但在新皮质和其他主要大脑结构中并不常见；此外，它与行为表现无关。我们的结果证明了双亚型 hUBE3A 基因转移治疗 AS 的可行性、耐受性和治疗潜力。
Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.
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影响因子：
15.9
作者：
Bruinsma, Caroline F.;Schonewille, Martijn;Elgersma, Ype
通讯作者：
Elgersma, Ype
影响因子：
2.5
作者：
Burette, Alain C.;Judson, Matthew C.;Burette, Susan;Phend, Kristen D.;Philpot, Benjamin D.;Weinberg, Richard J.
通讯作者：
Weinberg, Richard J.
影响因子：
1.9
作者：
Boronat, Susana;Mehan, William A.;Caruso, Paul
通讯作者：
Caruso, Paul
影响因子：
25
作者：
Fletcher EV;Simon CM;Pagiazitis JG;Chalif JI;Vukojicic A;Drobac E;Wang X;Mentis GZ
通讯作者：
Mentis GZ
DOI：
10.1126/science.aaa9344
发表时间：
2015-06-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chew J;Gendron TF;Prudencio M;Sasaguri H;Zhang YJ;Castanedes-Casey M;Lee CW;Jansen-West K;Kurti A;Murray ME;Bieniek KF;Bauer PO;Whitelaw EC;Rousseau L;Stankowski JN;Stetler C;Daughrity LM;Perkerson EA;Desaro P;Johnston A;Overstreet K;Edbauer D;Rademakers R;Boylan KB;Dickson DW;Fryer JD;Petrucelli L
通讯作者：
Petrucelli L