Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate.
Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate.
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DOI：
10.1038/s41467-022-28969-3
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发表时间：
2022-03-15
影响因子：
16.6
通讯作者：
Vandenberghe LH
中科院分区：
文献类型：
--
作者：
Andres-Mateos E;Landegger LD;Unzu C;Phillips J;Lin BM;Dewyer NA;Sanmiguel J;Nicolaou F;Valero MD;Bourdeu KI;Sewell WF;Beiler RJ;McKenna MJ;Stankovic KM;Vandenberghe LH
使用腺相关病毒载体（AAV）的内耳基因治疗有望减轻听力和平衡障碍。我们先前确定了Anc 80 L 65在靶向新生小鼠的内毛细胞和外毛细胞方面的益处。为了加速向人类的转化，我们现在报告在非人灵长类动物模型中手术方法和载体递送的可行性和效率。使用经乳突后鼓室切开术方法向五只恒河猴注射表达eGFP的AAV 1或Anc 80 L 65，以在卵圆窗中形成小孔后进入圆窗膜。手术耐受性良好。除一只动物外，所有动物在注射后7-14天显示耳蜗eGFP表达。在2只动物中，Anc 80 L 65转导了高达90%的顶端内毛细胞;在相同剂量下，AAV 1的效率明显较低。两个载体的转导从顶端到基部下降。这些数据激发了未来的翻译研究，以评估人类听力障碍的基因治疗。使用腺相关病毒载体（腺相关病毒载体）的基因治疗可以挽救人类疾病小鼠模型的听力和平衡缺陷。在这里，作者表明，AAVAnc 80 L 65允许在非人类灵长类动物中进行有效的耳蜗基因转移，并激励未来的研究评估听力和平衡障碍的基因治疗。
Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model. Five rhesus macaques were injected with AAV1 or Anc80L65 expressing eGFP using a transmastoid posterior tympanotomy approach to access the round window membrane after making a small fenestra in the oval window. The procedure was well tolerated. All but one animal showed cochlear eGFP expression 7–14 days following injection. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. These data motivate future translational studies to evaluate gene therapy for human hearing disorders. Gene therapy using Adeno-associated viral vectors (AAV) rescues hearing and balance deficits in mouse models of human disorders. Here, the authors show that AAVAnc80L65 allows efficient cochlear gene transfer in nonhuman primates, and motivate future studies to evaluate gene therapy for hearing and balance disorders.
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影响因子：
16.6
作者：
Isgrig, Kevin;McDougald, Devin S.;Chien, Wade W.
通讯作者：
Chien, Wade W.
影响因子：
13.6
作者：
Ikeda, Yoichiro;Sun, Zhao;Humphreys, Benjamin D.
通讯作者：
Humphreys, Benjamin D.
影响因子：
11.1
作者：
Al-Moyed, Hanan;Cepeda, Andreia P.;Reisinger, Ellen
通讯作者：
Reisinger, Ellen
影响因子：
46.9
作者：
Landegger LD;Pan B;Askew C;Wassmer SJ;Gluck SD;Galvin A;Taylor R;Forge A;Stankovic KM;Holt JR;Vandenberghe LH
通讯作者：
Vandenberghe LH
DOI：
10.1016/j.omtm.2021.03.019
发表时间：
2021-06-11
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Ivanchenko MV;Hanlon KS;Hathaway DM;Klein AJ;Peters CW;Li Y;Tamvakologos PI;Nammour J;Maguire CA;Corey DP
通讯作者：
Corey DP