Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2.
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2.
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DOI：
10.1016/j.omtm.2022.06.012
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发表时间：
2022-09-08
期刊：
影响因子：
--
通讯作者：
Breakefield, Xandra O.
中科院分区：
文献类型：
--
作者：
Prabhakar, Shilpa;Beauchamp, Roberta L.;Cheah, Pike See;Yoshinaga, Akiko;Abou Haidar, Edwina;Lule, Sevda;Mani, Gayathri;Maalouf, Katia;Stemmer-Rachamimov, Anat;Jung, David H.;Welling, Bradley;Giovannini, Marco;Plotkin, Scott R.;Maguire, Casey A.;Ramesh, Vijaya;Breakefield, Xandra O.
2型神经纤维瘤病（NF 2）肿瘤抑制基因功能的丧失导致神经鞘瘤、脑膜瘤和室管膜瘤的形成，占所有原发性神经系统肿瘤散发病例的约50%。NF 2综合征是一种常染色体显性疾病，其中生殖系和体细胞等位基因的双等位基因失活导致NF 2缺陷细胞中编码蛋白merlin的功能丧失和哺乳动物雷帕霉素靶蛋白（mTOR）途径信号传导的激活。在这里，我们描述了一种基因替代的方法，通过直接瘤内注射腺相关病毒载体表达梅林在一个新的人神经鞘瘤模型在裸鼠。在培养物中，将编码merlin的AAV 1载体引入CRISPR修饰的人NF 2缺失型蛛网膜细胞（AC）或许旺细胞（SC）中与尺寸减小和mT 0 RC 1途径活化相关，这与恢复的merlin活性一致。在体内，与载体相比，将AAV 1-merlin直接单次注射到裸鼠坐骨神经中生长的人NF 2缺失SC衍生肿瘤中导致肿瘤在10周内消退，与分裂细胞减少和凋亡增加相关。这些研究证实，在NF 2缺失的神经鞘瘤中通过基因置换进行merlin再表达足以引起肿瘤消退，从而可能为NF 2提供有效的治疗。我们的研究支持在临床前异种移植小鼠模型中通过NF 2基因替代抑制甚至消退体内人神经鞘瘤生长。这种方法的有希望的方面是，它是有效的，在一个单一的瘤内注射后，至少几个月的延长期。
Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2. Our studies support suppression, and even regression, of human schwannoma growth in vivo by NF2 gene replacement in a preclinical xenograft mouse model. Promising aspects of this approach are that it is effective over an extended period of at least months after a single intratumoral injection.
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影响因子：
--
作者：
Beauchamp RL;James MF;DeSouza PA;Wagh V;Zhao WN;Jordan JT;Stemmer-Rachamimov A;Plotkin SR;Gusella JF;Haggarty SJ;Ramesh V
通讯作者：
Ramesh V
影响因子：
14
作者：
Gyoergy, Bence;Fitzpatrick, Zachary;Crommentuijn, Matheus H. W.;Mu, Dakai;Maguire, Casey A.
通讯作者：
Maguire, Casey A.
影响因子：
5.2
作者：
Boetto J;Peyre M;Kalamarides M
通讯作者：
Kalamarides M
影响因子：
64.5
作者：
Li W;You L;Cooper J;Schiavon G;Pepe-Caprio A;Zhou L;Ishii R;Giovannini M;Hanemann CO;Long SB;Erdjument-Bromage H;Zhou P;Tempst P;Giancotti FG
通讯作者：
Giancotti FG
影响因子：
5.2
作者：
James, Marianne F.;Stivison, Elizabeth;Ramesh, Vijaya
通讯作者：
Ramesh, Vijaya