【广东会GDH基因靶向药物基因检测】与突变无关的 RNA 干扰工程替代品可挽救与 Tmc1 相关的听力损失

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研究基因肿瘤检测中的数据库比对与基因解码了解《Life Sci Alliance》在 2022 Dec 27;6(3):e202201592.发表了一篇题目为《》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Yoichiro Iwasa, Miles J Klimara, Hidekane Yoshimura, William D Walls, Ryotaro Omichi, Cody A West, Seiji B Shibata, Paul T Ranum, Richard Jh Smith等完成。促进了肿瘤的正确治疗与个性化用药的发展，进一步强调了基因信息检测与分析的重要性。

肿瘤基因检测及靶向药物治疗研究关键词：

听力损失,感觉缺陷,遗传病因,TMC1,编码,毛细胞,机械传导

肿瘤治疗检测基因临床应用结果

听力损失是贼常见的感觉缺陷，其中遗传病因是常见的原因。 TMC1 是一种编码毛细胞机械传导通道成孔亚基的基因，其显性突变和隐性突变分别导致 DFNA36 和 DFNB7/11，占遗传性听力损失的约 2%。以前的工作已经确定了突变靶向 RNAi 在治疗常染色体显性非综合征性耳聋小鼠模型中的疗效。然而，这种方法的应用受到为每个变体开发和验证新结构的不可行性的限制。我们开发了一种等位基因非特异性方法，包括突变体和 WT 等位基因的突变不可知 RNAi 抑制，与抗击倒工程 WT 等位基因共同递送，使用或不使用土拨鼠肝炎病毒转录后调控元件（WPRE ) 以增强转基因表达。这种治疗性构建体被输送到具有 AAV 载体的 DFNA36 成熟小鼠模型中，并实现了强大的毛细胞和听觉脑干反应保存。然而，WPRE 增强的 Tmc1 表达导致较差的结果，表明基因剂量优化在未来 TMC1 基因治疗开发中的作用。

肿瘤发生与革命国际数据库描述：

Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in TMC1, a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7/11, respectively, accounting for ∼2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness. However, application of such approaches is limited by the infeasibility of development and validation of novel constructs for each variant. We developed an allele-non-specific approach consisting of mutation-agnostic RNAi suppression of both mutant and WT alleles, co-delivered with a knockdown-resistant engineered WT allele with or without the use of woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to augment transgene expression. This therapeutic construct was delivered into the mature murine model of DFNA36 with an AAV vector and achieved robust hair cell and auditory brainstem response preservation. However, WPRE-enhanced Tmc1 expression resulted in inferior outcomes, suggesting a role for gene dosage optimization in future TMC1 gene therapy development.