【佳學(xué)基因靶向藥物基因檢測(cè)】與突變無(wú)關(guān)的 RNA 干擾工程替代品可挽救與 Tmc1 相關(guān)的聽(tīng)力損失

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研究基因腫瘤檢測(cè)中的數(shù)據(jù)庫(kù)比對(duì)與基因解碼了解《Life Sci Alliance》在?2022 Dec 27;6(3):e202201592.發(fā)表了一篇題目為《》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由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。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)了基因信息檢測(cè)與分析的重要性。

腫瘤基因檢測(cè)及靶向藥物治療研究關(guān)鍵詞：

聽(tīng)力損失,感覺(jué)缺陷,遺傳病因,TMC1,編碼,毛細(xì)胞,機(jī)械傳導(dǎo)

腫瘤治療檢測(cè)基因臨床應(yīng)用結(jié)果

聽(tīng)力損失是賊常見(jiàn)的感覺(jué)缺陷，其中遺傳病因是常見(jiàn)的原因。 TMC1 是一種編碼毛細(xì)胞機(jī)械傳導(dǎo)通道成孔亞基的基因，其顯性突變和隱性突變分別導(dǎo)致 DFNA36 和 DFNB7/11，占遺傳性聽(tīng)力損失的約 2%。以前的工作已經(jīng)確定了突變靶向 RNAi 在治療常染色體顯性非綜合征性耳聾小鼠模型中的療效。然而，這種方法的應(yīng)用受到為每個(gè)變體開(kāi)發(fā)和驗(yàn)證新結(jié)構(gòu)的不可行性的限制。我們開(kāi)發(fā)了一種等位基因非特異性方法，包括突變體和 WT 等位基因的突變不可知 RNAi 抑制，與抗擊倒工程 WT 等位基因共同遞送，使用或不使用土撥鼠肝炎病毒轉(zhuǎn)錄后調(diào)控元件（WPRE ) 以增強(qiáng)轉(zhuǎn)基因表達(dá)。這種治療性構(gòu)建體被輸送到具有 AAV 載體的 DFNA36 成熟小鼠模型中，并實(shí)現(xiàn)了強(qiáng)大的毛細(xì)胞和聽(tīng)覺(jué)腦干反應(yīng)保存。然而，WPRE 增強(qiáng)的 Tmc1 表達(dá)導(dǎo)致較差的結(jié)果，表明基因劑量?jī)?yōu)化在未來(lái) TMC1 基因治療開(kāi)發(fā)中的作用。

腫瘤發(fā)生與革命國(guó)際數(shù)據(jù)庫(kù)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.