【佳學(xué)基因檢測】用于1型神經(jīng)纖維瘤病基因解碼的自發(fā)和基因工程動(dòng)物模型

人體基因檢測需要多少錢—比較

不斷深化研究《腫瘤靶向藥物選擇的基因突變標(biāo)準(zhǔn)》時(shí)，神經(jīng)科疾病基因解碼團(tuán)隊(duì)《Int J Mol Sci》在 2021 Feb 16;22(4):1954發(fā)表了一篇題目為《1型神經(jīng)纖維瘤病的自發(fā)和工程大型動(dòng)物模型》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Sara H Osum, Adrienne L Watson, David A Largaespada 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)了基因信息檢測與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究內(nèi)容關(guān)鍵詞：

基因工程,大型動(dòng)物, 1型神經(jīng)纖維瘤病,自發(fā)的,靶向治療。

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

動(dòng)物模型對于了解人類疾病生物學(xué)包括疾病發(fā)生的基因原因和開發(fā)新療法至關(guān)重要。迄今為止，用于研究人類疾病普遍問題賊常見的動(dòng)物是小鼠。小鼠模型是強(qiáng)大的研究工具，因?yàn)樗鼈凅w積小、壽命有限和明確的基因信息背景使研究人員能夠輕松地操縱它們的基因組并在一般實(shí)驗(yàn)室空間中維持大量動(dòng)物。然而，正是這些屬性使它們與人類如此不同，并部分解釋了為什么這些模型不能正確預(yù)測人類患者的藥物反應(yīng)。神經(jīng)纖維瘤病 (NFs) 尤其如此，這是一組使個(gè)體易患神經(jīng)系統(tǒng)腫瘤的遺傳疾病，其中賊常見的是 1 型神經(jīng)纖維瘤病 (NF1)。盡管進(jìn)行了多年的研究，但對于1 型神經(jīng)纖維瘤病 (NF1)，仍有許多未解決的問題和有效的治療方法?；蚬こ绦∈髽O大地提高了我們對1 型神經(jīng)纖維瘤病 (NF1)的許多方面的理解，但它們并不能說明疾病的整體復(fù)雜性，并且由于體型和生理學(xué)的差異，一些研究成果不能很好地應(yīng)用于臨床治療。此外，1 型神經(jīng)纖維瘤病 (NF1)小鼠模型嚴(yán)重依賴 Cre-Lox 系統(tǒng)，該系統(tǒng)不能正確反映伴隨人類腫瘤發(fā)展的雜合性自發(fā)喪失的分子機(jī)制。自發(fā)和基因工程大型動(dòng)物模型可能為嚙齒動(dòng)物1 型神經(jīng)纖維瘤病 (NF1) 研究提供有價(jià)值的補(bǔ)充。自然發(fā)生的疾病比較模型具有有吸引力的前景，因?yàn)樗鼈儼l(fā)生在不同的遺傳背景上，并且是由于自發(fā)突變而不是工程突變。使用患有自然疾病的動(dòng)物對研究骨肉瘤、淋巴瘤和糖尿病是有效的。自發(fā)性神經(jīng)纖維瘤病樣癥狀包括神經(jīng)纖維瘤和惡性外周神經(jīng)鞘瘤 (MPNST) 已在幾種大型動(dòng)物物種中記錄，并與人類1 型神經(jīng)纖維瘤病 (NF1)具有生物學(xué)和臨床相似性。這些動(dòng)物可以提供對1 型神經(jīng)纖維瘤病 (NF1)復(fù)雜生物學(xué)的更多見解，并可能為臨床前試驗(yàn)提供平臺(tái)。此外，賊近開發(fā)了1 型神經(jīng)纖維瘤病 (NF1)的基因工程豬模型，并顯示出與 NF1 患者相似的各種臨床特征。它們的大尺寸和相對較長的使用壽命允許縱向成像研究和使用人體設(shè)備評估創(chuàng)新手術(shù)技術(shù)。與人類更大的遺傳、解剖學(xué)和生理學(xué)相似性使得能夠?qū)υ谌祟惢颊咧邪l(fā)現(xiàn)的正確疾病等位基因進(jìn)行工程改造，并使其成為在患者臨床試驗(yàn)之前對小分子、細(xì)胞和基因療法進(jìn)行臨床前藥代動(dòng)力學(xué)和藥效學(xué)研究的理想選擇。人類和患有自然疾病的動(dòng)物之間的比較基因組研究，以及大型動(dòng)物疾病模型的臨床前研究，可能有助于確定治療干預(yù)的新靶點(diǎn)并加快新療法的轉(zhuǎn)化。在《1 型神經(jīng)纖維瘤病 (NF1)的基因檢測基礎(chǔ)：動(dòng)物模型基因解碼》中，神經(jīng)纖維瘤病的基因解碼基因檢測團(tuán)隊(duì)討論了新的 NF1 基因工程大型動(dòng)物模型和大型動(dòng)物自發(fā)性 NF 樣表現(xiàn)的病例，特別強(qiáng)調(diào)了這些比較模型如何充當(dāng)專門的小鼠模型和 NF1 患者之間的關(guān)鍵轉(zhuǎn)化中介。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國際數(shù)據(jù)庫描述：

Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients.