Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
J Med Genet. 2010 Mar;47(3):145-9. doi: 10.1136/jmg.2008.064113. Epub 2009 Sep 14.
Mutations affecting over 2000 of the 20 000 or so genes in the human genome have been linked so far to specific inherited diseases, most of which are rare and have been poorly understood. Many of the genes involved encode components of intracellular signalling pathways that regulate processes such as the growth, proliferation, differentiation and survival or programmed death of cells during development and the maintenance of tissues and organs. Mutations that change the function of genes encoding signalling proteins thereby cause disorders ranging from birth defects to cancer. For Mendelian disorders, the essentially causal relationship between mutation and disease may present direct opportunities to therapeutically manipulate intracellular signalling. Here, we review recent examples of the use of small-molecule drugs to target components of signalling networks in single-gene disorders. We also consider the limitations of these "molecularly targeted" approaches and the difficulties in their clinical development as therapies for rare genetic diseases.
到目前为止，已经发现超过 20000 个人类基因组中的 2000 多个基因的突变与特定的遗传性疾病有关，其中大多数疾病都很罕见，并且了解甚少。许多涉及的基因编码细胞内信号通路的组成部分，这些通路调节细胞的生长、增殖、分化和存活或程序性死亡等过程，这些过程发生在发育过程中以及组织和器官的维持过程中。改变编码信号蛋白的基因功能的突变从而导致从出生缺陷到癌症等各种疾病。对于孟德尔疾病，突变和疾病之间的基本因果关系可能为治疗性地操纵细胞内信号提供直接机会。在这里，我们回顾了最近使用小分子药物靶向单基因疾病信号网络成分的例子。我们还考虑了这些“分子靶向”方法的局限性及其作为罕见遗传性疾病的治疗方法在临床开发中的困难。
