Hu Hailiang, Gatti Richard A
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1732, USA.
Curr Opin Allergy Clin Immunol. 2008 Dec;8(6):540-6. doi: 10.1097/ACI.0b013e328314b63b.
This review is to highlight the most current mutation-targeted therapeutic approaches and provide insights into new developments for treating primary immunodeficiencies.
Significant progress in mutation-targeted treatment was achieved in the past year with the identification and characterization of a translational read-through compound, PTC124. PTC124 demonstrates a new class of nontoxic bioavailable small drugs. Antisense oligonucleotide-mediated techniques such as splicing redirection, exon skipping, and mismatch repair have been successfully used to correct splicing, frameshift, and missense mutations, respectively. Delivery of antisense oligonucleotides to mammalian cells, including primary leukocytes and neurons, saw great progress during the past year. Recent advances for other approaches to correct frameshift and missense mutations are also considered.
Primary immunodeficiencies are monogenic disorders. The characterization and classification of disease-causing mutations facilitate the design and development of new mutation-targeted treatments. To date, using ataxia-telangiectasia (A-T) as a model primary immunodeficiency, the most promising advances have been with chemicals that read through various premature stop codons as well as with antisense oligonucleotides that mask aberrant splice sites. These principles can now be applied to other primary immunodeficiencies.
本综述旨在突出当前针对突变的治疗方法，并深入探讨治疗原发性免疫缺陷的新进展。
过去一年，在针对突变的治疗方面取得了重大进展，鉴定并表征了一种翻译通读化合物PTC124。PTC124展示了一类新型无毒且具有生物利用度的小分子药物。反义寡核苷酸介导的技术，如剪接重定向、外显子跳跃和错配修复，已分别成功用于纠正剪接突变、移码突变和错义突变。过去一年，将反义寡核苷酸递送至包括原代白细胞和神经元在内的哺乳动物细胞方面取得了重大进展。还考虑了其他纠正移码突变和错义突变方法的最新进展。
原发性免疫缺陷是单基因疾病。致病突变的表征和分类有助于设计和开发新的针对突变的治疗方法。迄今为止，以共济失调毛细血管扩张症（A-T）作为原发性免疫缺陷的模型，最有前景的进展是使用能够通读各种提前终止密码子的化学物质以及掩盖异常剪接位点的反义寡核苷酸。这些原则现在可应用于其他原发性免疫缺陷。
