In 2017, results from a clinical trial of the antisense oligonucleotide (ASO) nusinersen demonstrated potent effects in motor milestone responses and event-free survival in infants with spinal muscular atrophy, prompting early termination of the trial¹. ASOs represent a powerful drug platform, but because of their exquisitely specific binding to RNA nucleotides, most potential disease-altering ASOs would likely never be profitable for pharmaceutical companies. With nearly 7,000 single-gene disorders² and many more pathogenic mutations known in humans, the potential space for personalized ASOs is enormous³. Patient advocates have started connecting with research groups offering personalized ASOs and other disease-altering therapies, and are finding promising preclinical and clinical evidence of benefit in ‘n-of-1’ trials⁴. The challenge will be to scale personalized ASOs as drugs, to impact disease outcomes where possible and to learn which diseases do and do not show benefit if the effect of the mutation is reversed.

2017 年，反义寡核苷酸 (ASO) nusinersen 的临床试验结果显示，它对脊髓性肌萎缩症婴儿的运动里程碑反应和无事件生存具有强大影响，促使该试验提前终止¹。ASO 代表了一个强大的药物平台，但由于它们与 RNA 核苷酸的精确特异性结合，大多数潜在的改变疾病的 ASO 可能永远不会为制药公司带来利润。人类已知有近 7,000 种单基因疾病²和更多的致病突变，个性化 ASO 的潜在空间是巨大的³. 患者权益倡导者已开始与提供个性化 ASO 和其他疾病改变疗法的研究小组建立联系，并在“ n -of-1”试验⁴中寻找有希望的临床前和临床益处证据。挑战在于将个性化 ASO 扩展为药物，尽可能影响疾病结果，并了解如果突变的影响逆转，哪些疾病会显示出益处，哪些不会显示出益处。