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Abstract：
For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine.
Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators.
Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating <1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels.
This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.
Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators.
Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating <1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels.
This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.
摘要：
对于报道的大多数>2000CFTR基因变异，既不知道相关的疾病责任也不知道潜在的基本缺陷，然而这些对于疾病预后和基于CFTR的治疗是必不可少的。在这里，我们旨在表征两个超罕见突变-1717-2A>G（c.1585-2A>G）和S955P（p。Ser955Pro)-作为个性化医疗的案例研究。
来自两个具有这些突变和F508del的个体的患者来源的直肠活检和肠类器官（p。Phe508del）在其他等位基因中用于评估CFTR功能，对调节剂和RNA剪接模式的反应。并行,我们使用细胞模型进一步表征S955P独立于F508del,并评估其对CFTR调节剂的反应.
来自两个患者的直肠活检和肠道类器官的结果都证明了残余的CFTR功能。进一步的表征显示1717-2A>G导致产生<1%正常CFTRmRNA的选择性剪接,并且S955P影响CFTR门控。最后,对类器官的研究预测，两名患者都是单独VX-770的应答者，甚至更多的是VX-770联合VX-809或VX-661，尽管水平不同。
这项研究证明了个性化医疗的巨大潜力，通过治疗将批准的药物标签扩展到罕见突变的患者。
来自两个具有这些突变和F508del的个体的患者来源的直肠活检和肠类器官（p。Phe508del）在其他等位基因中用于评估CFTR功能，对调节剂和RNA剪接模式的反应。并行,我们使用细胞模型进一步表征S955P独立于F508del,并评估其对CFTR调节剂的反应.
来自两个患者的直肠活检和肠道类器官的结果都证明了残余的CFTR功能。进一步的表征显示1717-2A>G导致产生<1%正常CFTRmRNA的选择性剪接,并且S955P影响CFTR门控。最后,对类器官的研究预测，两名患者都是单独VX-770的应答者，甚至更多的是VX-770联合VX-809或VX-661，尽管水平不同。
这项研究证明了个性化医疗的巨大潜力，通过治疗将批准的药物标签扩展到罕见突变的患者。
