Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
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DOI：
10.1203/pdr.0b013e31822e1825
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发表时间：
2011-11-01
影响因子：
3.6
通讯作者：
Slaugenhaupt, Susan A.
中科院分区：
文献类型：
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作者：
Axelrod, Felicia B.;Liebes, Leonard;Slaugenhaupt, Susan A.
家族性自主神经功能障碍是由IKBKAP基因内含子剪接突变引起的，导致20号外显子的部分跳跃和I-kappa-B激酶复合体相关蛋白/延伸蛋白1(IKAP/ELP-1)表达的组织特异性降低。激动素(6-呋喃基氨基嘌呤)在FD细胞系和携带者中已被证明可以改善剪接，增加WT IKBKAP mRNA和IKAP蛋白的表达。为了确定口服激动素治疗是否可以改变FD受试者的mRNA剪接，以及是否可以耐受，我们对8名剪接突变纯合子的FD患者进行了激动素治疗。受试者服用23.5 mg/kg/d共28天。8名受试者中有6名在第8天发现WT IKBKAP mRNA表达增加；28天后，与基线相比平均增加显著(p=0.002)。我们已经证明了激动素在这个医学上脆弱的人群中是可以耐受的。激动素不仅在FD患者的剪接中产生了预期的效果，而且这种效果似乎随着时间的推移而改善，尽管缺乏剂量变化。这是一种在患有FD的患者体内产生mRNA剪接变化的药物的第一份报告，并支持未来的长期试验，以确定激动素是否对FD患者有效。(儿科研究报告70：480-483,2011)
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. (Pediatr Res 70: 480-483, 2011)