Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach.
Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach.
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DOI：
10.1016/j.omtn.2023.05.025
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发表时间：
2023-09-12
期刊：
影响因子：
--
通讯作者：
Hastings, Michelle L.
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文献类型：
--
作者：
Centa, Jessica L.;Stratton, Matthew P.;Pratt, Melissa A.;Oltmanns, Jenna R. Osterlund;Wallace, Douglas G.;Miller, Steven A.;Weimer, Jill M.;Hastings, Michelle L.
破坏开放阅读框并导致翻译终止的基因突变是人类疾病的常见原因，并且由于蛋白质截断和无意义介导的衰变导致mRNA降解而难以治疗，使得传统药物靶向的选择很少。剪接开关反义寡核苷酸通过诱导外显子跳变来纠正开放阅读框，为开放阅读框中断引起的疾病提供了一种潜在的治疗方案。我们最近报道了一种外显子跳跃反义寡核苷酸在CLN3巴滕病（一种致命的儿科溶酶体贮积病）小鼠模型中具有治疗作用。为了验证这种治疗方法，我们建立了一个小鼠模型，该模型可以组成性地表达由反义分子诱导的Cln3剪接异构体。这些小鼠的行为和病理分析表明，与CLN3疾病小鼠模型相比，这些小鼠的表型较轻，这证明反义寡核苷酸诱导的外显子跳变可能在治疗CLN3巴登病中具有治疗效果。该模型强调了通过RNA剪接调制的蛋白质工程如何成为有效的治疗方法。Hastings及其同事建立了CLN3 Batten病的治疗性小鼠模型，表明通过外显子跳变来纠正开放阅读框可减少疾病负担。这些发现验证了他们之前的工作，支持使用外显子跳跃反义寡核苷酸治疗CLN3Δex7/8突变患者。
Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping antisense oligonucleotide that has a therapeutic effect in a mouse model of CLN3 Batten disease, a fatal pediatric lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach. Hastings and colleagues generated a therapeutic mouse model of CLN3 Batten disease to show that correcting the open reading frame by exon skipping results in reduced disease burden. These findings validate their prior work, supporting the use of exon-skipping antisense oligonucleotides to treat patients with a CLN3Δex7/8 mutation.
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