Centa Jessica L, Stratton Matthew P, Pratt Melissa A, Osterlund Oltmanns Jenna R, Wallace Douglas G, Miller Steven A, Weimer Jill M, Hastings Michelle L
Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Mol Ther Nucleic Acids. 2023 Jun 3;33:15-27. doi: 10.1016/j.omtn.2023.05.025. eCollection 2023 Sep 12.
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 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.
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病因，由于蛋白质截短和无义介导的衰变导致mRNA降解，难以治疗，传统药物靶向几乎没有选择。剪接转换反义寡核苷酸通过诱导外显子跳跃来纠正开放阅读框，为因开放阅读框破坏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，它在CLN3型巴滕病（一种致命的儿童溶酶体贮积病）的小鼠模型中具有治疗作用。为了验证这种治疗方法，我们构建了一个组成性表达由反义分子诱导的剪接异构体的小鼠模型。对这些小鼠的行为和病理分析表明，与CLN3疾病小鼠模型相比，其表型较轻，这证明反义寡核苷酸诱导的外显子跳跃在治疗CLN3型巴滕病方面具有治疗效果。该模型突出了通过RNA剪接调控进行蛋白质工程如何能够成为一种有效的治疗方法。
