Bočkaj Irena, Moreno Garcia Anna, de Miguel Herraiz Pablo, Keskin Sonay, Zancanella Vanessa, Acar Broekmans Şeyda, Vallès Astrid, Liu Ying Poi, Evers Melvin, Wartel Morgane
Global Research, uniQure biopharma B.V., 1105 BP Amsterdam, the Netherlands.
Mol Ther Nucleic Acids. 2024 Aug 15;35(3):102307. doi: 10.1016/j.omtn.2024.102307. eCollection 2024 Sep 10.
Given that numerous genetic disorders, driven by diverse pathogenic mechanisms, may be amenable to recombinant adeno-associated virus (rAAV)-delivered gene therapies, the sustained innovation of rAAV-based therapeutic modalities is crucial. The progression and severity of genetic diseases can be reduced by targeting the toxic transcripts of a defective gene using microRNA (miRNA)-based miQURE technology delivered within an AAV vector. By adapting the delivered cassette, it may be possible to simultaneously regulate the expression profile of multiple genes involved in the pathogenesis of complex genetic diseases. The established miQURE gene silencing strategy was expanded by concatenating several miQURE molecules in a single construct, resulting in the novel linQURE platform. Here, a proof of mechanism is established by demonstrating that linQURE technology enables the concomitant expression of two synthetic miRNAs and , allowing more efficient downregulation of their disease-causing mRNA targets. This approach supports the development of multi-targeting therapeutic strategies, enabling gene therapy products to adapt to more complex multigenic indications, thus expanding the toolbox of readily available gene therapies.
鉴于许多由不同致病机制驱动的遗传疾病可能适用于重组腺相关病毒（rAAV）介导的基因治疗，基于rAAV的治疗方式的持续创新至关重要。通过在AAV载体中使用基于微小RNA（miRNA）的miQURE技术靶向缺陷基因的毒性转录本，可以降低遗传疾病的进展和严重程度。通过调整递送的盒式结构，有可能同时调节参与复杂遗传疾病发病机制的多个基因的表达谱。通过在单个构建体中串联几个miQURE分子，扩展了已建立的miQURE基因沉默策略，从而产生了新的linQURE平台。在此，通过证明linQURE技术能够同时表达两种合成miRNA和，从而更有效地下调其致病mRNA靶点，建立了机制验证。这种方法支持多靶点治疗策略的发展，使基因治疗产品能够适应更复杂的多基因适应症，从而扩展了现成基因治疗的工具箱。
