RNAI for DYT1 Dystonia

DYT1肌张力障碍是一种毁灭性的神经疾病，产生致残、持续的异常不自主运动，目前尚无可靠有效的治疗方法。DYT1肌张力障碍是由编码TorsinA(TA)基因的三个碱基对的框内Gag突变引起的，TorsinA(TA)是一种内质网(ER)糖蛋白，属于AAA(与各种细胞活动相关的ATPase)蛋白家族。利用患者组织，我们最近发现这种突变导致TA异常地重新定位到核膜(NE)。此外，我们的数据表明，DYT1突变体TA(Mutta)通过将野生型TA(WTTA)招募到NE而起到显性-负向或显性-毒性效应。基于这些观察，我们假设Mutta的等位基因特异性抑制将改善疾病。实现TA的等位基因特异性沉默的能力也将是进一步描述DYT1肌张力障碍的病理生理学特征的有价值的工具。我们已经证明了有效的等位基因特异性 在体外用RNAi抑制TA是可能的，我们目前的建议代表了一种在体内选择性沉默TA等位基因的尝试。我们的主要目标是探索这一策略作为DYT1肌张力障碍潜在治疗方法的实用性，但这些研究也可能揭示疾病发病机制中的重要分子事件。我们已经建立了DYT1肌张力障碍的神经细胞系和转基因动物模型，以及在体外和体内实现TA等位基因特异性抑制所需的各种实验工具。这些不同的试剂以及我们实验室的互补技能和对研究和治疗的承诺 DYT1肌张力障碍为我们提供了一个开始治疗这种疾病的独特机会。

DYT1 dystonia is a devastating neurological disorder, producing disabling, sustained abnormal involuntary movements for which reliably effective treatments do not exist. DYT1 dystonia is caused by a three base-pair in-frame GAG mutation in the TOR1A gene that encodes torsinA (TA), an endoplasmic reticulum (ER) glycoprotein belonging to the AAA (ATPases Associated with various cellular Activities) protein family. Using patient tissue, we recently discovered that this mutation causes TA to abnormally relocalize to the nuclear envelope (NE). Furthermore, our data suggest that DYT1 mutant TA (mutTA) acts through a dominant-negative or dominant-toxic effect, by recruiting wild type TA (wtTA) to the NE. Based on these observations, we hypothesize that allele-specific suppression of mutTA will ameliorate the disease. The ability to achieve allele-specific silencing of TA would also be a valuable tool for further characterizing the pathophysiology of DYT1 dystonia. We have already demonstrated that potent allele-specific suppression of TA with RNAi is possible in vitro, and our current proposal represents an attempt to selectively silence TA alleles in vivo. Our main goal is to explore the utility of this strategy as a potential therapy for DYT1 dystonia, but these studies may also uncover important molecular events in disease pathogenesis. We have already generated neural cell lines and transgenic animal models of DYT1 dystonia and the various experimental tools required to achieve allele-specific suppression of TA in vitro and in vivo. These diverse reagents and the complementary skills and commitment of our laboratories to the study and treatment of DYT1 dystonia present us with a unique opportunity to begin to tackle this disease.