2-5A ANTISENSE INHIBITION OF RESPIRATORY SYNCYTIAL VIRUS

呼吸道合胞病毒(RSV)是婴幼儿和老年人下呼吸道疾病的主要原因，特别是那些被收容的人。它是儿童病毒性毛细支气管炎和肺炎的最常见原因，美国的疫情在冬季经常达到流行的程度，每年约有9万人住院治疗，4500人死亡。双子座科技公司正在开发用于治疗呼吸道合胞病毒感染的新型反义化合物。这些化合物由反义成分和激活剂部分组成，称为2‘，5’-寡腺苷或2-5A。反义成分提供特异性，并将化合物导向靶向病毒RNA基因组，而嵌合体的2-5A部分吸引并激活核糖核酸酶L，这是一种可以直接切割基因组核糖核酸链的有效内切核酸酶。我们已经开发出一种早期的2-5A抗RSV化合物，它是一种在培养细胞中有效抑制RSV复制的化合物。我们的目标是通过增加其稳定性、对靶RNA的亲和力和抗病毒潜力来提高该化合物的疗效，为临床前动物研究做准备。如果这些研究成功，得到的化合物应该会填补一个重要的空白，为对抗RSV提供安全有效的治疗方法。建议的商业应用：RSV在美国是一个主要的健康问题。拟议的研究旨在改进我们的先导抗RSV 2-5A反义化合物，它有可能比目前市场上的RSV疗法更有效、毒性更低。拟议的化合物优化研究也提供了极大地提高2-5A反义方法的整体疗效的潜力，因为结果可以应用于我们公司目前正在开发的其他疗法。

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants, young children and the elderly, particularly those that are institutionalized. It is the most common cause of viral bronchiolitis and pneumonia in children, and outbreaks in the United States frequently reach epidemic proportions during the winter months, accounting for roughly 90,000 hospitalizations and 4500 deaths per year. Gemini Technologies Inc. is developing novel antisense compounds for use in the treatment of RSV infections. These compounds are comprised of an antisense component and an activator moiety, called 2',5'- oligoadenylate or 2-5A. The antisense component provides specificity, and directs the compound to the targeted viral RNA genome, while the 2- 5A portionof the chimera attracts and activates Rnase L, a potent endoribonuclease that can cleave the genomic RNA strands directly. We have developed an early stage 2-5A anti-RSV compound that is a potent inhibitor of RSV replication in cultured cells. Our goal is to improve upon the efficacy of this compound by increasing its stability, affinity for target RNA, and antiviral potential in preparation for preclinical animal studies. If these studies are successful, the resulting compound should fill an important void by providing a safe and effective therapeutic for the fight against RSV. PROPOSED COMMERCIAL APPLICATIONS: RSV is a major health concern in the United States. The proposed studies seek to improve upon our lead antiRSV 2-5A antisense compound, which has the potential to be more efficacious and less toxic than.the RSV therapeutics currently on the market. The proposed compound- optimization studies also offer the potential to dramatically improve the overall efficacy of the 2-5A antisense approach since the results can be applied to other therapeutics currently under development by our company.