PT -期刊文章盟Janaiah哥打盟-克里斯托弗先令AU -水晶蒙哥马利AU -莎拉·刘易斯AU -亚当·贝文盟金Shontz盟较Kaminoh AU -罗萨莱斯Xiomara盟Laurence Viollet AU -凯文Flanigan AU -里德克拉克盟-布莱恩·卡斯帕·盟Zarife Sahenk盟——杰瑞Mendell说TI -腺相关病毒(AAV)——卵泡介导过分生长(FS)基因转移毒理学研究,准备第一阶段临床试验(SC02.004) DP - 2012年4月27日TA -神经病学PG - SC02.004 SC02.004 VI - 78 IP - 1补充4099 - //www.ez-admanager.com/content/78/1_Supplement/SC02.004.short 4100 - //www.ez-admanager.com/content/78/1_Supplement/SC02.004.full所以Neurology2012 4月27日;首页78 AB -目的:建立rAAV.CMV安全。FS基因转移的肌内注射(坜)为提高股四头肌的力量,准备第一阶段的临床试验。背景FS是一个强有力的肌肉生长抑制素抑制剂,增加肌肉的大小和强度在老鼠和非人类的灵长类动物肌肉交付由AAV分泌。安全问题包括阻碍pituitary-gonadal轴激素的释放和通用器官毒性。在本研究中我们使用non-tissue绑定FS同种型(FS344)来解决这些安全问题在小鼠病毒剂量10倍高于计划在临床使用。设计/方法:小鼠被随机分配到三实验武器与双边贝聿铭rAAV1.CMV的股四头肌肌肉注射。FS344等于最高的临床剂量(2.0 e12汽油vg /公斤)或高10倍(2.0 e13 vg /公斤)。动物是牺牲时间点在6 - 12个月、24和36周(5动物/性/组/计算)post-injection (p)。结果包括:体重、血液学、化学面板、pituitary-gonadal激素;免疫研究,组织病理学24从每个动物器官。结果:没有观察和治疗相关的不良临床或毒理学迹象表明病毒DNA在身体组织中消散了24周。 Within 6 weeks, high dose animals showed scattered focal infiltrates of inflammatory cells corresponding to T-cell immunity to AAV1 identified by IFN-γ ELISpot, but no other pathology was observed. Wet weights of quadriceps increased by 3.5-fold at 36 weeks p.i. in high dose animals. Muscle fiber hypertrophy was observed at 6 weeks and fiber diameter increased by 50% compared to controls by 36 weeks. Hypertrophic-multinucleated fibers were observed at 12 weeks p.i. with increased density of PAX7 positive nuclei.Conclusions: This study shows rAAV1.CMV.FS344 is safe and well tolerated at the proposed clinical doses and causes satellite cell proliferation and significant muscle hypertrophy by fusion with differentiated satellite cells. Early transient inflammation in muscle is related to immune response to AAV1. These results support this approach for clinical trial use.Supported by: Grants from The Myositis Association and Parent Project Muscular Dystrophy, Inc; and support from the Foundation at Nationwide Children's Hospital.Disclosure: Dr. Kota has nothing to disclose. Dr. Shilling has nothing to disclose. Dr. Montgomery has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Bevan has nothing to disclose. Dr. Shontz has nothing to disclose. Dr. Kaminoh has nothing to disclose. Dr. Rosales has nothing to disclose. Dr. Viollet has nothing to disclose. Dr. Flanigan has received personal compensaiton for activities with AVI Therapeutics, Prosensa Therapeutics, and PTC, Inc. Dr. Flanigan has received research support from PTC Therapeutics. Dr. Clark has nothing to disclose. Dr. Kaspar has nothing to disclose. Dr. Sahenk has nothing to disclose. Dr. Mendell has received research support from AVI BioPharmaceuticals Inc.Friday, April 27 2012, 09:00 am-17:00 pm