AVI BioPharma, Bothell, WA, USA.
Int J Toxicol. 2010 Mar-Apr;29(2):143-56. doi: 10.1177/1091581809359206. Epub 2010 Jan 28.
Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations. Restoration of dystrophin by exon skipping was demonstrated with the phosphorodiamidate morpholino oligomers (PMO) class of splice-switching oligomers, in both mouse and dog disease models. The authors report the results of Good Laboratory Practice-compliant safety pharmacology and genotoxicity evaluations of AVI-4658, a PMO under clinical evaluation for DMD. In cynomolgus monkeys, no test article-related effects were seen on cardiovascular, respiratory, global neurological, renal, or liver parameters at the maximum feasible dose (320 mg/kg). Genotoxicity battery showed that AVI-4658 has no genotoxic potential at up to 5000 microg/mL in an in vitro mammalian chromosome aberration test and a bacterial reverse mutation assay. In the mouse bone marrow erythrocyte micronucleus test, a single intravenous injection up to 2000 mg/kg was generally well tolerated and resulted in no mutagenic potential. These results allowed initiation of systemic clinical trials in DMD patients in the United Kingdom.
杜氏肌营养不良症（DMD）是由肌营养不良蛋白基因突变引起的。通过使用带有磷酸二酰胺吗啉寡聚物（PMO）的外显子跳跃反义寡核苷酸，在小鼠和犬疾病模型中证明了肌营养不良蛋白的恢复。作者报告了临床评估用于 DMD 的 PMO AVI-4658 的符合良好实验室规范的安全药理学和遗传毒性评价的结果。在食蟹猴中，在最大可行剂量（320mg/kg）下，心血管、呼吸、整体神经、肾脏或肝脏参数均未见与试验药物相关的影响。遗传毒性电池表明，在体外哺乳动物染色体畸变试验和细菌回复突变试验中，AVI-4658 高达 5000μg/mL 时没有遗传毒性潜力。在小鼠骨髓红细胞微核试验中，单次静脉注射高达 2000mg/kg 通常耐受性良好，没有致突变潜力。这些结果允许在英国开始对 DMD 患者进行系统的临床试验。
