Biodistribution and Tolerability of AAV-PHP.B-CBh- SMN1 in Wistar Han Rats and Cynomolgus Macaques Reveal Different Toxicologic Profiles

作者：Xavier Palazzi, Ingrid D. Pardo, Madhu P. Sirivelu, Leah Newman, Steven W. Kumpf, Jessie Qian, Tania Franks, Sarah Lopes, June Liu, Laura Monarski, Sandra Casinghino, Casey Ritenour, Hayley N. Ritenour, Christopher DuBois, Jennifer Olson, John Graves, Kristin Alexander, Timothy Coskran, Thomas A. Lanz, Joseph T. Brady, Douglas M. McCarty, Somanathan Suryanarayan, Laurence O. Whiteley · 发表于：Human Gene Therapy · 年份：2021 · DOI：10.1089/hum.2021.116 · 被引用次数：62 · 研究领域：Virus-based gene therapy research、CRISPR and Genetic Engineering、CAR-T cell therapy research

Recombinant adeno-associated viruses (AAVs) have emerged as promising vectors for human gene therapy, but some variants have induced severe toxicity in Rhesus monkeys and piglets following high-dose intravenous (IV) administration. To characterize biodistribution, transduction, and toxicity among common preclinical species, an AAV9 neurotropic variant expressing the survival motor neuron 1 ( SMN1 ) transgene (AAV-PHP.B-CBh- SMN1 ) was administered by IV bolus injection to Wistar Han rats and cynomolgus monkeys at doses of 2 × 10 13 , 5 × 10 13 , or 1 × 10 14 vg/kg. A dose-dependent degeneration/necrosis of neurons without clinical manifestations occurred in dorsal root ganglia (DRGs) and sympathetic thoracic ganglia in rats, while liver injury was not observed in rats. In monkeys, one male at 5 × 10 13 vg/kg was found dead on day 4. Clinical pathology data on days 3 and/or 4 at all doses suggested liver dysfunction and coagulation disorders, which led to study termination. Histologic evaluation of the liver in monkeys showed hepatocyte degeneration and necrosis without inflammatory cell infiltrates or intravascular thrombi, suggesting that hepatocyte injury is a direct effect of the vector following hepatocyte transduction. In situ hybridization demonstrated a dose-dependent expression of SMN1 transgene mRNA in the cytoplasm and DNA in the nucleus of periportal to panlobular hepatocytes, while quantitative polymerase chain reaction confirmed the dose-dependent presence of SMN...