Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo
Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo
复制标题
DOI：
10.1161/01.res.0000237661.18885.f6
复制
发表时间：
2006-08-18
影响因子：
20.1
通讯作者：
Byrne, Barry J.
中科院分区：
文献类型：
--
作者：
Pacak, Christina A.;Mah, Cathryn S.;Byrne, Barry J.
心脏病通常是遗传性基因缺陷的最终结果，这可能是使用基因转移方法治疗的潜在方法。重组腺相关病毒（rAAV）介导的基因递送已成为治疗此类疾病的现实方法。在这里，我们证明和比较特定的AAV血清型衣壳的心脏组织的转导的天然亲和力。我们比较了先前接受的用于骨骼肌转导的最佳rAAV血清型rAAV 2/1与携带CMV-lacZ构建体的rAAV 2/8和较新的rAAV 2/9载体在新生小鼠中静脉内递送1 × 10（11）载体基因组后各自跨越脉管系统和心肌的能力。我们发现rAAV 2/8和rAAV 2/9都能够以比rAAV 2/1高约20倍和200倍的水平（分别）抑制心肌。生物分布分析显示rAAV 2/9和rAAV 2/8在心外组织中表现出相似的行为。载体基因组定量显示在施用后数周心脏组织中基因组拷贝数增加，这对应于表达数据。此外，我们将1 × 10（11）个rAAV 2/9- CMV-lacZ载体基因组静脉内给予成年小鼠，并获得了与递送给新生儿后发现的表达生物分布特征相似的表达生物分布特征。尽管需要更高剂量的病毒以接近新生儿注射后观察到的水平，但成人心肌也容易被rAAV 2/9转导。最后，我们已经通过ECG描记在庞贝氏症的小鼠模型中证明了通过AAV 9基因转移的生理疾病校正，并且相同载体的静脉内递送优先转导非人灵长类动物中的心脏组织。
Heart disease is often the end result of inherited genetic defects, which may potentially be treatable using a gene-transfer approach. Recombinant adeno-associated virus (rAAV)-mediated gene delivery has emerged as a realistic method for the treatment of such disorders. Here, we demonstrate and compare the natural affinity of specific AAV serotype capsids for transduction of cardiac tissue. We compared the previously accepted optimal rAAV serotype for transduction of skeletal muscle, rAAV2/1, with rAAV2/8 and the newer rAAV2/9 vectors carrying the CMV-lacZ construct in their respective abilities to transcend vasculature and transduce myocardium following intravenous delivery of 1 x 10(11) vector genomes in neonatal mice. We found that both rAAV2/8 and rAAV2/9 are able to transduce myocardium at approximate to 20- and 200-fold (respectively) higher levels than rAAV2/1. Biodistribution analysis revealed that rAAV2/9 and rAAV2/8 demonstrate similar behavior in extracardiac tissue. Vector genome quantification showed an increase in genome copy numbers in cardiac tissue for several weeks following administration, which corresponds to expression data. In addition, we intravenously administered 1 x 10(11) vector genomes of rAAV2/9- CMV-lacZ into adult mice and achieved an expression biodistribution profile similar to that found following delivery to newborns. Although higher doses of virus will be necessary to approach those levels observed following neonatal injections, adult myocardium is also readily transduced by rAAV2/9. Finally, we have demonstrated physiological disease correction by AAV9 gene transfer in a mouse model of Pompe disease via ECG tracings and that intravenous delivery of the same vector preferentially transduces cardiac tissue in nonhuman primates.