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用于提高 AAV2 载体体内转导效率的聚合物。

Polymers for improving the in vivo transduction efficiency of AAV2 vectors.

机构信息

Research Department, Genethon, Evry, France.

出版信息

PLoS One. 2010 Dec 28;5(12):e15576. doi: 10.1371/journal.pone.0015576.

DOI:10.1371/journal.pone.0015576
PMID:21203395
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3011005/
Abstract

BACKGROUND

Adeno-associated virus has attracted great attention as vehicle for body-wide gene delivery. However, for the successful treatment of a disease such as Duchenne muscular dystrophy infusion of very large amounts of vectors is required. This not only raises questions about the technical feasibility of the large scale production but also about the overall safety of the approach. One way to overcome these problems would be to find strategies able to increase the in vivo efficiency.

METHODOLOGY

Here, we investigated whether polymers can act as adjuvants to increase the in vivo efficiency of AAV2. Our strategy consisted in the pre-injection of polymers before intravenous administration of mice with AAV2 encoding a murine secreted alkaline phosphatase (mSeAP). The transgene expression, vector biodistribution and tissue transduction were studied by quantification of the mSeAP protein and real time PCR. The injection of polyinosinic acid and polylysine resulted in an increase of plasmatic mSeAP of 2- and 12-fold, respectively. Interestingly, polyinosinic acid pre-injection significantly reduced the neutralizing antibody titer raised against AAV2.

CONCLUSIONS

Our results show that the pre-injection of polymers can improve the overall transduction efficiency of systemically administered AAV2 and reduce the humoral response against the capsid proteins.

摘要

背景

腺相关病毒作为全身基因传递的载体引起了广泛关注。然而，为了成功治疗杜氏肌营养不良症等疾病，需要输注大量载体。这不仅引发了对大规模生产技术可行性的质疑，也对该方法的整体安全性提出了疑问。克服这些问题的一种方法是寻找能够提高体内效率的策略。

方法

在这里，我们研究了聚合物是否可以作为佐剂来提高 AAV2 的体内效率。我们的策略包括在静脉注射携带编码小鼠分泌型碱性磷酸酶（mSeAP）的 AAV2 之前预先注射聚合物。通过定量检测 mSeAP 蛋白和实时 PCR 研究转基因表达、载体分布和组织转导。聚肌氨酸和聚赖氨酸的注射分别使血浆 mSeAP 增加了 2 倍和 12 倍。有趣的是，聚肌氨酸的预先注射显著降低了针对 AAV2 的中和抗体滴度。

结论

我们的结果表明，聚合物的预先注射可以提高全身给予的 AAV2 的整体转导效率，并降低针对衣壳蛋白的体液免疫反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/7792aff37d4e/pone.0015576.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/bebe0949a68d/pone.0015576.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/bcf05aea36bf/pone.0015576.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/f48bf1e42e62/pone.0015576.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/e88f30f6605e/pone.0015576.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/242ec7fddd6e/pone.0015576.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/7792aff37d4e/pone.0015576.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/bebe0949a68d/pone.0015576.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/bcf05aea36bf/pone.0015576.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/f48bf1e42e62/pone.0015576.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/e88f30f6605e/pone.0015576.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/242ec7fddd6e/pone.0015576.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba52/3011005/7792aff37d4e/pone.0015576.g006.jpg

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