酪氨酸突变体AAV8载体介导的色素上皮衍生因子向小鼠肺的有效和安全的基因转移。

IF 2.5 Q3 CELL BIOLOGY Cellular Physiology and Biochemistry Pub Date : 2023-09-18 DOI:10.33594/000000660
Débora P Ferreira, Sabrina V Martini, Helena A Oliveira, Adriana L Silva, Siddharth Shenoy, Daiqin Chen, Valentina Simon, Eric Han, Natalie E West, Jung Soo Suk, Patricia R M Rocco, Hilda Petrs-Silva, Marcelo M Morales, Fernanda F Cruz
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引用次数: 1

摘要

背景/目的:重组腺相关病毒(rAAV)是肺靶向基因治疗的重要工具。衣壳中用苯丙氨酸残基(Y-F)取代酪氨酸已被证明可以保护AAV载体免受泛素/蛋白酶体降解,提高转导效率。我们测试了突变体Y733F-AAV8载体的粘液扩散,以及将色素上皮衍生因子(PEDF)基因转移到肺部的安全性和有效性。方法:C57BL/6小鼠气管内注射Y733F-AAV8-PEDF(1010病毒基因组)。在注射后7、14、21和28天评估肺力学、形态计量学和炎症。结果:酪氨酸突变体AAV8载体在离体分析中能有效穿透粘液,并在体内滴注后将基因转移到肺细胞。载体给药28天后,观察到转基因mRNA水平增加。PEDF的过表达不影响体内肺参数。结论:这些发现为进一步开发基于Y733F-AAV8的基因疗法提供了基础,用于安全有效地递送PEDF,PEDF具有抗血管生成、抗炎和抗纤维化活性,可能是治疗肺部炎症性疾病的一种有前景的疗法。
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Tyrosine-Mutant AAV8 Vector Mediated Efficient and Safe Gene Transfer of Pigment Epithelium-Derived Factor to Mouse Lungs.

Background/aims: Recombinant adeno-associated viruses (rAAV) are an important tool for lung targeted gene therapy. Substitution of tyrosine with phenylalanine residues (Y-F) in the capsid have been shown to protect the AAV vector from ubiquitin/proteasome degradation, increasing transduction efficiency. We tested the mutant Y733F-AAV8 vector for mucus diffusion, as well as the safety and efficacy of pigment epithelium-derived factor (PEDF) gene transfer to the lung.

Methods: For this purpose, Y733F-AAV8-PEDF (1010 viral genome) was administered intratracheally to C57BL/6 mice. Lung mechanics, morphometry, and inflammation were evaluated 7, 14, 21, and 28 days after injection.

Results: The tyrosine-mutant AAV8 vector was efficient at penetrating mucus in ex vivo assays and at transferring the gene to lung cells after in vivo instillation. Increased levels of transgene mRNA were observed 28 days after vector administration. Overexpression of PEDF did not affect in vivo lung parameters.

Conclusion: These findings provide a basis for further development of Y733F-AAV8-based gene therapies for safe and effective delivery of PEDF, which has anti-angiogenic, anti-inflammatory and anti-fibrotic activities and might be a promising therapy for lung inflammatory disorders.

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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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