A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System.

Q1 Medicine Human Gene Therapy Clinical Development Pub Date : 2017-09-01 Epub Date: 2017-07-19 DOI:10.1089/humc.2017.067
William B Guggino, Janet Benson, JeanClare Seagrave, Ziying Yan, John Engelhardt, Guangping Gao, Thomas J Conlon, Liudmila Cebotaru
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引用次数: 18

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease that is potentially treatable by gene therapy. Since the identification of the gene encoding CF transmembrane conductance regulator, a number of preclinical and clinical trials have been conducted using the first generation of adeno-associated virus, AAV2. All these studies showed that AAV gene therapy for CF is safe, but clinical benefit was not clearly demonstrated. Thus, a new generation of AAV vectors based on other serotypes is needed to move the field forward. This study tested two AAV serotypes (AAV1 and AAV5) using a dual-luciferase reporter system with firefly and Renilla luciferase genes packaged into AAV1 or AAV5, respectively. Two male and two female Rhesus macaques were each instilled in their lungs with both serotypes using a Penn-Century microsprayer. Both AAV1 and AAV5 vector genomes were detected in all the lung samples when measured at the time of necropsy, 45 days after instillation. However, the vector genome number for AAV1 was at least 10-fold higher than for AAV5. Likewise, luciferase activity was also detected in the same samples at 45 days. AAV1-derived activity was not statistically greater than that derived from AAV5. These data suggest that gene transfer is greater for AAV1 than for AAV5 in macaque lungs. Serum neutralizing antibodies were increased dramatically against both serotypes but were less abundant with AAV1 than with AAV5. No adverse events were noted, again indicating that AAV gene therapy is safe. These results suggest that with more lung-tropic serotypes such as AAV1, new clinical studies of gene therapy using AAV are warranted.

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利用双荧光素酶报告系统在恒河猴囊性纤维化中评估AAV1和AAV5基因转移和转导的临床前研究
囊性纤维化(CF)是一种常染色体隐性遗传病,可通过基因治疗。自从鉴定出CF跨膜传导调节因子的编码基因以来,已经使用第一代腺相关病毒AAV2进行了许多临床前和临床试验。这些研究均表明AAV基因治疗CF是安全的,但临床获益并未得到明确证明。因此,需要基于其他血清型的新一代AAV载体来推动该领域的发展。本研究使用双荧光素酶报告系统检测两种AAV血清型(AAV1和AAV5),该系统分别将萤火虫荧光素酶和豚鼠荧光素酶基因包装到AAV1或AAV5中。两只雄性和两只雌性恒河猴分别使用宾夕法尼亚世纪微喷雾器向其肺部注入两种血清型。在注射后45天尸检时,所有肺样本中均检测到AAV1和AAV5载体基因组。然而,AAV1的载体基因组数至少是AAV5的10倍。同样,在相同的样品中也检测了45天的荧光素酶活性。aav1衍生的活性不高于AAV5衍生的活性。这些数据表明,在猕猴肺中,AAV1的基因转移比AAV5的基因转移更大。血清中和抗体对两种血清型均显著增加,但与AAV1相比,AAV5的含量较少。未发现不良事件,再次表明AAV基因治疗是安全的。这些结果表明,对于更多的嗜肺血清型,如AAV1,使用AAV进行基因治疗的新临床研究是有必要的。
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来源期刊
Human Gene Therapy Clinical Development
Human Gene Therapy Clinical Development CRITICAL CARE MEDICINEMEDICINE, RESEARCH &-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
7.20
自引率
0.00%
发文量
0
期刊介绍: Human Gene Therapy (HGT) is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes important advances in DNA, RNA, cell and immune therapies, validating the latest advances in research and new technologies.
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