Safety of intravitreally delivered AAV2 vector-mediated multi-characteristic opsin genetic construct in wild type beagle dogs

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-07-23 DOI:10.1002/jgm.3720

Samarendra Mohanty, Subrata Batabyal, Ananta Ayyagari, Najam A. Sharif

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Abstract

Background

A novel adeno-associated virus 2 (AAV2)-carried multi-characteristic opsin (MCO) (MCO-010) is undergoing several clinical trials as a novel therapeutic modality for the treatment of degenerative retinal diseases including retinitis pigmentosa and Stargardt disease. The present study aimed to determine the ocular and systemic safety of MCO-010 and the AAV2 vehicle in adult Beagle dogs following intravitreal (IVT) injection.

Methods

The current safety/toxicology studies spanning 13 weeks described here utilized well-documented techniques to assess the effects of IVT injection of MCO-010 up to 2.2 × 10¹¹ genome copies (gc) per eye, or the AAV2 capsid (vehicle control) on gross behavioral and immunogenic changes, alterations in body weights, blood biochemistry, hematology, blood coagulation, gross necropsy lesions, organ weight changes and histopathology in the dogs (n = 4 per group; two males and two females per group). Immunohistochemical and functional electroretinogram studies were also conducted to determine MCO expression in the retina and determine any retinal toxicity associated with MCO-010.

Results

There were no significant deleterious effects of the MCO-010 (or the AAV2 at the tested doses) on any of the examined parameters, including the absence of any severe ocular or systemic adverse events. However, as expected, inflammation after IVT delivery of AAV2 and MCO-010 was observed in the conjunctivae of all groups of animals, although this self-resolved within 1 week post-injection. Quantitative immunohistochemical analyses of MCO-010-associated mCherry revealed successful delivery of the gene therapy within the inner retina.

Conclusions

In summary, MCO-010 demonstrated a favorable safety profile when administered to the eyes of adult Beagle dogs of both sexes at dose levels up to 2.2 × 10¹¹ gc per eye, with no adverse effects observed. This dose was identified as the No Observed Adverse Effect Level (i.e. NOAEL) and guided selection of safe doses for human clinical trials.

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在野生型小猎犬体内静脉注射 AAV2 向量介导的多特征蛋白基因构建物的安全性。

背景：一种新型腺相关病毒2（AAV2）携带的多特性视蛋白（MCO）（MCO-010）正在进行多项临床试验，它是治疗视网膜变性疾病（包括视网膜色素变性和Stargardt病）的一种新型治疗方法。本研究旨在确定 MCO-010 和 AAV2 载体在成年比格犬体内静脉注射后的眼部和全身安全性：本文所述的安全性/毒理学研究时间跨度为 13 周，采用的是有据可查的技术来评估 IVT 注射 MCO-010 的影响，最高剂量为 2.2 × 1011 个基因组拷贝 (gc) 或 AAV2 包膜（载体对照）对狗（每组 4 只；每组 2 只雌雄狗）行为和免疫原性变化、体重变化、血液生化、血液学、血液凝固、尸检病变、器官重量变化和组织病理学的影响。还进行了免疫组化和功能性视网膜电图研究，以确定视网膜中 MCO 的表达，并确定 MCO-010 是否对视网膜产生毒性：结果：MCO-010（或测试剂量的AAV2）对任何检查参数都没有明显的有害影响，包括没有出现任何严重的眼部或全身不良反应。不过，正如预期的那样，所有组别动物的结膜在静脉注射 AAV2 和 MCO-010 后都出现了炎症，不过这种炎症在注射后一周内自行消退。对 MCO-010 相关 mCherry 的定量免疫组化分析表明，基因疗法成功地在视网膜内层传递：总之，MCO-010在对成年比格犬（雌雄均可）的眼睛进行注射时表现出良好的安全性，每只眼睛的注射剂量最高可达2.2 × 1011 gc，且未观察到任何不良反应。该剂量被确定为未观察到不良反应水平（即 NOAEL），为人体临床试验选择安全剂量提供了指导。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.