Quantitative 3D reconstruction of viral vector distribution in rodent and ovine brain following local delivery

Q4 Neuroscience Neuroimage. Reports Pub Date : 2024-09-23 DOI:10.1016/j.ynirp.2024.100218
Roberta Poceviciute, Kenneth Mitchell, Angeliki Maria Nikolakopoulou, Suehyun K. Cho, Xiaobo Ma, Phillip Chen, Samantha Figueroa, Ethan J. Sarmiento, Aryan Singh, Oren Hartstein, William G. Loudon, Florent Cros, Alexander S. Kiselyov
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Abstract

Viral vectors are an active area of research and development to treat diseases of the central nervous system (CNS). However, systemic delivery of large-molecular weight biologics is complicated by limited crossing of the blood-brain barrier, immunological clearance from the circulation, off-target effects, and systemic or organ toxicity. Local drug delivery can mitigate these obstacles, however, the drug must still be distributed over sufficiently large tissue volume to achieve the desired efficacy. In the field of drug delivery, quantitative, high resolution spatial analysis of drug distribution in the brain and other organs poses a challenge. To address this issue, we introduce a computational pipeline to reconstruct and quantify 3D distribution of locally delivered viral vectors from 2D microscopy images of subsampled brain sections. This pipeline, which combined existing and newly developed machine-learning and other computational tools, effectively removed false positive artifacts abundant in large-scale images of uncleared tissue sections, and subsampling adequately predicted the dispersion of model viral vectors from the point of local drug delivery. Furthermore, the pipeline successfully captured differences in the distribution of adeno virus (AdV) and adeno-associated virus (AAV) vectors exhibiting varying sizes and transport properties. Notably, the proposed method is directly applicable to the distribution studies of therapeutics in large animal models. Thus, our developed pipeline is an accessible tool that can aid the research and development of local drug delivery strategies for the treatment of CNS diseases with viral vectors and potentially other therapeutics.
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局部给药后病毒载体在啮齿动物和绵羊大脑中分布的定量三维重建
病毒载体是治疗中枢神经系统疾病的一个活跃研发领域。然而,大分子量生物制剂的全身给药由于难以穿越血脑屏障、血液循环中的免疫清除、脱靶效应以及全身或器官毒性而变得复杂。局部给药可减轻这些障碍,但药物仍必须分布在足够大的组织体积内才能达到预期疗效。在给药领域,对药物在大脑和其他器官中的分布进行定量、高分辨率的空间分析是一项挑战。为了解决这个问题,我们引入了一个计算管道,从亚取样脑切片的二维显微图像中重建和量化局部给药病毒载体的三维分布。该管道结合了现有和新开发的机器学习及其他计算工具,有效消除了未清除组织切片的大规模图像中大量存在的假阳性伪影,子采样充分预测了模型病毒载体从局部给药点的分散情况。此外,该管道还成功捕捉到了腺病毒(AdV)和腺相关病毒(AAV)载体在大小和运输特性上的分布差异。值得注意的是,所提出的方法可直接用于治疗药物在大型动物模型中的分布研究。因此,我们开发的流水线是一种易于使用的工具,可以帮助研究和开发局部给药策略,利用病毒载体和潜在的其他疗法治疗中枢神经系统疾病。
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来源期刊
Neuroimage. Reports
Neuroimage. Reports Neuroscience (General)
CiteScore
1.90
自引率
0.00%
发文量
0
审稿时长
87 days
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