Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics

Vervaeke, Pieter; Borgos, Sven Even F.; Sanders, Niek N.; Combes, Francis

doi:10.1016/j.addr.2022.114236

Cited by 27 publications

(26 citation statements)

References 139 publications

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“…As a result, proper treatment can be prescribed for the patients based on the detected factors [ 41 ]. Moreover, if the quantity of miRNAs can be directly and stably monitored in vivo [ 42 ], the test would greatly increase the success rate of individuals undergoing IVF by measuring effectiveness of the treatment.…”

Section: Discussionmentioning

confidence: 99%

Development of a Predictive Model for Optimization of Embryo Transfer Timing Using Blood-Based microRNA Expression Profile

Chen,

Hsu,

Lin

et al. 2023

IJMS

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MicroRNAs (miRNAs) can regulate the expression of genes involved in the establishment of the window of implantation (WOI) in the endometrium. Recent studies indicated that cell-free miRNAs in uterine fluid and blood samples could act as alternative and non-invasive sample types for endometrial receptivity analysis. In this study, we attempt to systematically evaluate whether the expression levels of cell-free microRNAs in blood samples could be used as non-invasive biomarkers for assessing endometrial receptivity status. We profiled the miRNA expression levels of 111 blood samples using next-generation sequencing to establish a predictive model for the assessment of endometrial receptivity status. This model was validated with an independent dataset (n = 73). The overall accuracy is 95.9%. Specifically, we achieved accuracies of 95.9%, 95.9%, and 100.0% for the pre-receptive group, the receptive group, and the post-respective group, respectively. Additionally, we identified a set of differentially expressed miRNAs between different endometrial receptivity statuses using the following criteria: p-value < 0.05 and fold change greater than 1.5 or less than −1.5. In conclusion, the expression levels of cell-free miRNAs in blood samples can be utilized in a non-invasive manner to distinguish different endometrial receptivity statuses.

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Section: Discussionmentioning

confidence: 99%

Development of a Predictive Model for Optimization of Embryo Transfer Timing Using Blood-Based microRNA Expression Profile

Chen,

Hsu,

Lin

et al. 2023

IJMS

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“…Current guidelines issued by key regulatory bodies including the FDA and EMA covering preclinical biodistribution studies on RNA therapeutics have recently highlighted many of the options available to detect ASOs in tissues ( Vervaeke et al 2022 ). These include hybridization-based techniques, and the novel assays presented here fit the required criteria and represent a useful alternative that have application beyond ASO detection, including the ability to specifically detect other RNA-based therapeutics including siRNA, in tissues.…”

Section: Discussionmentioning

confidence: 99%

Localization of unlabeled bepirovirsen antisense oligonucleotide in murine tissues using in situ hybridization and CARS imaging

Spencer‐Dene¹,

Mukherjee

Alex³

et al. 2023

RNA

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Current methods for detecting unlabelled ASOs rely on immunohistochemistry and/or conjugated molecules, which lack sufficient sensitivity, specificity and resolution to fully investigate their bio-distribution. Our aim was to demonstrate the qualitative and quantitative distribution of unlabelled bepirovirsen, a clinical stage ASO, in livers and kidneys of dosed mice using novel staining and imaging technologies at sub-cellular resolution. ASOs were detected in FFPE and frozen tissues using an automated chromogenic in situ hybridization assay: miRNAscope. This was then combined with immunohistochemical detection of cell lineage markers. ASO distribution in hepatocytes versus non-parenchymal cell lineages, was quantified using HALO AI image analysis. To complement this, Coherent anti-Stokes Raman Scattering (CARS) imaging microscopy was used to specifically detect the unique cellular Raman spectral signatures following ASO treatment. Bepirovirsen was localized primarily in non-parenchymal liver cells and proximal renal tubules. Co-detection of ASO with distinct cell lineage markers of liver and kidney populations aided target cell identity facilitating quantification. Positive liver signal was quantified using HALO AI, with 12.9% of the ASO localized to the hepatocytes and 87.1% in non-parenchymal cells. CARS imaging specifically detected the unique vibrational signatures following unlabelled ASO treatment in a totally non-perturbative manner at subcellular resolution. Together, these novel detection and imaging modalities represent a significant increase in our ability to detect unlabelled ASOs in tissues, demonstrating improved levels of specificity and resolution. These methods help us understand their underlying mechanisms of action and ultimately improve the therapeutic potential of these important drugs for treating globally significant human diseases.

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“…Comparable to other pharmaceutical drugs, market authorization requires preclinical safety and efficacy studies in vitro and in vivo, animal models, biodistribution patterns, and clinical studies. For example, regulatory guidelines and preclinical tools related to RNA biodistribution have been reviewed recently [ 83 ].…”

Section: The Chemistry: Sirna Modificationsmentioning

confidence: 99%

Therapeutic siRNA: State-of-the-Art and Future Perspectives

2022

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The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.

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Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics

Cited by 27 publications

References 139 publications

Development of a Predictive Model for Optimization of Embryo Transfer Timing Using Blood-Based microRNA Expression Profile

Development of a Predictive Model for Optimization of Embryo Transfer Timing Using Blood-Based microRNA Expression Profile

Localization of unlabeled bepirovirsen antisense oligonucleotide in murine tissues using in situ hybridization and CARS imaging

Therapeutic siRNA: State-of-the-Art and Future Perspectives

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