Preclinical Safety Assessment of Therapeutic Oligonucleotides

Andersson, Patrik

doi:10.1007/978-1-0716-2010-6_25

Cited by 8 publications

(5 citation statements)

References 104 publications

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“…As with every gene-expression-modulating therapy, there is an inherited carcinogenicity risk [ 29 ]. Even though this risk is relatively small for siRNA-based gene expression modulation due to its transient nature and relatively short half-life, currently, there are no clear regulations defining the carcinogenicity potential of siRNA therapies [ 29 , 30 ]. Moreover, MELK is associated with cancer progression and aggressiveness [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

siRNA-Mediated MELK Knockdown Induces Accelerated Wound Healing with Increased Collagen Deposition

Szymański

Lewicki

Markiewicz

et al. 2023

IJMS

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Skin wounds remain a significant problem for the healthcare system, affecting the clinical outcome, patients’ quality of life, and financial costs. Reduced wound healing times would improve clinical, economic, and social aspects for both patients and the healthcare system. Skin wound healing has been studied for years, but effective therapy that leads to accelerated wound healing remains to be discovered. This study aimed to evaluate the potential of MELK silencing to accelerate wound healing. A vectorless, transient knockdown of the MELK gene using siRNA was performed in a murine skin wound model. The wound size, total collagen, type 3 collagen, vessel size, vessel number, cell proliferation, cell apoptosis, number of mast cells, and immune infiltration by CD45, CD11b, CD45, and CD8a cells were evaluated. We observed that treatment with MELK siRNA leads to significantly faster wound closing associated with increased collagen deposition.

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Section: Discussionmentioning

confidence: 99%

siRNA-Mediated MELK Knockdown Induces Accelerated Wound Healing with Increased Collagen Deposition

Szymański

Lewicki

Markiewicz

et al. 2023

IJMS

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“…Thrombocytopenia, that is, decrease in platelet counts, has been occasionally reported in preclinical models (rodents and NHPs) and in three recent clinical trials following treatment with ONDs, in particular PS-ASO (volanesorsen, inotersen, and drisapersen) [ 84 ]. Two phenotypes of platelet count decrease have been distinguished: phenotype 1 characterized by a moderate but not clinically severe drop in platelet count and the rarer phenotype 2 of severe thrombocytopenia [ 85 ].…”

Section: Hybridization Independent But Sequence-dependent Toxicitiesmentioning

confidence: 99%

Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides

Goyenvalle

Jiménez-Mallebrera

Roon-Mom

et al. 2023

Nucleic Acid Therapeutics

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The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network “DARTER,” a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.

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“…Regarding the safety profile of the oligonucleotides, these could be related to the potential inhibition of the expression of off-target genes. However, performing a robust process of bioinformatic prediction of the complementary target sequences, and by the selection of optimal unique sequences only present in the target gene, followed by the experimental evaluation of potential off-target genes, means that it is possible to identify potent and specific drug-candidate oligonucleotides that maximize the on-target effects and greatly minimize the potential for off-target effects at a level that do not impact healthy cells [ 138 , 139 , 140 ]. Moreover, the introduction of the different chemical modifications to the oligonucleotide is reported to confer different improved characteristics.…”

Section: Challenges and Solutions For The Clinical Success Of Oligonu...mentioning

confidence: 99%

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

et al. 2022

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Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by conventional drugs, such as the small molecules. Moreover, the mRNA itself retains oncological functions, and its targeting offers the double advantage of blocking the tumorigenic activities of the mRNA and the translation into protein. Finally, a large family of non-coding RNAs (ncRNAs) has recently emerged that are also dysregulated in cancer, but they could not be targeted by drugs directed against the proteins. In this context, this review describes how the oligonucleotide therapeutics targeting RNA or DNA sequences, are emerging as a new class of drugs, able to tackle the limitations described above. Numerous clinical trials are evaluating oligonucleotides for tumor treatment, and in the next few years some of them are expected to reach the market. We describe the oligonucleotide therapeutics targeting undruggable proteins (focusing on the most relevant, such as those originating from the MYC and RAS gene families), and for ncRNAs, in particular on those that are under clinical trial evaluation in oncology. We highlight the challenges and solutions for the clinical success of oligonucleotide therapeutics, with particular emphasis on the peculiar challenges that render it arduous to treat tumors, such as heterogeneity and the high mutation rate. In the review are presented these and other advantages offered by the oligonucleotide as an emerging class of biotherapeutics for a new era of precision anti-cancer medicine.

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Preclinical Safety Assessment of Therapeutic Oligonucleotides

Cited by 8 publications

References 104 publications

siRNA-Mediated MELK Knockdown Induces Accelerated Wound Healing with Increased Collagen Deposition

siRNA-Mediated MELK Knockdown Induces Accelerated Wound Healing with Increased Collagen Deposition

Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

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