Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-Based Therapeutics

Cavagnaro, Joy A.; Berman, Cindy L.; Kornbrust, Doug; White, Tacey E.K.; Campion, Sarah N.; Henry, Scott P.

doi:10.1089/nat.2014.0490

Cited by 32 publications

(18 citation statements)

References 41 publications

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“…Various classes of nucleic acid drugs have been marketed or are being developed. Attention must be paid to toxicity issues during the development of nucleic acid drugs 1 . Nucleic acid drug candidates have several toxicity issues, including off-target effects, immune stimulation, hematoxicity, hepatotoxicity, and nephrotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene

Ohtsuki

Takahashi

Inoué

et al. 2017

Sci Rep

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We used human Toll-like receptor 9 (hTLR9)-expressing HEK-Blue hTLR9 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon response to CpG DNA, to evaluate the immunological properties of nucleic acid drug candidates. Our preliminary studies showed that phosphodiester CpG DNA hardly induced any SEAP secretion in HEK-Blue hTLR9 cells. In the current study, therefore, we developed HEK-Blue hTLR9 cells transduced with human macrophage scavenger receptor-1 (hMSR1), a cell-surface DNA receptor, and determined whether HEK-Blue hTLR9/hMSR1 cells respond to phosphorothioate (PS) CpG DNA and phosphodiester (PO) CpG DNA. We selected PS CpG2006, a single-stranded PO CpG DNA (ssCpG), and a tetrapod-like structured DNA (tetrapodna) containing ssCpG (tetraCpG) as model TLR9 ligands. Alexa Fluor 488-labeled ligands were used for flow cytometry. Unlike the mock-transfected HEK-Blue hTLR9 cells, the HEK-Blue hTLR9/hMSR1 cells efficiently took up all three CpG DNAs. SEAP release was almost proportional to the uptake. Treatment of HEK-Blue hTLR9/hMSR1 cells with an anti-hMSR1 antibody significantly reduced the uptake of ssCpG and tetraCpG. Collectively, reconstruction of TLR9-mediated responses to CpG DNA in HEK-Blue hTLR9 cells can be used to evaluate the toxicity of nucleic acid drug candidates with diverse physicochemical properties.

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Section: Introductionmentioning

confidence: 99%

Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene

Ohtsuki

Takahashi

Inoué

et al. 2017

Sci Rep

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“…The information about therapeutic DNA oligonucleotides' reproductive and developmental toxicology is limited. However, a review of current data leads to consensus recommendations for such studies based on the individual product attributes and the species employed to conduct the analysis (Cavagnaro et al, 2014). Of interest, changes in fertility and embryonal and fetal development were more common among DNA oligonucleotide products containing CpG motifs known to activate Toll-like receptor 9 (TLR9) mediated innate immune responses (Cavagnaro et al, 2014).…”

Section: Potential For Genotoxicity and Reproductive Effectsmentioning

confidence: 99%

“…Fever and fever-like reactions Berman et al (2016), Cavagnaro et al (2014), Henry, Grillone, et al (1997), Henry, Taylor, et al (1997), Henry et al (1999), Monteith et al (1998), Burel et al (2013), Sparwasser et al (1999) TBI Activation of TLR9 pathway Yacyshyn et al (1998) Schuller et al (2011 Activation of cytosolic PRR (IPS-1, MDA-5) Sheehan and Lan (1998) TBI…”

Section: Immunotoxicity Due To the Dna Componentmentioning

confidence: 99%

Opportunities and challenges for the clinical translation of structuredDNAassemblies as gene therapeutic delivery and vaccine vectors

Dobrovolskaia

Bathe

2020

WIREs Nanomed Nanobiotechnol

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Gene therapeutics including siRNAs, anti‐sense oligos, messenger RNAs, and CRISPR ribonucleoprotein complexes offer unmet potential to treat over 7,000 known genetic diseases, as well as cancer, through targeted in vivo modulation of aberrant gene expression and immune cell activation. Compared with viral vectors, nonviral delivery vectors offer controlled immunogenicity and low manufacturing cost, yet suffer from limitations in toxicity, targeting, and transduction efficiency. Structured DNA assemblies fabricated using the principle of scaffolded DNA origami offer a new nonviral delivery vector with intrinsic, yet controllable immunostimulatory properties and virus‐like spatial presentation of ligands and immunogens for cell‐specific targeting, activation, and control over intracellular trafficking, in addition to low manufacturing cost. However, the relative utilities and limitations of these vectors must clearly be demonstrated in preclinical studies for their clinical potential to be realized. Here, we review the major capabilities, opportunities, and challenges we foresee in translating these next‐generation delivery and vaccine vectors to the clinic. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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“…The timing of reproductive and developmental studies depends on when women of childbearing potential are to be included in clinical trials. If NHPs are required for the assessment, the timing is more flexible due to the length and complexity of the studies [83].…”

Section: Reproductive and Developmental Toxicitymentioning

confidence: 99%

Preclinical Development of RNAi-Inducing Oligonucleotide Therapeutics for Eye Diseases

Martínez¹,

González²,

Vargas³

et al. 2016

RNA Interference

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RNA interference (RNAi) is a posttranscriptional mechanism of gene regulation present in eukaryotic cells. Inducers of RNAi are small molecules of RNA that act in the cytoplasm where they are able to impair translation of a specific mRNA to protein, hence modifying gene expression. The discovery of this mechanism in mammals led to the development of a new class of therapeutics with the aim of exploiting this endogenous mechanism of action. In the last decade, great efforts have been put into understanding RNAi and translating this accumulated knowledge into the design of modern therapeutics. With several compounds in phase III clinical development, the field is getting closer to its first market authorization. Here we make a thorough overview of the field of RNAi therapeutics in ophthalmology, one of the fields in which RNAi has been most successful.

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Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-Based Therapeutics

Cited by 32 publications

References 41 publications

Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene

Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene

Opportunities and challenges for the clinical translation of structuredDNAassemblies as gene therapeutic delivery and vaccine vectors

Preclinical Development of RNAi-Inducing Oligonucleotide Therapeutics for Eye Diseases

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