Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii

Batista-Duharte, Alexander; Sendra, Luis; Herrero, Marí­a José; Portuondo, Deivys Leandro; Téllez-Martínez, Damiana; Olivera, Gladys; Fernández-Delgado, Manuel; Jávega, Beatriz; Herrera, Guadalupe; Martínez, Antonio; Costa, Paulo Inácio da; Carlos, Iracilda Zeppone; Aliño, Salvador F.

doi:10.3390/ijms22073470

Cited by 6 publications

(3 citation statements)

References 41 publications

(65 reference statements)

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“…The optimal length as an antisense molecule has been established in 20-mer since it is believed that offers the best risk/benefit ratio, considering that can access most of the cells and permits specifically identifying its target with a very low risk of off-target events. ‘In vitro’ studies using ONs are often performed in established cell line cultures or in purified cells [ 17 , 18 ]. We decided to use human complete blood to study their behavior in the milieu where they are administered.…”

Section: Discussionmentioning

confidence: 99%

Study of Oligonucleotides Access and Distribution in Human Peripheral Blood Mononuclear Cells

Fernández-Delgado

Sendra

Herrero

et al. 2022

IJMS

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Therapeutic oligonucleotides have achieved great clinical interest since their approval as drug agents by regulatory agencies but their access and distribution in blood cells are not completely known. We evaluated by flow cytometry the ability of short fluorescent scramble oligonucleotides (ON*) to access human peripheral blood mononuclear cells (PBMC) after incubating with ON* during 1 h and 7 days of culture follow-up ‘in vitro’. Blood samples were treated with chemically modified oligonucleotides (phosphorothioate backbone and 2′ O-Me ends) to resist nuclease digestion under culture conditions. The ON* internalization was determined after discarding the membrane-associated fluorescence by trypan blue quenching. Whereas the oligonucleotide accessed neutrophils and monocytes rapidly, achieving their maximum in 1 h and 24 h, respectively, lymphocytes required 7 days to achieve the maximum (80% of cells) transfection. The ON*ability to access lymphocyte types (T, B, and NK) and T cell subtypes (CD4+, CD8+, and CD4-CD8-) were similar, with T cells being more accessible. Regulatory CD4+ and CD8+ T cells were classified in low and high Foxp3 expressers, whose expression proved not to alter the ON* internalization during the first hour, achieving 53% of CD4+Foxp3+ and 40% of CD8+Foxp3+ cells. Our results contribute to understanding and improving the management of therapeutic ONs.

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Section: Discussionmentioning

confidence: 99%

Study of Oligonucleotides Access and Distribution in Human Peripheral Blood Mononuclear Cells

Fernández-Delgado

Sendra

Herrero

et al. 2022

IJMS

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“…This approach has been investigated in other medical fields and has gained FDA approval to treat several afflictions. Unsurprisingly, antisense therapy is being studied as a novel laboratory tool within the fungal field and as a potential innovative antifungal strategy for the treatment of mycoses [ 181 , 182 , 183 ]. Since the most common fungal pathogens, Candida, Aspergillus , and Cryptococcus species, have been studied for decades, their virulence traits are well documented.…”

Section: Non-traditional Antifungal Optionsmentioning

confidence: 99%

Sources of Antifungal Drugs

Vanreppelen

Wuyts

Dijck

et al. 2023

JoF

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Due to their eukaryotic heritage, the differences between a fungal pathogen’s molecular makeup and its human host are small. Therefore, the discovery and subsequent development of novel antifungal drugs are extremely challenging. Nevertheless, since the 1940s, researchers have successfully uncovered potent candidates from natural or synthetic sources. Analogs and novel formulations of these drugs enhanced the pharmacological parameters and improved overall drug efficiency. These compounds ultimately became the founding members of novel drug classes and were successfully applied in clinical settings, offering valuable and efficient treatment of mycosis for decades. Currently, only five different antifungal drug classes exist, all characterized by a unique mode of action; these are polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. The latter, being the latest addition to the antifungal armamentarium, was introduced over two decades ago. As a result of this limited arsenal, antifungal resistance development has exponentially increased and, with it, a growing healthcare crisis. In this review, we discuss the original sources of antifungal compounds, either natural or synthetic. Additionally, we summarize the existing drug classes, potential novel candidates in the clinical pipeline, and emerging non-traditional treatment options.

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“…The use of ASOs as vaccine adjuvants is a newly emerging area of research [100]. ASOs as vaccine adjuvants have been designed against diverse types of suppressor components such as transcription factors [101,102], cytokines [103][104][105], and immune checkpoints [101,106,107].…”

Section: Asosmentioning

confidence: 99%

Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches

et al. 2022

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In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, thereby achieving increased immunogenicity and efficacy. Most of the information on the use of ICIs combined with vaccines derives from studies on certain anti-tumor vaccines combined with monoclonal antibodies (mAbs) against either cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). However, over the past few years, emerging strategies to use new-generation ICIs as molecular adjuvants are paving the way for future advances in vaccine research. Here, we review the current state and future directions of the use of ICIs in experimental and clinical settings, including mAbs and alternative new approaches using antisense oligonucleotides (ASOs), small non-coding RNAs, aptamers, peptides, and other small molecules for improving vaccine efficacy. The scope of this review mainly includes the use of ICIs in therapeutic antitumor vaccines, although recent research on anti-infective vaccines will also be addressed.

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Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii

Cited by 6 publications

References 41 publications

Study of Oligonucleotides Access and Distribution in Human Peripheral Blood Mononuclear Cells

Study of Oligonucleotides Access and Distribution in Human Peripheral Blood Mononuclear Cells

Sources of Antifungal Drugs

Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches

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