Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement
Identifieur interne : 000879 ( Pmc/Curation ); précédent : 000878; suivant : 000880Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement
Auteurs : Alexander Batista-Duharte ; Luis Sendra ; Maria José Herrero ; Damiana Téllez-Martínez ; Iracilda Zeppone Carlos ; Salvador Francisco Ali OSource :
- Biomolecules [ 2218-273X ] ; 2020.
Abstract
Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.
Url:
DOI: 10.3390/biom10020316
PubMed: 32079263
PubMed Central: 7072586
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement</title><author><name sortKey="Batista Duharte, Alexander" sort="Batista Duharte, Alexander" uniqKey="Batista Duharte A" first="Alexander" last="Batista-Duharte">Alexander Batista-Duharte</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Sendra, Luis" sort="Sendra, Luis" uniqKey="Sendra L" first="Luis" last="Sendra">Luis Sendra</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Herrero, Maria Jose" sort="Herrero, Maria Jose" uniqKey="Herrero M" first="Maria José" last="Herrero">Maria José Herrero</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Tellez Martinez, Damiana" sort="Tellez Martinez, Damiana" uniqKey="Tellez Martinez D" first="Damiana" last="Téllez-Martínez">Damiana Téllez-Martínez</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation></author><author><name sortKey="Carlos, Iracilda Zeppone" sort="Carlos, Iracilda Zeppone" uniqKey="Carlos I" first="Iracilda Zeppone" last="Carlos">Iracilda Zeppone Carlos</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation></author><author><name sortKey="Ali O, Salvador Francisco" sort="Ali O, Salvador Francisco" uniqKey="Ali O S" first="Salvador Francisco" last="Ali O">Salvador Francisco Ali O</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32079263</idno><idno type="pmc">7072586</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072586</idno><idno type="RBID">PMC:7072586</idno><idno type="doi">10.3390/biom10020316</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000879</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000879</idno><idno type="wicri:Area/Pmc/Curation">000879</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000879</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement</title><author><name sortKey="Batista Duharte, Alexander" sort="Batista Duharte, Alexander" uniqKey="Batista Duharte A" first="Alexander" last="Batista-Duharte">Alexander Batista-Duharte</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Sendra, Luis" sort="Sendra, Luis" uniqKey="Sendra L" first="Luis" last="Sendra">Luis Sendra</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Herrero, Maria Jose" sort="Herrero, Maria Jose" uniqKey="Herrero M" first="Maria José" last="Herrero">Maria José Herrero</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author><author><name sortKey="Tellez Martinez, Damiana" sort="Tellez Martinez, Damiana" uniqKey="Tellez Martinez D" first="Damiana" last="Téllez-Martínez">Damiana Téllez-Martínez</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation></author><author><name sortKey="Carlos, Iracilda Zeppone" sort="Carlos, Iracilda Zeppone" uniqKey="Carlos I" first="Iracilda Zeppone" last="Carlos">Iracilda Zeppone Carlos</name><affiliation><nlm:aff id="af1-biomolecules-10-00316">School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</nlm:aff></affiliation></author><author><name sortKey="Ali O, Salvador Francisco" sort="Ali O, Salvador Francisco" uniqKey="Ali O S" first="Salvador Francisco" last="Ali O">Salvador Francisco Ali O</name><affiliation><nlm:aff id="af2-biomolecules-10-00316">Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</nlm:aff></affiliation></author></analytic><series><title level="j">Biomolecules</title><idno type="eISSN">2218-273X</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rappuoli, R" uniqKey="Rappuoli R">R. Rappuoli</name></author><author><name sortKey="Mandl, C W" uniqKey="Mandl C">C.W. Mandl</name></author><author><name sortKey="Black, S" uniqKey="Black S">S. Black</name></author><author><name sortKey="De Gregorio, E" uniqKey="De Gregorio E">E. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Biomolecules</journal-id><journal-id journal-id-type="iso-abbrev">Biomolecules</journal-id><journal-id journal-id-type="publisher-id">biomolecules</journal-id><journal-title-group><journal-title>Biomolecules</journal-title></journal-title-group><issn pub-type="epub">2218-273X</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32079263</article-id><article-id pub-id-type="pmc">7072586</article-id><article-id pub-id-type="doi">10.3390/biom10020316</article-id><article-id pub-id-type="publisher-id">biomolecules-10-00316</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1875-0518</contrib-id><name><surname>Batista-Duharte</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="af1-biomolecules-10-00316">1</xref><xref ref-type="aff" rid="af2-biomolecules-10-00316">2</xref><xref rid="c1-biomolecules-10-00316" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3176-9763</contrib-id><name><surname>Sendra</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="af2-biomolecules-10-00316">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-6042-4185</contrib-id><name><surname>Herrero</surname><given-names>Maria José</given-names></name><xref ref-type="aff" rid="af2-biomolecules-10-00316">2</xref><xref rid="c1-biomolecules-10-00316" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6957-094X</contrib-id><name><surname>Téllez-Martínez</surname><given-names>Damiana</given-names></name><xref ref-type="aff" rid="af1-biomolecules-10-00316">1</xref></contrib><contrib contrib-type="author"><name><surname>Carlos</surname><given-names>Iracilda Zeppone</given-names></name><xref ref-type="aff" rid="af1-biomolecules-10-00316">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7830-8713</contrib-id><name><surname>Aliño</surname><given-names>Salvador Francisco</given-names></name><xref ref-type="aff" rid="af2-biomolecules-10-00316">2</xref></contrib></contrib-group><aff id="af1-biomolecules-10-00316"><label>1</label>School of Pharmaceutical Sciences, Department of Clinical Analysis, São Paulo State University (UNESP), Rod. Araraquara-Jaú - Km 1, 14800-903 Araraquara, SP, Brazil;<email>damianatellezm@gmail.com</email> (D.T.-M.);<email>carlosiz@fcfar.unesp.br</email> (I.Z.C.)</aff><aff id="af2-biomolecules-10-00316"><label>2</label>Pharmacology Department, Faculty of Medicine, Universidad Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;<email>luis.sendra@uv.es</email> (L.S.);<email>salvador.f.alino@uv.es</email> (S.F.A.)</aff><author-notes><corresp id="c1-biomolecules-10-00316"><label>*</label>Correspondence: <email>batistaduhartea@gmail.com</email> (A.B.-D.); <email>Maria.Jose.Herrero@uv.es</email> (M.J.H.)</corresp></author-notes><pub-date pub-type="epub"><day>17</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>2</month><year>2020</year></pub-date><volume>10</volume><issue>2</issue><elocation-id>316</elocation-id><history><date date-type="received"><day>31</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>11</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.</p></abstract><kwd-group><kwd>antisense oligonucleotide</kwd><kwd>vaccines</kwd><kwd>adjuvants</kwd><kwd>infectious disease</kwd><kwd>cancer</kwd></kwd-group></article-meta></front><floats-group><fig id="biomolecules-10-00316-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Main mechanisms of action of antisense oligonucleotides. (<bold>A</bold>) Normal gene and protein expression in the absence of ASO. (<bold>B</bold>) In cytoplasm, ASOs can bind to a complementary mRNA region. ASO-mRNA heteroduplex can induce the activation of RNase H, leading to mRNA degradation. Alternatively, ASOs can block the translation process without promoting RNA degradation by steric interference of ribosomal assembly. (<bold>C</bold>) ASO can enter the nucleus and hinder mRNA maturation by inhibition of 5′ cap formation, RNase H-mediated pre-RNA cleavage, and inhibition of mRNA splicing.</p></caption><graphic xlink:href="biomolecules-10-00316-g001"></graphic></fig><fig id="biomolecules-10-00316-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Types of ASOs-mediated toxicity: (1) Hybridization-independent toxicity represent those effects that are not due to Watson–Crick base pairing between an ASO and RNA. This type of toxicity occurs by three possible mechanisms: (<bold>A</bold>) ASOs accumulation effect is manifested as cytoplasmic granule accumulation, degenerative changes in kidney or liver epithelium, and presence of vacuolated macrophages. (<bold>B</bold>) Proinflammatory mechanisms due to ASOs interaction with innate immune receptors, inducing macrophages activation, complement activation, and immunocomplex formation. (<bold>C</bold>) Aptameric binding to intracellular cell surface or extracellular proteins. (2) Hybridization-dependent toxicity can be caused by partial or complete ASO interaction with unintended transcripts (hybridization-dependent off-target effects [OTEs]); or with intended transcripts (on-target toxicity).</p></caption><graphic xlink:href="biomolecules-10-00316-g002"></graphic></fig><fig id="biomolecules-10-00316-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Tumor cells are forced to present their own tumor antigens to the immune system by anti-li ASO treatment. Left, MHC class I presents endogenous tumor antigens to CD8+ cytotoxic T cells (CTL). Ii protein blocks the binding of endogenous antigens to MHC class II in the endoplasmic reticulum (ER). Right, anti li-ASO blocks Ii protein expression, and endogenous tumor antigens are also presented by MHC class II molecules and recognized by specific Th1 lymphocytes. The simultaneous presentation of tumor antigens by both MHC class I to CTL and MHC II to Th1 lymphocytes induces a stronger antitumor response. (Adapted from [<xref rid="B117-biomolecules-10-00316" ref-type="bibr">117</xref>]).</p></caption><graphic xlink:href="biomolecules-10-00316-g003"></graphic></fig><fig id="biomolecules-10-00316-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Some examples of the use of ASOs as vaccine adjuvant by modulating the regulatory T cells (Tregs) response. Left, molecules involved in Tregs function that are currently being studied as target for vaccine improvement with ASOs. CTLA-4, T-lymphocyte antigen4; DC, dendritic cells; IL-, interleukin; LAG-3, lymphocyte activation gene-3; TGFβ, transforming growth factor beta; TCR, T cells receptor. Right, (<bold>A</bold>) Normal post-vaccination immune response without Tregs modulation. (<bold>B</bold>) ASO-mediated transitory Tregs depletion/inhibition elicit a stronger vaccine immune response.</p></caption><graphic xlink:href="biomolecules-10-00316-g004"></graphic></fig><table-wrap id="biomolecules-10-00316-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">biomolecules-10-00316-t001_Table 1</object-id><label>Table 1</label><caption><p>Summary of three generations of the most studied ASOs chemical modifications.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Chemical Modifications</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Characteristics</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanisms</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Clinical Use</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Limitations</th></tr><tr><th colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">First Generation</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phosphorothioate (PTO), Methylphosphonate<break></break>(MPO)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Either a sulfur atom (PTO), or a methyl group (MPO) substitutes the non-bridging oxygen atoms in the phosphodiester bond.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">First generation ASOs promote degradation of target mRNA by RNase H enzyme. They also confer higher solubility, resistance to nuclease degradation, antisense activity and longer plasma half-life as compared with phosphodiester oligonucleotides.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PTO is the most widely used modification of ASOs. Fomivirsen, is a PTO-modified ASO, used as local treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) [<xref rid="B48-biomolecules-10-00316" ref-type="bibr">48</xref>].</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">High affinity for various cellular proteins and components of the innate immune system, such as Toll-like receptors (TLRs), with proinflammatory effects.<break></break>Commonly reported side effects<break></break>following systemic administration of PTO ASOs include fever, activated partial thromboplastin time prolongation, thrombocytopenia,<break></break>and leukopenia.</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Second Generation</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ASOs with 2’-O-alkyl modifications of the ribose.<break></break>Chimeric ‘gapmer’ ASOs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2’-O-Methyl (2’-OMe) and 2’-O-Methoxyethyl (2’-MOE) are the most widely studied.<break></break>Chimeric ‘gapmer’ ASOs consist in a central ‘gap’ region containing 10 DNA or PTO DNA monomers, flanked on both 5’ and 3’extremities by alkyl modified nucleotides such as 2′-OM or 2’-MOE.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The PTO DNA induces RNase H cleavage while 2′-OME or 2′-MOE on both sides (5′- and 3′-directions) confers nuclease-resistance, and they can exert activity by a steric interference of translation process.<break></break>They are safer than PTO-modified ASOs and exhibit enhanced affinity towards the complementary RNA with better tissue uptake and longer in vivo half-life.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mipomersen is used as an adjunct therapy for homozygous familial hypercholesterolemia [<xref rid="B49-biomolecules-10-00316" ref-type="bibr">49</xref>].<break></break>Nusinersen was approved for spinal muscular atrophy treatment [<xref rid="B50-biomolecules-10-00316" ref-type="bibr">50</xref>].<break></break>Apatorsen is a HSP27 targeting ASO that is being studied in phase II clinical trials in patients with metastatic castration resistant prostate cancer [<xref rid="B51-biomolecules-10-00316" ref-type="bibr">51</xref>] and Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer [<xref rid="B52-biomolecules-10-00316" ref-type="bibr">52</xref>].</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A subset of 2´-MOE-modified ASOs induced pro-inflammatory cytokines and type I interferons (IFN-α/β) and interaction with innate immune receptors such as TLR9, melanoma-differentiation associated-5 (MDA-5) and IFN-β promoter stimulator-1 (IPS-1).</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Third Generation</bold></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Peptide nucleic acid (PNA)</td><td align="center" valign="middle" rowspan="1" colspan="1">PNA is a synthetic DNA in which the deoxyribose phosphate backbone is replaced by polyamide linkages.</td><td align="center" valign="middle" rowspan="1" colspan="1">PNA block the protein expression, by steric hindrance, forming sequence-specific duplex with the targeted mRNA. They are biologically stable and have good hybridization properties.</td><td align="center" valign="middle" rowspan="1" colspan="1">The potential of PNA as drugs in gene therapy has been hampered by the poor intrinsic uptake of PNA by living cells. Current strategies for improving PNA delivery into the cytosolic space and nucleus include microinjection, electroporation, co-transfection with DNA, or conjugation to lipophilic moieties, nanoparticles, cell-penetrating peptides (CPPs), oligo-aspartic acid, or nuclear localization signal (NLS) peptides to enhance cellular internalization </td><td align="center" valign="middle" rowspan="1" colspan="1">PNA do not activate the RNase H to cleave the target hybridized RNA. PNA have low solubility and cellular uptake.</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phosphoramidate morpholino oligomer (PMO)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PMOs are neutral ASOs. The pentose sugar is substituted by a morpholino ring and the inter-nucleotide linkages are phosphoramidate bonds in place of phosphodiester bonds.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The mechanism of PMO is the translational arrest mediated by steric interference of ribosomal assembly. PMO show fewer nonspecific properties and lesser toxicity than PTO.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Eteplirsen was approved for Duchenne muscular dystrophy (DMD) treatment [<xref rid="B53-biomolecules-10-00316" ref-type="bibr">53</xref>]. Other potential applications include the treatment of viral infections, antibiotic-resistant bacterial infections, and cancers [<xref rid="B54-biomolecules-10-00316" ref-type="bibr">54</xref>].</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PMOs exhibit reduced cellular uptake. Conjugation with peptides such as arginine-rich peptide (ARP) can enhance its cellular uptake and antisense efficacy.</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Locked nucleic acid (LNA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LNAs are chemically modified nucleotides with a ribose containing a methylene bridge between the 2′-oxygen and the 4′-carbon of the ribose.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LNA modifications improve the affinity of ASO hybridization towards mRNA target, by increase of the DNA/RNA heteroduplexes thermal stability. LNAs avoid nuclease degradation.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diverse LNAs are currently in clinical trials by several biotechnology firms.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LNA does not activate RNase. LNA nucleotides can be incorporated at the ends of RNA and DNA sequences to form chimeric oligonucleotides resulting in restoration of RNase H-mediated cleavage of mRNA.</td></tr></tbody></table></table-wrap><table-wrap id="biomolecules-10-00316-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">biomolecules-10-00316-t002_Table 2</object-id><label>Table 2</label><caption><p>Key advantages of ASOs compared to monoclonal antibodies.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">ASOs</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">mAb</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Molecular Weight</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">~6 to10 kDa</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">~150 kDa</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Structure</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Relatively simple structure. Usually 13–20 mer with chemical modifications</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycoproteins with complex structure</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Thermal Stability</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly stable. Lyophilization and freezing does not modify its biological activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Low stability. Cold chain through the storage, handling, and transportation is necessary</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Cellular Bioavailability</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ASOs can penetrate the cells and act on intracellular targets</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">They are unable to penetrate the cells</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Immunogenicity</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ASOs are not properly immunogenic</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly immunogenic by xenogeneic differences, e.g., between mice and humans</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Specificity</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly specific but off target interaction can be observed</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly specific but cross-reactivity can be observed</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Toxicity</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Relatively low toxicity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Different grades of toxicity have been described</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Development and Manufacturing</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ASOs are obtained synthetically.The use of vehicles can add complexity to the manufacture process</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The production for pharmacological proposes requires high level of technological complexity</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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