Tricyclo-DNA (tcDNA) is a synthetic nucleic acid analog modified with a rigid tricyclic structure in the sugar backbone. This modification enhances the properties of nucleic acids. Due to its structural modification, tcDNA has many applications in therapeutics, diagnostics, and molecular biology. TcDNA analogs are result of a search for novel oligonucleotide analogs for use in therapeutics and DNA-based diagnostics. This analog is part of a series of analogs exhibiting interesting biological properties useful for enhanced oligonucleotides. The solved crystal structure of a DNA duplex with tricyclo-DNA residues explains the increased RNA affinity of tcDNA relative to DNA. The resistance of tcDNA to nucleases can also be gleaned from the structure. The Leumann group at the University of Bern studied the effect of restricted conformational flexibility on the pairing of nuclei acids (Leumann 2001). Modeling studies suggest that the cyclopropane ring in tcDNA causes an unfavorable steric interaction at exo- and endonuclease active sites resulting in a higher protection against degradation. The incorporation of one tricyclo-thymidine residue in the center of the self-complementary dodecamer duplex (d(CGCGAATtCGCG), t = tricyclothymidine) resulted in a strongly stabilized monomolecular hairpin loop structure compared to that of the corresponding pure DNA dodecamer with a ΔTm = +20 ºC. This result indicated the effect of tcT on the (tetra)loop-stabilizing properties of this rigid nucleoside analog.
Structures of tricyclo-DNA compared with DNA
Applications
Therapeutics Antisense Oligonucleotides (ASOs): ASOs can use tcDNA in various ASO-based treatments for the downregulation of gene expression by binding to mRNA and preventing translation, for example, for treating Duchenne Muscular Dystrophy (DMD) via exon skipping. tcDNA is helpful for the development of antisense therapeutics targeting mRNA. Its high binding affinity and nuclease resistance allow downregulation of gene expression.
Gene Silencing and Editing: Oligonucleotides modified with tcDNA exhibit improved delivery and stability of CRISPR guide RNAs or other RNA-interfering molecules, increasing gene-editing precision.
RNA Modulation and Splicing Correction: Oligonucleotides modified with tcDNA can restore proper gene function by modulating pre-mRNA splicing, making it suitable for treating diseases caused by splicing mutations.
Exon Skipping in DMD (Duchenne Muscular Dystrophy): tcDNA can induce exon skipping in pre-mRNA to restore the reading frame of defective genes, especially in genetic disorders like DMD.
RNA Targeting in Central Nervous System (CNS) Disorders: The ability of tcDNA to cross the blood-brain barrier makes it a promising candidate for central nervous system (CNS) therapies for effectively delivering therapeutic nucleic acids for treating neurological diseases like Huntington's or ALS.
Molecular Probes and Diagnostics
Increased Stability: Molecular probes modified with tcDNA have enhanced stability in biological environments, making them ideal for diagnostics and molecular probes for studying biological systems, including qPCR and hybridization-based technologies.
Biomarker Detection: tcDNA incorporated into molecular probes enhance the sensitivity and specificity of nucleic acid-based biomarker detection in complex biological samples.
High Binding Specificity: tcDNA's structural modifications allow precise hybridization with complementary DNA or RNA strands, reducing off-target effects in diagnostic applications.
Drug Delivery
Nucleic Acid Delivery
Improved Cellular Uptake: tcDNA modifications can enhance the delivery of oligonucleotides into cells without the need for additional transfection agents. To enhance delivery into specific tissues or cells, conjugation of tcDNA-modified oligonucleotides to targeting moieties such as lipids, for example, cholesterol or peptides, is possible.
Lipid Nanoparticles and Conjugates: Formulation of conjugated tcDNA-based oligonucleotides into lipid nanoparticles (LNPs) enhances therapeutics' delivery more effectively while ensuring stability.
Tools for Research and Development
Gene Function Studies: Inhibiting or modifying the expression of specific RNA transcripts in cellular and animal models with the help of tcDNA-based molecular probes allows exploring gene functions.
Structural Studies: The rigid structure of tcDNA enales detailed studies of nucleic acid-protein interactions hopefully contributiong ot our understanding of fundamental biological processes.
Study of Nucleic Acid-Protein Interactions: The rigid structure of tcDNA provides insights into nucleic acid-protein interactions, aiding in the development of novel drugs.
CRISPR Modifications: Oligonucleotides modified with tcDNA may enhance the stability and delivery of guide RNAs in CRISPR systems.
Benefits of tcDNA
Blood-Brain Barrier Penetration: Expands application to CNS-related disorders.
Enhanced Nuclease Resistance: Protects from degradation in biological systems.
Good Pharmacokinetic Profile: Allows for better therapeutic distribution.
High Binding Affinity: Improved hybridization to target RNA/DNA.
Low Toxicity: Reduces adverse effects in therapeutic applications.
Reduced Immunogenicity: tcDNA incorporated into therapeutic oligonucleotides minimizes immune response.
References
Aupy P, Echevarría L, Relizani K, Goyenvalle A. The Use of Tricyclo-DNA Oligomers for the Treatment of Genetic Disorders. Biomedicines. 2017 Dec 22;6(1):2 [PMC]. The authors discuss the potential of tricyclo-DNA oligomers as a therapeutic approach for genetic diseases, particularly focusing on their application in antisense therapy strategies to target and correct genetic mutations at the RNA level.
Aupy P, Echevarría L, Relizani K, Zarrouki F, Haeberli A, Komisarski M, Tensorer T, Jouvion G, Svinartchouk F, Garcia L, Goyenvalle A. Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy. Mol Ther Nucleic Acids. 2020 Mar 6;19:371-383 [PMC]. The authors discuss the potential of tricyclo-DNA oligomers as a therapeutic splice-switching application for the treatment of Duchenne muscular dystrophy (DMD).
Bizot F, Fayssoil A, Gastaldi C, Irawan T, Phongsavanh X, Mansart A, Tensorer T, Brisebard E, Garcia L, Juliano RL, Goyenvalle A. Oligonucleotide Enhancing Compound Increases Tricyclo-DNA Mediated Exon-Skipping Efficacy in the Mdx Mouse Model. Cells. 2023 Feb 23;12(5):702 [PMC]. The authors demonstrated the normalization of cardiac function in mdx mice after a 12-week-long treatment with a combined ASO + OEC therapy. The findings indicate that compounds facilitating endosomal escape can significantly improve the therapeutic potential of exon-skipping therapeutics offering promising perspectives for the treatment of DMD.
Bizot F, Tensorer T, Garcia L, Goyenvalle A. Impact of the Inhibition of Organic Anion Transporter on Tricyclo-DNA-Mediated Exon Skipping in the <i>mdx</i> Mouse Model. Nucleic Acid Ther. 2023 Dec;33(6):374-380. [PubMed]. The authors discuss how OAT inhibition does not improve the therapeutic potential of ASO-mediated exon-skipping approaches for the treatment of DMD.
Blitek M, Phongsavanh X, Goyenvalle A. The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy. RSC Med Chem. 2024 Jul 19;15(9):3017-3025. [PubMed]. The authors review the bench to bedside journey of tricyclo-DNA-ASOs from their early preclinical evaluation as fully phosphorotiated-ASOs to the latest generation of lipid-conjugated-ASOs and the remaining challenges of ASO-mediated exon-skipping therapy for DMD and future perspectives for this promising chemistry of ASOs.
Doisy M, Vacca O, Fergus C, Gileadi T, Verhaeg M, Saoudi A, Tensorer T, Garcia L, Kelly VP, Montanaro F, Morgan JE, van Putten M, Aartsma-Rus A, Vaillend C, Muntoni F, Goyenvalle A. Networking to Optimize Dmd exon 53 Skipping in the Brain of Dmdx52 Mouse Model. Biomedicines. 2023 Dec 7;11(12):3243. [PMC]. The authors discuss the difficulty of exon 53 skipping in mdx52 mice when using a combination of multiple ASOs simultaneously to reach substantial levels of exon 53 skipping, regardless of their chemistry (tcDNA, PMO, or 2′MOE).
Doisy M, Vacca O, Saoudi A, Goyenvalle A. Levels of Exon-Skipping Are Not Artificially Overestimated Because of the Increased Affinity of Tricyclo-DNA-Modified Antisense Oligonucleotides to the Target Dmd Exon. Nucleic Acid Ther. 2024 Oct;34(5):214-220. [PubMed]. The authors discuss that the use of tricyclo-DNA for exon skipping therapeutics does not inflate the observed levels of exon skipping due to the AON binding too strongly to the target exon in the DMD gene, which could potentially lead to inaccurate results in assessing the effectiveness of exon skipping therapy.
Dugovic B, Wagner M, Leumann CJ. Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bc(en)-T and iso-tricyclo-T nucleosides. Beilstein J Org Chem. 2014 Aug 12;10:1840-7. doi: 10.3762/bjoc.10.194. PMID: 25161745; PMCID: PMC4142851. [PMC]. The authors discuss how the incorporation of modified thymine nucleosides, specifically "bc(en)-T" (a bicyclo[2.2.1]heptene-modified thymine) and "iso-tricyclo-T" (an isomeric tricyclic thymine derivative) impact the stability and binding properties of the resulting oligonucleotide duplexes.
Echevarría L, Aupy P, Relizani K, Bestetti T, Griffith G, Blandel F, Komisarski M, Haeberli A, Svinartchouk F, Garcia L, Goyenvalle A. Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model. Nucleic Acid Ther. 2019 Jun;29(3):148-160. [PubMed]. The authors discuss how varying the amount of phosphorothioate (PS) modifications on the backbone of tricyclo-DNA antisense oligonucleotides (tcDNA-ASOs) affects their ability to induce exon skipping in a mouse model of Duchenne Muscular Dystrophy (DMD), assessing the optimal level of PS modification for achieving efficient therapeutic outcomes while minimizing potential toxicities associated with high PS content.
Egli M, Pallan PS. Insights from crystallographic studies into the structural and pairing properties of nucleic acid analogs and chemically modified DNA and RNA oligonucleotides. Annu Rev Biophys Biomol Struct. 2007;36:281-305. [PubMed]. The review provides insights into the structural changes and pairing behaviors of modified nucleic acids, particularly when studying analogs with altered sugar moieties or base modifications. These types of studies can reveal how modifications impact the overall structure of the nucleic acid duplex, its stability, and its interaction with other molecules, allowing for rational design of new therapeutic agents with desired properties.
Egli M, Pallan PS. Crystallographic studies of chemically modified nucleic acids: a backward glance. Chem Biodivers. 2010 Jan;7(1):60-89. [PMC]. A scientific review looking back at research using X-ray crystallography for the analysis of nucleic acid structures (DNA and RNA) that have been chemically altered, providing insights into how these modifications affect their molecular shape and potential applications in fields like drug development and gene therapy.
Ezzat K, Aoki Y, Koo T, McClorey G, Benner L, Coenen-Stass A, O'Donovan L, Lehto T, Garcia-Guerra A, Nordin J, Saleh AF, Behlke M, Morris J, Goyenvalle A, Dugovic B, Leumann C, Gordon S, Gait MJ, El-Andaloussi S, Wood MJ. Self-Assembly into Nanoparticles Is Essential for Receptor Mediated Uptake of Therapeutic Antisense Oligonucleotides. Nano Lett. 2015 Jul 8;15(7):4364-73. [PMC]. This research paper reports that for therapeutic antisense oligonucleotide (ASO) drugs to be effectively taken up by cells through receptor-mediated endocytosis, they need to self-assemble into nanoparticles, they must spontaneously form tiny particles through molecular interactions, which significantly enhances their cellular uptake compared to single, free ASOs
Gerber AB, Leumann CJ. Synthesis and properties of isobicyclo-DNA. Chemistry. 2013 May 27;19(22):6990-7006. doi: 10.1002/chem.201300487. Epub 2013 Apr 23. PMID: 23613358. [PubMed]. This study reports the chemical synthesis of isobicyclo-DNA building blocks, which are modified DNA nucleotides featuring a unique bicyclic structure, along with an investigation into their biophysical and biological properties; essentially creating a new type of DNA with altered structural features for potential applications in research related to nucleic acid chemistry and biology.
Goyenvalle A, Griffith G, Avril A, Amthor H, Garcia L. Un nouvel outil pour le traitement de la myopathie de Duchenne : les tricyclo-ADN [Functional correction and cognitive improvement in dystrophic mice using splice-switching tricyclo-DNA oligomers]. Med Sci (Paris). 2015 Mar;31(3):253-6. French. [medisci]
Goyenvalle A, Griffith G, Babbs A, El Andaloussi S, Ezzat K, Avril A, Dugovic B, Chaussenot R, Ferry A, Voit T, Amthor H, Bühr C, Schürch S, Wood MJ, Davies KE, Vaillend C, Leumann C, Garcia L. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med. 2015 Mar;21(3):270-5. [PubMed]. This report demonstrated the physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice making tcDNA-AON chemistry attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.
Goyenvalle A, Leumann C, Garcia L. Therapeutic Potential of Tricyclo-DNA antisense oligonucleotides. J Neuromuscul Dis. 2016 May 27;3(2):157-167. [PMC]. This research paper demonstrated the potential of tricyclo-DNA ASOs for treating a range of diseases, particularly neuromuscular disorders like Duchenne muscular dystrophy (DMD), due to their unique pharmacological properties, including the ability to be taken up by various tissues after systemic administration, allowing for exon-skipping and splicing correction at the genetic level, offering a promising avenue for therapeutic intervention in genetic diseases affecting the muscles.
Guncay A, Yokota T. Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold? Future Med Chem. 2015;7(13):1631-5. [PubMed]. This research paper discusses the use of ASOs for the treatment of Duchenne muscular dystrophy.
Hari Y, Dugovič B, Istrate A, Fignolé A, Leumann CJ, Schürch S. The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes. J Am Soc Mass Spectrom. 2016 Jul;27(7):1186-96. [ACS]. This research paper discusses how the gas-phase behavior of tcDNA duplexes impact the activation entropy on the fragmentation kinetics in tandem mass spectrometric experiments, indicating that this type of analysis may not be suited to determine the relative stability of different types of nucleic acid duplexes.
Hollenstein M, Leumann CJ. Synthesis and biochemical characterization of tricyclothymidine triphosphate (tc-TTP). Chembiochem. 2014 Sep 5;15(13):1901-4. [PubMed]. This research paper reported that Tc-TTP is a substrate for the Vent (exo−) DNA polymerase, a polymerase that allows for multiple incorporations of tc-T nucleotides under primer extension reaction conditions. The substrate acceptance was found to be rather low, as also observed for other sugar-modified analogues. However, Tc-TTP and tc-nucleotide-containing templates do not sustain enzymatic polymerization under physiological conditions indicating that tc-DNA-based antisense agents will not enter natural metabolic pathways that can lead to long-term toxicity.
Imbert M, Blandel F, Leumann C, Garcia L, Goyenvalle A. Lowering Mutant Huntingtin Using Tricyclo-DNA Antisense Oligonucleotides As a Therapeutic Approach for Huntington's Disease. Nucleic Acid Ther. 2019 Oct;29(5):256-265. doi: 10.1089/nat.2018.0775. Epub 2019 Jun 11. PMID: 31184975.
Istrate A, Johannsen S, Istrate A, Sigel RKO, Leumann CJ. NMR solution structure of tricyclo-DNA containing duplexes: insight into enhanced thermal stability and nuclease resistance. Nucleic Acids Res. 2019 May 21;47(9):4872-4882. doi: 10.1093/nar/gkz197. PMID: 30916334; PMCID: PMC6511864.
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Bio-Synthesis provides a full spectrum of high quality custom oligonucleotide modification services including 5'-triphosphate and back-bone modifications, conjugation to fatty acids, biotinylation by direct solid-phase chemical synthesis or enzyme-assisted approaches to obtain artificially modified oligonucleotides, such as BNA antisense oligonucleotides, mRNAs or siRNAs, containing a natural or modified backbone, as well as base, sugar and internucleotide linkages.
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