Mathias G. Svahn
Karolinska University Hospital
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Featured researches published by Mathias G. Svahn.
The FASEB Journal | 2007
Rongbin Ge; Juhana E. Heinonen; Mathias G. Svahn; Abdalla J. Mohamed; Karin E. Lundin; C. I. Edvard Smith
Locked nucleic acids (LNAs) are synthetic analogs of nucleic acids that contain a bridging methylene carbon between the 2′ and 4′ positions of the ribose ring. In this study, we generated a novel sequence‐specific antigene molecule “Zorro LNA”, which simultaneously binds to both strands, and that induced effective and specific strand invasion into DNA duplexes and potent inhibition of gene transcription, also in a cellular context. By comparing the Zorro LNA with linear LNA as well as an optimized bisPNA (pep‐tide nucleic acid) oligonucleotide directed against the same target sites, respectively, we found that the Zorro LNA construct was unique in its ability to arrest gene transcription in mammalian cells. To our knowledge, this is the first time that in mammalian cells, gene transcription was blocked by a nucleic acid analog in a sequence‐specific way using low but saturated binding of a blocking agent. This offers a novel type of antigene drug that is easy to synthesize.—Ge R., Heinonen, J. E., Svahn, M. G., Mohamed, A. J., Lundin, K. E., Smith C. I. E. Zorro locked nucleic acid induces sequence‐specific gene silencing. FASEB J. 21, 1902–1914 (2007)
Journal of Gene Medicine | 2004
Mathias G. Svahn; Karin E. Lundin; Rongbin Ge; Elisabeth Törnquist; E. O. Simonson; S. Oscarsson; M. Leijon; Lars J. Brandén; C I E Smith
Non‐viral gene therapy constitutes an alternative to the more common use of viral‐mediated gene transfer. Most gene transfer methods using naked DNA are based upon non‐sequence‐specific interactions between the nucleic acid and cationic lipids (lipoplex) or polymers (polyplex). We have developed a technology in which functional entities hybridize in a sequence‐specific manner to the nucleic acid (bioplex). This technology is still in its infancy, but has the potential to become a useful tool, since it allows the construction of highly defined complexes containing a variety of functional entities. In its present form the bioplex technology is based upon the use of peptide/nucleic acids (PNA) as anchors. Single, or multiple, functional entities are directly coupled to the anchors. By designing plasmids, or oligonucleotides, with the corresponding anchor target sequence, complexes with desired composition can easily be generated. The long‐term aim is to combine functional entities in order to achieve optimal, synergistic interactions allowing enhanced gene transfer in vivo. Copyright
Genetica | 2009
Karin E. Lundin; Oscar E. Simonson; Pedro M. D. Moreno; Eman M. Zaghloul; Iulian I. Oprea; Mathias G. Svahn; C. I. Edvard Smith
In both basic research as well as experimental gene therapy the need to transfer genetic material into a cell is of vital importance. The cellular compartment, which is the target for the genetic material, depends upon application. An siRNA that mediates silencing is preferably delivered to the cytosol while a transgene would need to end up in the nucleus for successful transcription to occur. Furthermore the ability to regulate gene expression has grown substantially since the discovery of RNA interference. In such diverse fields as medical research and agricultural pest control, the capability to alter the genetic output has been a useful tool for pushing the scientific frontiers. This review is focused on nanotechnological approaches to assemble optimised structures of nucleic acid derivatives to facilitate gene delivery as well as promoting down regulation of endogenous genes.
Current Pharmaceutical Design | 2005
Oscar E. Simonson; Mathias G. Svahn; Elisabeth Törnquist; Karin E. Lundin; C I E Smith
Non-viral gene delivery is an important approach in order to establish safe in vivo gene therapy in the clinic. Although viral vectors currently exhibit superior gene transfer efficacy, the safety aspect of viral gene delivery is a concern. In order to improve non-viral in vivo gene delivery we have designed a pharmaceutical platform called Bioplex (biological complex). The concept of Bioplex is to link functional entities via hybridising anchors, such as Peptide Nucleic Acids (PNA), directly to naked DNA. In order to promote delivery functional entities consisting of biologically active peptides or carbohydrates, are linked to the PNA anchor. The PNA acts as genetic glue and hybridises with DNA in a sequence specific manner. By using functional entities, which elicit receptor-mediated endocytosis, improved endosomal escape and enhance nuclear entry we wish to improve the transfer of genetic material into the cell. An important aspect is that the functional entities should also have tissue-targeting properties in vivo. Examples of functional entities investigated to date are the Simian virus 40 nuclear localisation signal to improve nuclear uptake and different carbohydrate ligands in order to achieve receptor specific uptake. The delivery system is also endowed with regulatory capability, since the release of functional entities can be controlled. The aim is to create a safe, pharmaceutically defined and stable delivery system for nucleic acids with enhanced transfection properties that can be used in the clinic.
Journal of Gene Medicine | 2008
Rongbin Ge; Mathias G. Svahn; Oscar E. Simonson; Abdalla J. Mohamed; Karin E. Lundin; C. I. Edvard Smith
RNA polymerase III (pol III)‐dependent transcripts are involved in many fundamental activities in a cell, such as splicing and protein synthesis. They also regulate cell growth and influence tumor formation. During recent years vector‐based systems for expression of short hairpin (sh) RNA under the control of a pol III promoter have been developed as gene‐based medicines. Therefore, there is an increasing interest in means to regulate pol III‐dependent transcription. Recently, we have developed a novel anti‐gene molecule ‘Zorro LNA (Locked Nucleic Acid)’, which simultaneously hybridizes to both strands of super‐coiled DNA and potently inhibits RNA polymerase II‐derived transcription. We have now applied Zorro LNA in an attempt to also control U6 promoter‐driven expression of shRNA.
Nucleic acids symposium series (2004) | 2008
C. I. Edvard Smith; Karin E. Lundin; Oscar E. Simonson; Pedro M. D. Moreno; Mathias G. Svahn; Malgorzata Wenska; Roger Strömberg
The Bioplex technology allows the hybridization of functional entities to various forms of nucleic acids by the use of synthetic nucleic acid analogs. Such supramolecular assemblies can be made in a predetermined fashion and can confer new properties. The Zorro technology is based on a novel construct generated to simultaneously bind to both DNA strands. Such compounds may have gene silencing activity.
Nucleosides, Nucleotides & Nucleic Acids | 2007
Peter Steunenberg; Hans Leijonmarck; Mathias G. Svahn; C. I. Edvard Smith; Roger Strömberg
As initial studies of block coupling of peptides with C-terminal glycines, we have evaluated of coupling of glycine building blocks under various conditions to a preassembled solid support bound LNA-fragment. Potentially competing side reaction have been studied and we have worked out a procedure for trifluoroacetyl protection of peptides.
Molecular Therapy | 2006
Rongbin Ge; Juhana E. Heinonen; Mathias G. Svahn; Abdalla J. Mohamed; Karin E. Lundin; C. I. Edvard Smith
Top of pageAbstract Locked Nucleic Acids (LNA) are synthetic analogs of nucleic acids, which contain a bridging methylene carbon between the 2’ and 4’ positions of the ribose ring. In this study, we generated a novel sequence-specific anti-gene LNA molecule, which induced effective binding into DNA duplexes and potent inhibition of gene transcription in the mammalian cells (|[ge]| 90 %). By comparing the novel anti-gene LNA construct with traditional LNA oligonucleotides as well as a tail-clamp bisPNA (Peptide Nucleic Acid) directed against the same target sites, respectively, we found that the novel LNA construct had unique properties for inducing gene silencing in mammalian cells. Silencing was also seen using PNA, but at doses higher than required for saturated binding suggesting the formation of inhibitory supramolecular complexes. To our knowledge, this is the first time that in mammalian cells, gene transcription was blocked by a nucleic acid analog in a sequence-specific way using low, but saturated binding of a blocking agent. This offers a novel type of anti-gene drug, which is easy to synthesize.
Molecular Therapy | 2004
Karin E. Lundin; Rongbin Ge; Mathias G. Svahn; Elisabeth Törnquist; Lars J. Brandén; C. I. Edvard Smith
Peptide nucleic acid (PNA) is a DNA analog with broad biotechnical applications, and possibly also treatment applications. Its suggested uses include that of a specific anchor sequence for biologically active peptides to plasmids in a sequence-specific manner. Such complexes, referred to as Bioplex, have already been used to enhance non-viral gene transfer in vitro. To investigate how hybridization of PNAs to supercoiled plasmids would be affected by the binding of multiple PNA-peptides to the same strand of DNA, we have developed a method of quantifying the specific binding of PNA using a PNA labeled with a derivative of the fluorophore thiazole orange (TO). Cooperative effects were found at a distance of up to three bases. With a peptide present at the end of one of the PNAs, steric hindrance occurred, reducing the increase in binding rate when the distance between the two sites was less than two bases. In addition, we found increased binding kinetics when two PNAs binding to overlapping sites on opposite DNA strands were used, without the use of chemically modified bases in the PNAs.
Biomolecular Engineering | 2004
Karin E. Lundin; Rongbin Ge; Mathias G. Svahn; Elisabeth Törnquist; Mikael Leijon; Lars J. Brandén; C. I. Edvard Smith