Spiegelmers for Therapeutic Applications – Use of Chiral Principles in Evolutionary Selection Techniques

Eulberg, Dirk; Jarosch, Florian; Vonhoff, Stefan; Klussmann, Sven

doi:10.1002/3527608192.ch18

Cited by 21 publications

(12 citation statements)

References 54 publications

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“…In contrast to classic hormone antagonists, Spiegelmers do not interact with the hormone receptor but reduce hormone action by a direct binding and thus reduce the biologically active circulating hormone. As Spiegelmers are L-RNA compounds, they are not targets for nucleases that metabolize D-oligonucleotides [19]. This leads to a tremendous stability of Spiegelmers in biological fluids [19].…”

Section: Discussionmentioning

confidence: 99%

“…Spiegelmers are mirror image L-oligonucleotides with high affinity toward a given target molecule, leading to a blockade of its biological activity [see Ref. [19] for review]. Owing to their L-ribose containing sugarphosphate backbone, Spiegelmers are highly resistant to nuclease degradation and remain stable for more than 60 h in biological fluids such as human plasma [19].…”

Section: Introductionmentioning

confidence: 99%

“…[19] for review]. Owing to their L-ribose containing sugarphosphate backbone, Spiegelmers are highly resistant to nuclease degradation and remain stable for more than 60 h in biological fluids such as human plasma [19]. In addition to their usefulness as experimental tools, they may also be used as therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

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In-vitro and in-vivo antagonistic action of an anti-amylin Spiegelmer

et al. 2007

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The anorectic and dipsogenic effects of the pancreatic hormone amylin are mediated by the area postrema and the subfornical organ. We tested the effectiveness of a new amylin antagonist, a so-called RNA Spiegelmer, by electrophysiological in-vitro recordings from the rat subfornical organ and by immunohistological c-Fos studies in the area postrema. Amylin's excitatory effect on subfornical organ neurons was blocked by the anti-amylin Spiegelmer. Peripheral administration 5 h prior to amylin also suppressed the amylin-induced activation (c-Fos expression) in the area postrema. The biostable anti-amylin Spiegelmer may be therapeutically beneficial in conditions associated with high plasma amylin levels, such as cancer anorexia occurring during certain pancreatic tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In-vitro and in-vivo antagonistic action of an anti-amylin Spiegelmer

et al. 2007

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“…Spiegelmer antagonists to a number of extracellular targets have been described (11,14,24,35). Two Spiegelmers have proven to be safe and well tolerated in Phase I clinical studies 4 providing evidence that the Spiegelmer technology is suitable to generate human medicines.…”

Section: Discussionmentioning

confidence: 99%

“…Spiegelmers (German: Spiegel ϭ mirror) are structured biostable L-oligonucleotides that differ from their aptamer counterparts in their sugar moiety, which consists of mirrorimage L-(deoxy)ribose rather than D-(deoxy)ribose and makes Spiegelmers highly resistant to nucleases (11,12). Spiegelmers have already been described to act potently as inhibitors in vivo (13-15) and have proven to be exceptionally safe in two Phase I clinical studies.…”

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confidence: 99%

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

Maasch¹,

Vater²,

Purschke

et al. 2010

Journal of Biological Chemistry

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High mobility group A1 (HMGA1) proteins belong to a group of architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. They promote anchorage-independent growth and epithelial-mesenchymal transition and are therefore suggested as potential therapeutic targets. Employing in vitro selection techniques against a chosen fragment of HMGA1, we have generated biostable L-RNA oligonucleotides, so-called Spiegelmers, that specifically bind HMGA1b with low nanomolar affinity. We demonstrate that the best binding Spiegelmers, NOX-A50 and NOX-f33, compete HMGA1b from binding to its natural binding partner, AT-rich doublestranded DNA. We describe a formulation method based on polyplex formation with branched polyethylenimine for efficient delivery of polyethylene glycol-modified Spiegelmers and show improved tissue distribution and persistence in mice. In a xenograft mouse study using the pancreatic cancer cell line PSN-1, subcutaneous administration of 2 mg/kg per day NOX-A50 formulated in polyplexes showed an enhanced delivery of NOX-A50 to the tumor and a significant reduction of tumor volume. Our results demonstrate that intracellular targets can be successfully addressed with a Spiegelmer using polyethylenimine-based delivery and underline the importance of HMGA1 as a therapeutic target in pancreatic cancer.The mammalian nonhistone chromatin high mobility group A1 proteins HMGA1a, 3 HMGA1b, and HMGA1c belong to one protein family encoded by the HMGA1 gene. They act as architectural transcription factors by binding via AT hook motifs to the minor groove of AT-rich DNA, leading to modulation of chromatin and nucleosome remodeling. Their ability to regulate the activity of several genes through the recognition and alteration of the DNA double helix and chromatin substrates has been linked to the development of human cancers (1-3). The overexpression of HMGA proteins is associated with different types of tumors, e.g. pancreas, breast, prostate, cervical, gastric, colorectal cancer as well as lymphomas and neuroblastic malignancies (4 -6). The level of expression of HMGA1a/b is low or almost undetectable in most differentiated or nonproliferating normal cells (7-9) but is rapidly up-regulated in response to growth-stimulatory factors (8, 10). Thus, HMGA1 is considered a promising target to treat cancer development, progression, and metastasis.The aim of our study was to evaluate whether the intracellular HMGA1 protein family can be successfully targeted with a Spiegelmer, a large structured molecule that is comparable with a monoclonal antibody in terms of specific target binding. Spiegelmers (German: Spiegel ϭ mirror) are structured biostable L-oligonucleotides that differ from their aptamer counterparts in their sugar moiety, which consists of mirrorimage L-(deoxy)ribose rather than D-(deoxy)ribose and makes Spiegelmers highly resistant to nucleases (11,12). Spiegelmers have already been described to act potently as inhibitors in vivo (13-15) and have ...

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A Status Update of Modified Oligonucleotides for Chemotherapeutics Applications

Sanghvi¹

2011

CP Nucleic Acid Chemistry

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This unit presents an update of recent developments and clinical progress in chemically modified oliogonucleotides useful for therapeutic applications. During the last decade, the number of therapeutic oligonucleotides in clinical trials has nearly tripled. This is primarily due to advances in the synthesis protocols, better understanding of the biology, improved delivery, and better formulation technologies. Currently, over 100 clinical trials with oligonucleotide-based drugs are ongoing in the United States for potential treatment of a variety of life-threatening diseases. Among various oligonucleotides, antisense technology has been at the forefront, with one product on the market. Antisense technologies represent about half of the active clinical trials. Similarly, siRNA, aptamers, spiegelmers microRNA, shRNA, IMO, and CpG have been other active classes of oligonucleotides that are also undergoing clinical trials. This review attempts to summarize the current status of synthesis, chemical modifications, purification, and analysis in light of the rapid progress with multitude of oligonucleotides pursued as therapeutic modality.

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Spiegelmers for Therapeutic Applications – Use of Chiral Principles in Evolutionary Selection Techniques

Cited by 21 publications

References 54 publications

In-vitro and in-vivo antagonistic action of an anti-amylin Spiegelmer

In-vitro and in-vivo antagonistic action of an anti-amylin Spiegelmer

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

A Status Update of Modified Oligonucleotides for Chemotherapeutics Applications

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