The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Giorgio Palù - One of the best experts on this subject based on the ideXlab platform.
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Human cytomegalovirus DNA replication: antiviral targets and drugs
Reviews in medical virology, 2008Co-Authors: Beatrice Mercorelli, Elisa Sinigalia, Arianna Loregian, Giorgio PalùAbstract:Human cytomegalovirus (HCMV) infection is associated with severe morbidity and mortality in immunocompromised individuals, in particular transplant recipients and AIDS patients, and is the most frequent congenital viral infection in humans. There are currently five drugs approved for HCMV treatment: ganciclovir and its prodrug valganciclovir, foscarnet, cidofovir and Fomivirsen. These drugs have provided a major advance in HCMV disease management, but they suffer from poor bioavailability, significant toxicity and limited effectiveness, mainly due to the development of drug resistance. Fortunately, there are several novel and potentially very effective new compounds which are under pre-clinical and clinical evaluation and may address these limitations. This review focuses on HCMV proteins that are directly or indirectly involved in viral DNA replication and represent already established or potential novel antiviral targets, and describes both currently available drugs and new compounds against such protein targets. Copyright © 2007 John Wiley & Sons, Ltd.
Volker Wacheck - One of the best experts on this subject based on the ideXlab platform.
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Oligonukleotid Therapeutika – eine neu entstehende Substanzklasse
Wiener Medizinische Wochenschrift, 2006Co-Authors: Volker WacheckAbstract:Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10–50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level. Within this novel emerging class of compounds oligonucleotide therapeutics are discriminated by their structure, function and mode of action. While antisense oligonucleotides, ribozymes and siRNAs suppress the expression of a protein by complementary hybridizing with their target mRNA, aptamers bind like antibodies to their target protein and thereby inhibit its function. Immunostimulatory oligonucleotides are due to sequence motifs within their nucleotide sequence able to trigger a therapeutic exploitable immune response. Currently, there are only two oligonucleotide therapeutics approved by the FDA, namely the antisense oligonucleotide Fomivirsen and the aptamer Macugen. In this review the mode of action of the diverse oligonucleotide therapeutics and their current status in clinical development will be discussed. Oligonukleotid Therapeutika sind kurzkettige DNA oder RNA Moleküle, die aus Einzeloder Doppelsträngen von 10–50 Nukleotiden bestehen. Sie ermöglichen gezielt die Expression von Genen zu beeinflussen, um Erkrankungen auf ihrer molekularen Ebene der Entstehung zu therapieren. Innerhalb dieser neuen Substanzklasse unterscheidet man je nach Struktur, Wirkungs- und Funktionsweise zwischen Antisense Oligonukleotiden, Ribozymen, siRNAs, Aptameren und immunstimulatorischen Oligonukleotiden. Während Antisense Oligonukleotide, Ribozyme und siRNAs gezielt die Expression eines Proteins durch komplementäre Basenpaarung an ihre Ziel-mRNA unterdrücken, binden Aptamere ähnlich wie Antikörper spezifisch an ihr Zielprotein und hemmen damit dessen Funktion. Immunstimulatorische Oligonukleotide sind aufgrund bestimmter in ihrer Nukleotidsequenz enthaltener "Sequenzmotive" in der Lage eine therapeutisch nutzbare Immunreaktion hervorzurufen. Derzeit sind mit dem Antisense Oligonukleotid Fomivirsen und dem Aptamer Macugen zwei Oligonukleotide als Arzneimittel zugelassen. Im vorliegenden Artikel sollen die Wirkungsmechanismen der unterschiedlichen Oligonukleotide dargestellt und eine Übersicht über den derzeitigen Entwicklungsstand als Therapeutika in den unterschiedlichen Indikationsbereichen gegeben werden.
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Oligonukleotid Therapeutika : eine neu entstehende Substanzklasse
Wiener Medizinische Wochenschrift, 2006Co-Authors: Volker WacheckAbstract:Oligonukleotid Therapeutika sind kurzkettige DNA oder RNA Molekule, die aus Einzeloder Doppelstrangen von 10–50 Nukleotiden bestehen. Sie ermoglichen gezielt die Expression von Genen zu beeinflussen, um Erkrankungen auf ihrer molekularen Ebene der Entstehung zu therapieren. Innerhalb dieser neuen Substanzklasse unterscheidet man je nach Struktur, Wirkungs- und Funktionsweise zwischen Antisense Oligonukleotiden, Ribozymen, siRNAs, Aptameren und immunstimulatorischen Oligonukleotiden. Wahrend Antisense Oligonukleotide, Ribozyme und siRNAs gezielt die Expression eines Proteins durch komplementare Basenpaarung an ihre Ziel-mRNA unterdrucken, binden Aptamere ahnlich wie Antikorper spezifisch an ihr Zielprotein und hemmen damit dessen Funktion. Immunstimulatorische Oligonukleotide sind aufgrund bestimmter in ihrer Nukleotidsequenz enthaltener "Sequenzmotive" in der Lage eine therapeutisch nutzbare Immunreaktion hervorzurufen. Derzeit sind mit dem Antisense Oligonukleotid Fomivirsen und dem Aptamer Macugen zwei Oligonukleotide als Arzneimittel zugelassen. Im vorliegenden Artikel sollen die Wirkungsmechanismen der unterschiedlichen Oligonukleotide dargestellt und eine Ubersicht uber den derzeitigen Entwicklungsstand als Therapeutika in den unterschiedlichen Indikationsbereichen gegeben werden.
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Oligonucleotide therapeutics - an emerging novel class of compounds
Wiener medizinische Wochenschrift (1946), 2006Co-Authors: Volker WacheckAbstract:Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10-50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level. Within this novel emerging class of compounds oligonucleotide therapeutics are discriminated by their structure, function and mode of action. While antisense oligonucleotides, ribozymes and siRNAs suppress the expression of a protein by complementary hybridizing with their target mRNA, aptamers bind like antibodies to their target protein and thereby inhibit its function. Immunostimulatory oligonucleotides are due to sequence motifs within their nucleotide sequence able to trigger a therapeutic exploitable immune response. Currently, there are only two oligonucleotide therapeutics approved by the FDA, namely the antisense oligonucleotide Fomivirsen and the aptamer Macugen. In this review the mode of action of the diverse oligonucleotide therapeutics and their current status in clinical development will be discussed.
Lisa R. Grillone - One of the best experts on this subject based on the ideXlab platform.
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Evolving guidelines for intravitreous injections.
Retina-the Journal of Retinal and Vitreous Diseases, 2004Co-Authors: Lloyd Paul Aiello, Lisa R. Grillone, Alexander J. Brucker, Stanley Chang, Emmett T. Cunningham, Donald J. D'amico, Harry W. Flynn, Steve Hutcherson, Jeffrey M. Liebmann, Terrence P. O'brienAbstract:Intravitreous (IVT) injection is increasingly being incorporated into the management of ocular diseases. While only Fomivirsen sodium (Vitravene™) is currently approved by the Food and Drug Administration as an IVT injection, the number of approved IVT injections indications is anticipated to grow o
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Evolving guidelines for intravitreous injections.
Retina (Philadelphia Pa.), 2004Co-Authors: Lloyd Paul Aiello, Lisa R. Grillone, Alexander J. Brucker, Stanley Chang, Emmett T. Cunningham, Donald J. D'amico, Harry W. Flynn, Steve Hutcherson, Jeffrey M. Liebmann, Terrence P. O'brienAbstract:Intravitreous (i.v.t.) injection is increasingly being incorporated into the management of ocular diseases. While only Fomivirsen sodium (Vitravene) is currently approved by the Food and Drug Administration as an i.v.t. injection, the number of approved i.v.t. injections indications is anticipated to grow on the basis of promising results from ongoing clinical studies. Despite the potential benefits that may be derived from intraocular injections of different agents, no guidelines have been published previously for i.v.t. injection. The purpose of this document is to identify specific strategies for the delivery of i.v.t. injection that may reduce risks and improve outcomes. Consensus was sought among a panel of investigators, surgeons experienced with this technique, and industry representatives. Objective evidence was sought for all guidelines, but consensus was accepted where evidence remains incomplete. In the absence of either evidence or consensus, the current manuscript identifies outstanding issues in need of further investigation. It is anticipated that more complete guidelines will evolve over time, potentially altering some of the guidelines included here, based on new applications of i.v.t. injection, additional clinical experience, and results of clinical trials.
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Fomivirsen
Clinical Pharmacokinetics, 2002Co-Authors: Richard S. Geary, Scott P. Henry, Lisa R. GrilloneAbstract:Fomivirsen sodium is a 21-base phosphorothioate oligodeoxynucleotide complementary to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, and is a potent and selective antiviral agent for cytomegalovirus retinitis. Following intravitreal administration, Fomivirsen is slowly cleared from vitreous with a half-life of approximately 55 hours in humans. Preclinical studies show that Fomivirsen distributes to retina and is slowly metabolised by exonuclease digestion. Clearance from retina was shown to be similarly slow following loading from the vitreous. The estimated half-life for clearance of Fomivirsen from retina was 78 hours in monkeys following a 115μg dose. Because of the low doses coupled with slow disposition from the eye, measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Systemically administered phosphorothioate oligodeoxynucleotides are highly bound to albumin and α2-macroglobulin in blood plasma. Because Fomivirsen does not compete for oxidative metabolic processes involved in clearance of many xenobiotics, the most likely mechanism for drug interactions may be altered protein binding of a coadministered drug. The extremely low systemic exposure to this oligodeoxynucleotide following intravitreal administration largely negates its potential ability to interact with systemically administered drugs. Even if Fomivirsen were able to access the blood, protein binding assays indicate that drugs that are site I and site II binders of albumin (warfarin, ibuprofen, salicylic acid) are not displaced in the presence of phosphorothioate oligodeoxynucleotides of various sequences at concentrations orders of magnitude higher than that seen for Fomivirsen. Administration of Fomivirsen with numerous systemically administered antiretrovirals (for example zidovudine and zalcitabine) as well as systemically administered anticytomegalovirus agents such as foscarnet and ganciclovir has been reported to be well tolerated. The only reported warning is a recommendation against administration within 2 to 4 weeks of cidofovir treatment due to an increased risk of ocular inflammation.
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Fomivirsen: clinical pharmacology and potential drug interactions.
Clinical Pharmacokinetics, 2002Co-Authors: Richard S. Geary, Scott P. Henry, Lisa R. GrilloneAbstract:Fomivirsen sodium is a 21-base phosphorothioate oligodeoxynucleotide complementary to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, and is a potent and selective antiviral agent for cytomegalovirus retinitis. Following intravitreal administration, Fomivirsen is slowly cleared from vitreous with a half-life of approximately 55 hours in humans. Preclinical studies show that Fomivirsen distributes to retina and is slowly metabolised by exonuclease digestion. Clearance from retina was shown to be similarly slow following loading from the vitreous. The estimated half-life for clearance of Fomivirsen from retina was 78 hours in monkeys following a 115-microg dose. Because of the low doses coupled with slow disposition from the eye, measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Systemically administered phosphorothioate oligodeoxynucleotides are highly bound to albumin and alpha2-macroglobulin in blood plasma. Because Fomivirsen does not compete for oxidative metabolic processes involved in clearance of many xenobiotics, the most likely mechanism for drug interactions may be altered protein binding of a coadministered drug. The extremely low systemic exposure to this oligodeoxynucleotide following intravitreal administration largely negates its potential ability to interact with systemically administered drugs. Even if Fomivirsen were able to access the blood, protein binding assays indicate that drugs that are site I and site II binders of albumin (warfarin, ibuprofen, salicylic acid) are not displaced in the presence of phosphorothioate oligodeoxynucleotides of various sequences at concentrations orders of magnitude higher than that seen for Fomivirsen. Administration of Fomivirsen with numerous systemically administered antiretrovirals (for example zidovudine and zalcitabine) as well as systemically administered anticytomegalovirus agents such as foscarnet and ganciclovir has been reported to be well tolerated. The only reported warning is a recommendation against administration within 2 to 4 weeks of cidofovir treatment due to an increased risk of ocular inflammation.
Ana Paula Pêgo - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic antisense oligonucleotides against cancer: hurdling to the clinic
Frontiers in chemistry, 2014Co-Authors: Pedro M. D. Moreno, Ana Paula PêgoAbstract:Under clinical development since the early 90’s and with two successfully approved drugs (Fomivirsen and Mipomersen), oligonucleotide-based therapeutics have not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given towards a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.
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Therapeutic antisense oligonucleotides against cancer: Hurdling to the clinic
'Frontiers Media SA', 2014Co-Authors: Pm Moreno, Ana Paula PêgoAbstract:Under clinical development since the early 90's and with two successfully approved drugs (Fomivirsen and Mipomersen), oligonucleotide-based therapeutics has not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given toward a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.The authors would like to acknowledge the FEDER funds through the Programa Operacional Factores de Competitividade - COMPETE and the Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia (PTDC/CTM-NAN/115124/2009, HMSP-ICT/0020/2010 and PEst-C/SAU/LA0002/2013) that supported this work. Pedro M. D. Moreno is supported by a Marie Curie Action of the European Community’s Seventh Framework Program (PIEF-GA2 011300485)
Beatrice Mercorelli - One of the best experts on this subject based on the ideXlab platform.
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Human cytomegalovirus DNA replication: antiviral targets and drugs
Reviews in medical virology, 2008Co-Authors: Beatrice Mercorelli, Elisa Sinigalia, Arianna Loregian, Giorgio PalùAbstract:Human cytomegalovirus (HCMV) infection is associated with severe morbidity and mortality in immunocompromised individuals, in particular transplant recipients and AIDS patients, and is the most frequent congenital viral infection in humans. There are currently five drugs approved for HCMV treatment: ganciclovir and its prodrug valganciclovir, foscarnet, cidofovir and Fomivirsen. These drugs have provided a major advance in HCMV disease management, but they suffer from poor bioavailability, significant toxicity and limited effectiveness, mainly due to the development of drug resistance. Fortunately, there are several novel and potentially very effective new compounds which are under pre-clinical and clinical evaluation and may address these limitations. This review focuses on HCMV proteins that are directly or indirectly involved in viral DNA replication and represent already established or potential novel antiviral targets, and describes both currently available drugs and new compounds against such protein targets. Copyright © 2007 John Wiley & Sons, Ltd.