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Feature

TherapeuticAdvances: 23rd January 2003

Posted on: 03 Feb 03

Summary

The current edition of TherapeuticAdvances features data on the targeting of ion channels and TNF-alpha for treatment of inflammation; stem cell approaches to cardiovascular angiogenesis; improved pro
November 14th

 

An overview of TherapeuticAdvances

23rd January 2003

Free log-on at http://www.leaddiscovery.co.uk/TherapeuticAdvances%20Archive/230103/index.html

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As usual TherapeuticAdvances highlights 14 publications selected from recent updates of DailyUpdates, LeadDiscovery's daily feed of scientific publications with drug development importance.

The current edition of TherapeuticAdvances features data on the targeting of ion channels and TNF-alpha for treatment of inflammation; stem cell approaches to cardiovascular angiogenesis; improved proof of concept and screening tools for the development of GSK-3 inhibitors for the treatment of Alzheimer's disease; and recent advances from industrial R&D. In addition we announce a major new initiative in drug discovery.

In this weeks edition:

  • Improved approaches to inflammation [more]
  • Stem cell treatment stimulates cardiovascular angiogenesis  [more]
  • Further support for targeting GSK-3 as a treatment Alzheimer's disease [more]
  • Advances from industry [more]
  • New dossiers [more]:
    • The retinoids
    • Endogenous inhibitors of apoptosis
    • Colon cancer
  • New services [more]:
    • Medicinal Chemistry/Molecular Modelling
    • Publication tracking

Improved approaches to inflammation

As research into ion channels continues to identify novel targets for multiple and diverse diseases, therapeutic successes surrounding the development of channel modulators will boom (for a full overview of this area, Click here to access Ion Channels as Therapeutic Targets for Multiple Diseases). One channel that is attracting particular attention is the voltage-gated K + channel, Kv1.3. Interest in this channel is growing since it is one of two potassium channels expressed by human T lymphocytes that are involved in proliferation and cytokine secretion. T cells expressing this channel have been associated with multiple sclerosis and hence Kv1.3 blockers or molecules able to prevent its expression are being developed by a number of companies involved in autoimmune disease and inflammation in general. Of note Merck researchers have recently published a series of Kv1.3 channel inhibitors. Development of therapeutic candidates is however being slowed by a relative lack of high-throughput screening tools, a problem common to much activity surrounding ion channels. To address this problem, researchers from the University of California have developed a fluorescence-based assay that can screen for molecules able to modulate Kv1.3 expression under HTS conditions. This assay is therefore expected to help identify mechanisms involved in the over-expression of Kv1.3 and therapeutic candidates that can prevent this occurrence

In contrast to the Kv1.3 channel which is a relatively recent entrant into the inflammatory disease arena, research into TNF-alpha is more mature. As a result decoy receptors such as Etanercept, monoclonal antibodies such as Infliximab, and antisense technology have all been developed to limit the expression or activity of TNF-alpha and hence to treat a number of serious inflammatory diseases such as rheumatoid arthritis and psoriasis. As with these two diseases, TNF-alpha is also a key cytokine involved in the pathogenesis of IBD. The number of prevalent cases of this serious and debilitating disease is around 1.5 million in the major pharmaceutical markets driving pharmaceutical sales in excess of $0.5 billion. Current treatment options are sub-optimal and the present focus is on the identification of inflammatory mediators involved in IBD. Reflecting this need, ISIS have evaluated a second-generation antisense oligonucleotide (ISIS 25302) specific for murine TNF-alpha in models of gut inflammation. ISIS 25302 decreased TNF-alpha mRNA in macrophages and reduced disease activity in these models. Importantly, efficacy was obtained with both a prophylactic treatment regimen or a therapeutic dosing protocol begun after colitis was already present. These data establish a proof of concept for further testing of molecules such as ISIS 25302 in IBD patients. Of interest this study also reported that ISIS 25302 reduced TNF-alpha mRNA in whole adipose tissue and in macrophages isolated from the adipose tissue of db/db mice, a strain of mouse with constitutively high expression of TNF-alpha and which is used in the development of treatments of diabetes. TNF-alpha has been implicated in the development of insulin resistance and indeed Etanercept is in phase I, while Humicade (a second TNF-alpha antibody) is in phase II development for the treatment of diabetes. The effects of ISIS 25302 in models of diabetes are therefore eagerly awaited [for further details of these and other projects log on to TherapeuticAdvances]

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Stem cell treatment stimulates cardiovascular angiogenesis 

Three publications highlighted in this edition of TherapeuticAdvances have focused on angiogenesis. Although inhibitors of this process have stolen much of the lime-light over recent years interest has recently been growing in the development of agiogenesis stimulators for the treatment of diverse cardiovascular disorders. Myocardial infarction, stroke, peripheral artery occlusive disease (PAOD) are common and serious ischemic disorders. Thrombolytic, antithrombotic and anticoagulant treatments represent the major acute therapeutic options for the treatment of myocardial infarction and peripheral arterial occlusive disease (click here for "Heart/ Cardiovascular Disease 2002" an analysis of future directions in cardiovascular therapeutics). However, in the days and weeks following myocardial damage, strategies to prevent further ischemic cell death or to promote the recovery of damaged tissue may be of greater advantage, particularly for patients with congestive heart failure. Stimulators of angiogenesis may help meet this clinical demand and in doing so this therapeutic class is expected to boost the market for modulators of angiogenesis. The majority of angiogenesis-related molecules in advanced development target VEGF however stem cell treatment is rapidly emerging as an alternative. Direct myocardial injection of bone marrow cells in a rat ischemic heart model induced angiogenesis. Similar results have also been achieved in a number of human trials. Most recently injection of autologous mononuclear bone marrow cells into the ischemic myocardium of eight patients with severe ischemic heart disease via novel catheter-based technology has been reported to produce an improvement in symptoms, myocardial perfusion, and function at the ischemic region. This data is all the more impressive considering that none of the patients were responding to traditional medical and surgical therapy. This new procedure avoids the risks and complications of open-heart surgery, and can be performed under local anaesthesia as a day procedure 

Angiogenesis has also been the subject of recent studies into new treatments of erectile dysfunction. In a recent report we have analyzed therapeutic and pharmaceutical opportunities surrounding this common condition. While sildenafil and second generation PDE5 inhibitors have cornered much of the market for the treatment of this condition, alternative approaches are required for a significant number of patients with severe disease (click here for our analysis of emerging treatments of erectile dysfunction and female arousal disorder). The major types of vascular problems that can result in erectile dysfunction are arterial insufficiency, inadequate impedance of venous outflow (venous leaks), or a combination of both. With age and underlying diseases, especially atherosclerosis, the amount of blood entering the penis is decreased impeding penile erection. As erectile dysfunction becomes more long-term, treatment becomes more difficult, partly due to ischemia. In this patient group optimal therapeutic strategies should include the use of molecules able to regenerate vascular smooth muscle rather than (or as well as) controlling the level of contractility of the existing musculature. Hence, the development of pro-angiogenic therapies for the treatment of erectile dysfunction may be beneficial to patients with severe disease. American researchers have therefore evaluated the ex vivo expression of IGF-I, VEGF, and their receptors (IGF-IR, Flt-1, and KDR) in human penile cavernosal smooth muscle cells to identify cellular and molecular pathways involved in the regulation of penile tissue vascularity. IGF-I and VEGF and their receptors were identified in primary smooth muscle cultures. RT-PCR evaluation revealed the expression of four splice variants of VEGF messenger RNA (VEGFs 121, 145, 165, and 189) and two of its receptors (Flt-1 and KDR). VEGF165 and VEGF121 were the most abundant forms of messenger RNA and Flt-1 appeared to be the most prominent receptor type in these cells. Exposure to VEGF elicited a twofold to threefold increase in smooth muscle cell proliferation. These data add further support to the concept of targeting angiogenesis for the treatment of erectile dysfunction, an approach that has also been validated in a number of studies investigating the effects of VEGF on penile erection, and furthermore describe in greater details the molecular targets for such an approach [for further details of these and other projects log on to TherapeuticAdvances]

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Further support for targeting GSK-3 as a treatment Alzheimer's disease

Regular readers of TherapeuticAdvances may have followed the emergence of glycogen synthase kinase (GSK)-3 inhibitors as candidate therapies of a variety of conditions including diabetes, stroke, bipolar disease and Alzheimer's disease (click here for dossier access). GSK-3 is elevated in Alzheimer's disease brain, and has also been implicated in the phosphorylation of tau and also the release and toxicity of Aß. Spanish researchers have recently characterized transgenic mice that conditionally over-express GSK-3beta in hippocampal and cortical neurons. These mice show many of the biochemical and cellular aspects of Alzheimer's disease. These mice have now been shown to exhibit spatial learning deficit, neurological dysfunction that mirrors the cognitive disorder hallmarking Alzheimer's disease. These data demonstrate that GSK-3 deregulation contributes not only to biochemical and cellular events characteristic of Alzheimer's disease, but that this enzyme contributes to neurological deficits associated with disease. Furthermore this strain of mouse may be used as a model for the screening of GSK-3 inhibitors that may be of use in the treatment of Alzheimer's disease [for further details of these and other projects log on to TherapeuticAdvances]

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Advances from industry

  • Retinoids from Ligand Pharmaceuticals: Our understanding of the complexities of transcription is rapidly expanding and key targets for the treatment of cancer are therefore emerging. Histone deacetylase inhibitors represent one area of recent and massive growth (click here to access our analysis of this area). Likewise, the retinoic acids are going through a period of resurgence (click here to access a second analysis of the retinoids). An increase in retinoid research in the early 1990's culminated in the identification of the nuclear retinoid receptors boosting pharmaceutical activity in this area. Current efforts are being placed on improving the affinity of candidates for the retinoid receptors and optimizing the mix of activity against the different members of this receptor family. Of interest in this respect is recent research emerging from Ligand Pharmaceuticals describing a series of pan-agonist that stimulated the RAR and RXR receptors with EC50 values of 17-59nM and 6-14nM respectively and showed good antiproliferative properties in multiple myeloma and cervical cancer cell lines
  • CXCR2 antagonists from GSK for the treatment of rheumatoid arthritis: About 1% of all populations are affected by rheumatoid arthritis driving a market of $1.6 billion for agents used to treat this disease. Emerging trends in the treatment of rheumatoid arthritis largely focus on the cytokines. Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. GlaxoSmithKline researchers have recently investigated the effects of a potent and selective nonpeptide antagonist of human CXCR2 in models of arthritis. This antagonist displayed anti-inflammatory properties in various models of rheumatoid arthritis.

[for further details of these and other projects log on to TherapeuticAdvances]


New dossiers:
  • The retinoids: Therapeutic & pharmaceutical opportunities [More]
  • Targeting endogenous inhibitors of apoptosis: Therapeutic Opportunities [More]
  • Advances in Colon Cancer Therapeutics [More]

In order that we may serve you better, we are now offering you the opportunity to vote for future dossiers. Please click here to see our list of possible future dossiers or to suggest titles that may be of use to you - currently voting on "Emerging therapeutic proteins: Improved technology and broadening targets" "Schizophrenia: Therapeutic targets & Pharmaceutical opportunities" and "Controlling multi drug resistance proteins: Emerging strategies for the treatment of cancer and the improvement of efficacy of CNS therapeutics"


New services: DiscoveryDossiers such as those described above are in depth analyses conceptualizing emerging drug discovery targets. Readers are able to use these dossiers as a framework around which decisions can be made for launching or advancing drug discovery projects. Thanks to a collaboration with ChemOvation a leading provider of chemistry- and screening-based drug discovery services to the pharmaceutical and biotechnology sector, PharmaceuticalSolutions now offers a seamless pathway from concept to lead identification. If, for example, our "inhibitors of apoptosis" convinces you of the potential of inhibitors of this family PharmaceuticalSolutions, can take rapidly and cost-effectively towards the development of lead compounds. Alternatively if you wish to identify leads for targets identified in house PharmaceuticalSolutions may also provide the service you require [more]

DailyUpdates was launched by LeadDiscovery in 2002 and represents the first "newsfeed" that identifies breaking scientific publications with drug development potential. Following significant refinements we are pleased to announce the full launch of a series of targeted DailyUpdates channels allowing you identify those articles of especial interest to you [more]


Dr Jon Goldhill

Last updated on: 27/08/2010 11:40:18

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