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Therapeutic Advances: 17th October 2002

Posted on: 24 Oct 02


This week’s TherapeuticAdvances focuses on new targets for Alzheimer's disease. In particular the topic of the moment, GSK-3 (which is also featured in our recent DiscoveryDossier) and clusterin have
October 17th is a company founded by industrial researchers for the drug development sector. Our panel of pharmaceutical scientists produces TherapeuticAdvances, a twice-monthly bulletin of cutting edge scientific research with therapeutic potential. Selected research is fully analyzed in DiscoveryDossiers. These dossiers can be produced for institutions as due diligence reports or to boost technology transfer/partnering activity. Alternatively, dossiers can be purchased as overviews to support target identification or development efforts.


An overview of TherapeuticAdvances

17th October 2002

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This week’s TherapeuticAdvances focuses on new targets for Alzheimer's disease. In particular the topic of the moment, GSK-3 (which is also featured in our recent DiscoveryDossier) and clusterin have both emerged as candidate targets. We also feature clinical data reporting on advances in the treatment of female sexual dysfunction, and two exciting advances in inflammation. Finally we highlight the growing support for the use of ET-1 receptor antagonists as treatments of cancer.

In this weeks edition:

  • Alzheimer’s disease: New targets, new hopes [more]
  • Sexual equality meets sexual dysfunction  [more]
  • Advances in the treatment of inflammatory disease [more]
  • Endothelin-1 receptors as a target for the treatment of cancer [more]

Alzheimer’s disease: New targets, new hopes

Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving its value to over $1.2 billion in 2001. Last month LeadDiscovery published a report analyzing the rational for developing angiotensin receptor ligands as treatments of various CNS diseases including AD (click here for more). This month TherapeuticAdvances features glycogen synthase kinase (GSK)-3. This tonically active kinase is elevated in the brain of AD patients while on the other hand its inhibition prevents tau hyperphosphorylation, reduces the release of Aß and protects cultured neurons from consequent cell death. GSK-3 is therefore one exciting target for the treatment of AD. This however highlights just one of many potential applications of GSK-3 inhibitors since this enzyme has been implicated in insulin resistance, stroke and bipolar disorder. The broad range of therapeutic applications for this therapeutic class has prompted LeadDiscovery to produce a full analysis of the therapeutic potential of GSK-3 inhibitors (click here for more)

A second target highlighted in TherapeuticAdvances is clusterin. Recent studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of Aß in vitro. Now studies looking at the course of disease in a transgenic mouse model of AD have demonstrated that although clusterin deficiency fails to alter Aß deposition, fibrillar Aß deposits are rarer and associated neuritic dystrophy is markedly reduced. These findings demonstrate that clusterin markedly influences Aß structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis. Of interest OncoGenex have developed OGX-011, which is an antisense oligonucleotide inhibitor of clusterin expected to enter phase I trials for the treatment of cancer. Examining the therapeutic benefit of this and similar molecules in models of AD would therefore be of immense interest. [for further details of these and other projects log on to TherapeuticAdvances]

Sexual equality meets sexual dysfunction 

The launch of sildenafil heralded a major revolution not only for the pharmaceutical industry but also for one third of adult males that suffer erectile dysfunction. This milestone opened a major market and also offered effective therapy to 30-50% of men with this condition. Considerable work is now being conducted to treat men that are unresponsive to or are unable to use sildenafil. More American women than men experience some form of sexual disorder and it has been suggested that treatments of female sexual dysfunction represent a market of similar size to that of erectile dysfunction. Treatments of female sexual dysfunction have however yet to be marketed. In light of major unmet needs in the sexual health sector LeadDiscovery has recently produced a report entitled "Male and female sexual dysfunction: Blockbuster indication for multiple pharmacological targets" (click here to access). TherapeuticAdvances highlights two targets discussed in this report, NO and adrenoceptors. In particular a recent University of Texas trial is featured. This study demonstrated that the nitric oxide-precursor L-arginine with or without the alpha 2-blocker yohimbine increased vaginal blood flow supporting the development of one or both of these targets for female sexual dysfunction. [for further details of this and other projects log on to TherapeuticAdvances]

Advances in the treatment of inflammatory disease

The mainstay of anti-inflammatory treatments centers round the use of NSAIDs and steroids. These two drug classes are used to treat a wide range of inflammatory conditions. More recently there has been an increase in R&D activity relating to the development of products that target specific disease processes thus allowing continued improvements both in efficacy and therapeutic margin. Two major inflammatory diseases that will benefit from this activity are inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). IBD, a chronic and debilitating disease of the intestinal tract affects over 1.5 million people in the major pharmaceutical markets and supports pharmaceutical sales in excess of $0.5 billion. Greater understanding of the etiology of IBD will expand this market and offer hope to the patient. The neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) have been extensively implicated in a number of disease states (see our dossier "Tachykinins receptor antagonists: One therapeutic class for multiple indications?") as well as IBD. SP is known to stimulate production of inflammatory cytokines however the molecular pathways leading to cytokine production have, up until now remained unclear. In the current issue of TherapeuticAdvances we highlight the work of IBD field-leaders showing that the Rho family mediates some of the proinflammatory effects of SP and suggests that inhibitors of this family may offer a novel and rational approach to inflammatory conditions such as IBD. Even more common than IBD is RA, which affects 5 million sufferers in the major pharmaceutical markets and supports pharmaceutical sales in excess of $1.6 billion. The bisphosphonate were originally indicated for osteoporosis. However recent data emerging from researchers at Novartis suggests that this class may inhibit angiogenesis, a feature of RA and may therefore represent a new approach to this disease. [for further details of this and other projects log on to TherapeuticAdvances]

Endothelin-1 receptors as a target for the treatment of cancer

Between 1970 and 1994, cancer claimed the lives of about 123 million Americans. Most recent statistics suggest that 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Hence the pharmaceutical industry continues to pour massive resources into the development of anti-cancer drugs (click here for "Cancer Treatment 2002", which analyzes this activity). The current issue of TherapeuticAdvances highlights growing evidence to suggest that endothelin-1 (ET-1), a 21 amino acid peptide with vasoconstrictor, positive inotropic, mitogenic, and metabolic properties, may be a target for the treatment of cancer. ET-1 is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumors ET-1 appears to contribute to neovascularization and is also an autocrine growth factor. Italian researchers have recently shown that the ET(A)-selective antagonist ABT-627 prevents ET-1-induced growth of ovarian cancer primary cultures and cell lines. Recent data from a multinational Phase II trials in 419 advanced prostate cancer patients, demonstrated that ABT-627 stabilizes prostate cancer metastasis to the bone and in a subset of patients, disease progression was delayed. Likewise, Yamanouchi's YM-598 is also in development for prostate cancer. The present data confirm that ET(A) receptor antagonists may be of use in the treatment of ovarian as well as prostrate cancer and supports the use of drugs such as ABT-627 as a therapeutic candidate for tumor or various origins. [for further details of this and other projects log on to TherapeuticAdvances]

Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit. In addition please note that we are currently featuring 3 new reports:

  • Glycogen synthase kinase 3: Proof of concept and therapeutic opportunities for the treatment of diabetes, Alzheimer's disease, stroke & bipolar disorder [more]
  • Opportunities in the hepatitis C market [more]
  • Anti-Infectives 2002 [more]

Dr Jon Goldhill

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

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