Co-development opportunities at the cross-roads of cardiovascular and infectious diseases

E Sussex, UK --- 24th May 2002 --- Sepsis represents one of the major unmet markets. Due to the lack of effective treatments, the prognosis for the many millions of patients with this condition is poor with up to 60% dying once shock develops and the condition progresses to what is essentially a cardiovascular problem. This clinical need is expected to generate annual sales of $1.25 billion by 2005. In stark contrast, the global alpha interferon market is saturated with a large number of products that together represent a total annual market value of $2 billion. These products represent a powerful arsenal for the treatment of neoplastic and infectious diseases, however the cost of treatment has forced this class of drugs out of the reach of many. A recent dossier produced by the pharmaceutical consultants, LeadDiscovery, for The Center for Genetic Engineering and Biotechnology (CIGB, Havana, Cuba) describes a therapy that could, at the same time, offer an effective treatment for sepsis and efficient and affordable anti-viral therapy.

Sepsis, a condition usually but not always secondary to the appearance of bacterial toxins is diagnosed in 1-2% of hospital admissions. Almost any bacterial infection can cause sepsis with the respiratory, intestinal and urinary tracts representing the most common sites of primary infection. The appearance of systemic toxin precipitates a clinical decline that has traditionally been attributed to inflammation. More recently, an imbalance in hemostatic mechanisms manifesting as disorders in coagulation and thrombosis has been suggested to be a primary factor driving organ dysfunction and death.

Activation of the coagulation cascade frequently provokes the development of sepsis to septic shock and underlies the most common cause of death in non-coronary intensive care units and the 11th most common cause of death overall.

Once sepsis has been diagnosed patients require rapid stabilization to reverse hypotension and to improve tissue perfusion. Likewise respiratory support is required with nearly 85% of patients requiring artificial ventilation. At the same time antibacterial treatment must be initiated, however a lack of tools able to rapidly identify the cause of infection precludes the use of specific antibiotics. However the fact that toxin levels are already dangerously high at the time of diagnosis has driven the development of cardiovascular treatments able to tip the coagulation/fibrinolysis balance back in favor of fibrinolysis.

Protein C and tissue factor pathway inhibitor both represent promising cardiovascular approaches and indeed Eli Lilly's Drotrecogin alfa, a human recombinant form of protein C became the first product to be launched specifically for sepsis.

Toxins bind to specific host cell Toll-like receptors (TLRs) evoking a cascade of biochemical events centering round a sequential increase in various cytokines. Targeting individual biochemical mediators has proved ineffective in the treatment of sepsis and moreover, this strategy can be counter-productive due to the risk of provoking of "immunoparalysis" and consequent opportunistic infection. Instead immunological reprogramming of the cytokine cascade, neutralizing LPS or blocking its binding to TLRs offer the most promising approaches.

Limulus anti-LPS factor (LALF) is a small, basic protein found in hemocytes from both Tachypleus tridentatus and Limulus polyphemus crabs that binds LPS thereby inhibiting endotoxin-mediated activation of the coagulation cascade.

This protein factor reduces mortality in experimental animals when administered before or after LPS challenge or gram-negative bacterial infection. A major problem with anti-endotoxin therapy is that, whereas endotoxemia can be intermittent and recurrent, the administered LPS-binding proteins are, in general, rapidly cleared; consequently, LPS is only transiently neutralized by these therapies. Thus the identification of LALF derivatives more suited to therapeutic use could be of immense benefit. The LPS binding site of LALF has been localized to residues 36-45. With this in mind, researchers from the CIGB have produced a therapeutic lead, CIGB-2001 (LALF31-52), through the design and synthesis of peptides based on the study of the three-dimensional structure of the LPS-binding sequence.

CIGB-2001 is able to bind and neutralize LPS, however in addition CIGB-2001 has also been shown to produce macrophage "reprogramming". According to Dr Jon Goldhill, chief analyst at LeadDiscovery, "CIGB-2001 represents a highly exciting lead for the treatment of sepsis. We were particularly impressed with the ability of this molecule to treat both the cause and effect of sepsis.

Previous attempts to treat the immunological effects of LPS have involved the targeting of individual cytokines. The involvement of multiple inflammatory mediators and their precise temporal organization contributes to the ineffectiveness of this approach. Instead, simultaneous removal of LPS and alteration of macrophage responses to this toxin represents a highly appealing approach to sepsis. The use of therapies related to CIGB-2001, especially in combination with existing therapies that act further down-stream, such as Drotrecogin alfa therefore offers considerable promise".

CIGB researchers have shown that macrophage "reprogramming" may result from the ability of CIGB-2001 to increase the release of -interferon and -interferon from human mononuclear cells. Interferons are natural cellular products which are released from infected host cells in response to viral or other foreign nucleic acids and selectively block translation and transcription of viral RNA without disturbing normal host cell function. This effect of CIGB-2001 results in a dramatic antiviral effect and thus offers an alternative to the use of expensive recombinant forms of interferon.

Continues Dr Goldhill, "these further anti-viral effects of CIGB-2001 boost its potential. The CIGB holds a proprietary position with respect to this effect of CIGB-2001 and researchers are at present developing a series of other molecules including mimetics that will strengthen and widen the center's present patent position. We are also looking forward to this further development optimizing certain aspects of CIGB-2001 such as its plasma stability. In a recent dossier we describe the development of a highly effective thrombolytic, ThromboGenics' SY-161P5. This molecule is a variant of staphylokinase, the development of which has included PEGylation to increase plasma stability. This kind of peptide optimization could lead to a variant of CIGB-2001 with immense therapeutic potential."

According to Dr. Ricardo Silva, a member of the Business Development Group of CIGB, "our institution has considerable chemistry and biology resources and these should be invaluable in optimizing CIGB-2001. Furthermore, our resources can be used to assess the potential of non-peptide blockers of LPS:LPS binding protein through the development of high-throughput screens or rational approaches to the identification of LPS binding molecules".

The profile of CIGB-2001 and the expertise available at the CIGB suggests that this molecule could form the basis of new approaches to both sepsis and viral infection. Corporate partners are being sought and partnerships with companies with an expertise in the development of therapeutic peptides or HTS technology are particularly desired. Interested parties are invited to contact LeadDiscovery (leaddisc@leaddiscovery.co.uk) or Dr. Ricardo Silva at the CIGB directly (ricardo.silva@cigb.edu.cu).
For further information access "Improved approaches to infectious diseases: Novel approaches to controlling toxic shock and viral infection" at http://www.leaddiscovery.co.uk/dossiers/0602/index.html. Or alternatively access http://www.cigb.edu.cu/GNDP/HomeFrameset-1.htm, the home page of the CIGB's Business Development Group.

LeadDiscovery is a UK based pharmaceutical consultancy company supported by a web platform (www.leaddiscovery.co.uk) offering three key services. TherapeuticAdvances is a bulletin of cutting edge research with commercial potential circulated to over 4,500 industrial personnel. DiscoveryDossiers represent in depth analyses of drug discovery options selected by LeadDiscovery specialists or produced for institutions wishing to stimulate strategic partnerships. PharmaceuticalSolutions is a client-lead service through which LeadDiscovery is able to offer advice and project management relating to pre-clinical target selection and drug development.




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