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METHODS OF PREVENTION AND TREATMENT OF DISEASES CAUSED BY THE FUNGAL PATHOGEN CANDIDA ALBICANS

The yeast Candida albicans is the most common fungal pathogen of humans. Most adult females experience sporadic incidents of vaginitis during the course of their reproductive lives and recurrent disease is not unusual. Oral lesions termed thrush regularly afflict infants and immunosuppressed adults with HIV or other forms of immunosuppression. Mucosal disease may serve as a conduit for the organism to invade the vasculature, enter the bloodstream, seed internal organs to cause extensive morbidity and mortality in hospitalized patients with underlying debilitating conditions such trauma, organ transplant or malignancy. The antifungal drugs available to treat these mucosal and systemic diseases are narrow in spectrum, few in number and may have adverse side effects.

While the ability of C. albicans to form tight attachments to the mucosa prior to tissue invasion has long been appreciated, mechanisms for forming these attachments have not been elucidated until recently. Researchers at Dartmouth have cloned a gene that encodes a fungal surface protein adhesin that serves as a substrate for a mammalian cross-linking enzyme, transglutaminase, located on the surfaces of epithelial cells. The interaction of the fungal adhesin with transglutaminase brings about the covalent attachment of the fungus to epithelial proteins on the mammalian mucosa. A mutant strain with a disruption in the adhesin gene is defective for in vitro adherence to human mucosal epithelial cells and is attenuated in both mucosal and systemic models of candidiasis in mice. These experiments show that the adhesin allows the fungus to maintain microcolonies enmeshed in epithelial cell layers, despite the normal sloughing of epithelial cells from the mucosal surface and the washing actions created by salivary secretions and swallowing. This fungal adhesin termed Hwp1 (hyphal wall protein 1) is abundantly produced when the fungus is undergoing apical tip extension in hyphal growth and not during yeast growth, thereby linking the hyphal growth form to enhanced adherence.

The inventions consist of methods to inhibit transglutaminase-mediated adhesion to mammalian cells, either directly by interfering with attachment, or indirectly by interfering with yeast -to-hypha transitions or by inhibiting expression of the HWP1 gene. Large amounts of the transglutaminase substrate domain of Hwp1, or functional derivatives, are expressed in cell-free culture systems and serve as specific inhibitors of fungal adherence. The invention also enables researchers to screen for chemicals that hinder bud hypha transitions by inhibiting the action of the Adenylate Cyclase-Associated Protein, encoded by the CAP1gene, which the Dartmouth researchers have shown to be essential for proper control of yeast-to-hypha transitions during infection. A final application is the pursuit of chemicals that interfere with the activation of the HWP1 promoter during hyphal growth.

The high frequency and wide spectrum of diseases caused by this fungus, coupled with the restricted availability of anti-fungal drugs makes the development of drugs to inhibit this novel adhesive target compelling for therapeutic prevention and treatment of candidiasis.

Dartmouth has an extensive patent portfolio claiming these findings including the issued United States Patent Nos. 6,388,056, 7,135,182 and 6,706,688, the published Patent Corporation Treaty Application Nos. PCT/US00/32464, and PCT/US02/06986, and the published United States Patent Application Nos. 11/082,746, 10/755,399, and 10/672,074. We are seeking an industrial partner who is interested in their further refinement and commercialization. (Ref: J285, J287, J288, J289)


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