Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-02-18
2003-03-25
Smith, Lynette R. F. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S069100, C435S091200, C435S243000, C435S252300, C435S254100, C435S254220, C435S255400, C435S320100, C536S023100, C536S023200, C536S023740, C536S024320, C536S024330, C530S324000, C530S350000, C424S274100
Reexamination Certificate
active
06537753
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for diagnosing and/or detecting and/or preventing and/or treating
Candida albicans
or conditions or symptoms associated therewith, as well as to process and products for preparing such compositions and methods.
The present invention further relates to CaESS1, an important
Candida albicans
gene, e.g., nucleic acid molecules therefor, and/or fragments or portions thereof, expression products therefrom, e.g., the protein CaEss1 or fragments or portions thereof, methods for making and using the gene, portions thereof and expression products therefrom, and to targeting the gene or portions thereof and/or the expression products therefrom for antifungal applications.
The identification of the CaESS1 gene allows for identifying compounds or agents that specifically bind to and/or inhibit the gene, or portions thereof and/or expression products therefrom, and methods for preventing and/or treating
Candida albicans
and/or symptoms or conditions associated therewith, as well as generally for making and using such compounds or agents. Thus, the invention relates to antifungal preparations and/or compositions and methods for making and using them.
The CaEss1 amino acid sequence and the CaESS1 DNA or nucleic acid sequences can be used for diagnostic purposes. For instance, the nucleic acid sequences can be used to generate primers for diagnostic DNA, and the invention comprehends such primers. Primers are preferably derived from those parts of the CaESS1 gene which are least conserved among the ESS1/PIN1 family members. The gene or the primers can be used to detect if the gene is present in a sample or specimen and/or if the gene was expressed as RNA in a sample or specimen. Accordingly, the invention relates to compositions and methods for detecting and/or diagnosing
Candida albicans.
The CaESS1 gene and portions thereof are useful for generating or expressing the CaEss1 protein and epitopic portions thereof (epitopic portions of the protein can be derived from, generated by, or expressed from those parts of the CaESS1 gene which are least conserved among the ESS1/PIN1 family members). The protein or portions thereof is useful for generating antibodies, such as monoclonal and/or polyclonal antibodies. These antibodies can be used for diagnostic purposes; and, the protein or portions thereof can be used for diagnostic purposes, e.g., the antibodies can be used to detect or determine, e.g., via binding, whether the proteins or portions thereof are present in a sample or specimen and the protein or portions thereof can be used to detect or determine, e.g., via binding, whether antibodies thereto are present in a sample or specimen. Further, the antibodies can be used to block CaEss1 activity. Accordingly, the invention relates to diagnostic compositions and methods, as well as therapeutic or preventive compositions and methods.
The invention further relates to methods for screening compounds for the ability to inhibit CaEss1 and/or PIN1. Compounds which selectively inhibit CaEss1 and do not inhibit PIN1 or do not inhibit PIN1 greatly are compounds useful in the prevention and/or treatment of
Candida albicans
. Compounds which inhibit PIN1 are useful in antiproliferative applications, e.g., as antineoplastic, anti-tumor or anticancer agents. Furthermore, the screening methods of the invention can be adapted and used for screening compounds which inhibit other fungal infection as fungus other than
Candida albicans
have ESS1 genes. Accordingly, the invention relates to methods for screening for inhibitors of CaEss1, PIN1 or other ESS1s, as well as to inhibitors of these enzymes.
Various documents are cited in this text, or in a reference section preceding the claims. Each of the documents cited herein, and each of the documents cited or referenced in each of those various documents, is hereby incorporated herein by reference. None of the documents cited in the following text is admitted to be prior art with respect to the present invention.
BACKGROUND OF THE INVENTION
Candida albicans
is an asexual yeast species.
Candida albicans
is a major fungal pathogen of humans. It is can be found as a harmless commensal organism, inhabiting mucosal membranes and the digestive tract; a benign saprophyte. However,
Candida albicans
, can infect both internal organs and mucous membranes of the mouth, throat, and genital tract, and can cause a chronic infection; it can cause superficial infections, such as oral thrush, and can cause severe, often fatal, systemic infections, especially in immunocompromised patients.
There has been a growing number of cases of thrush and other diseases caused by
Candida albicans
; and, this can be attributed mainly to medical advances in antibiotic, steroid and immunosuppressive treatments, as well as to immunocompromising ailments such as HIV and AIDS. Indeed, surveillance of nosocomial blood stream infections (BSI) in the USA between April 1995 and June 1996 revealed that
Candida albicans
was the fourth leading cause of nosocomial BSI (Pfaller et al., “National surveillance of nosocomial blood stream infection due to
Candida albicans
: frequency of occurrence and antifungal susceptibility in the SCOPE Program,” Diagn Microbiol Infect Dis 1998 May;3 1(1):327-32). Accordingly,
Candida albicans
, and compositions and methods for detecting, diagnosing, preventing or treating
Candida albicans
are medically significant.
Thrush is characterized by creamy-white, curdlike patches on the tongue and other mucosal surfaces of the mouth. The disease is caused by an overgrowth of
Candida albicans
. Patients susceptible to thrush include immunocompromised individuals, e.g., adults whose immune systems have been weakened by antibiotics, steroids, immunosuppression treatments, AIDS, and the like, as well as infants, for instance if the mother had a vaginal yeast infection.
Painful, raw and bleeding areas result if the curdlike discharge is removed from patches of thrush. These superficial lesions may allow the yeast to spread to other areas of the body.
Candida albicans
can invade major organs, causing serious complications.
While thrush is typically treated with a topical agent, and there are oral and intravenous treatments for
Candida albicans
infections, chronically infected patients may require long term therapy with oral and/or intravenous therapy.
Moreover, strains of
Candida albicans
resistant to present treatments or therapies such as amphotericin B, fluconazole, itraconazole and other azole antifungals have been isolated (Mori et al., “Analysis by pulsed-field gel electrophoresis of
Candida albicans
that developed resistance during antifungal therapy,”
Nippon Ishitkin Gakkiai Zasshi
1998;39(4):229-33; Pfaller et al., supra; Rex et al., “A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia,”
N Engl J Med
1994 Nov 17;331(20):1325-30). Indeed, in Rex et al., in certain individuals, treatment failed to clear infection from the bloodstream, and
Candida albicans
was infection commonly associated with the treatment failure.
Thus, there is a need for new treatments or therapies against
Candida albicans.
Diagnosis of
Candida albicans
requires microscopic identification of the pseudomycelial (branching-arms) forms. There is likewise a need for new compositions and methods for diagnosing or detecting
Candida albicans.
The ESS1 gene was originally discovered in
Saccharomyces cerevisiae
, by inventor Hanes working in the laboratory of Dr. Peter Shank and Dr. Keith Bostian (Hanes 1988). It was discovered in a search for cell growth control genes. By gene disruption techniques, ESS1 was shown to be essential for yeast cell growth, hence the name (Essential) (Hanes et al. 1989). ESS1 genes are highly conserved. Homologs of the ESS1 gene have been found in Drosophila, humans and several other organisms. The fly gene (called dodo) and the human gene (called PIN1) encode proteins that are 45% identical to the
Chaturvedi Vishnu
Devasahayam Gina
Hanes Steven D.
Baskar Padma
Frommer William S.
Frommer & Lawrence & Haug LLP
Health Research Incorporated
Kowalski Thomas J.
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