Use of purinergic receptor modulators and related reagents

Abstract

The invention provides a method of treatment for an animal having a disease state associated with a genitourinary disorder with a purinergic receptor modulator. Also provided, is a transgenic animal having a disrupted purinergic receptor gene. The invention further provides for a method of screening using the transgenic animal as a positive control.

Description

CROSS-REFERENCE TO RELATED INVENTIONS[0001] This application claims benefit under Title 35 U.S.C. 119(e) of U.S. Provisional Application Nos. 60 / 182,445, filed Feb. 15, 2000 and 60 / 205,798 filed May 17, 2000; all applications are hereby incorporated by reference in its entirety.[0002] The present invention relates to a method of treating or preventing a disease state associated with a genitourinary or pain disorder using a purinergic receptor modulator. Also provided are transgenic or knockout animals deficient in a purinergic receptor and a method of screening for therapeutic compounds using the transgenic or knockout animals as positive controls.[0003] The urinary bladder is responsible for two important physiological functions: urine storage and urine emptying. This process involves two main steps: (1) the bladder fills progressively until the tension in its walls rises above a threshold level; and (2) a nervous reflex, called the micturition reflex, occurs that empties the bladd...

AI Technical Summary

Benefits of technology

[0056] The present invention is based on the discovery that disruption of the gene encoding the P2X.sub.3 receptor subunit in a gene knockout (KO) animal, results in increased urinary bladder capacity, less frequent urine voiding (e.g., approximately two-fold longer interval between voiding when compared to a wild-type control mouse), and larger voided volumes (e.g., approximately two-fold higher when compared to a wild-type control mouse), all without a significant increase in cystometric pressure. Therefore, P2X receptor complex modulators will be useful in the treatment or prevention of disease states associated with various genitourinary disorders, where the P2X receptor complex comprises at least one P2X.sub.3 receptor subunit.

[0064] Examples of these techniques include: 1) Insertion of normal or mutant versions of DNA encoding P2X.sub.3 receptor subunit or homologous animal versions of these genes, by microinjection, retroviral infection, or other means well known to those skilled in the art, into appropriate fertilized embryos in order to produce a transgenic animal (see, e.g., Hogan, supra); and 2) homologous recombination (see, e.g., Capecchi, supra; and Zimmer and Gruss (1989) Nature 338:150-153) into embryonic stem cells allowing for the introduction of mutant or normal, human or animal versions of genes into the germline of an animal. Resulting KO animals can have altered regulation of expression or structure of P2X.sub.3 receptor subunit .

[0068] As the present invention illustrates, P2X.sub.3 receptor subunit knockout animals have phenotypic characteristics including, but not limited to, larger bladder capacity, lower frequency of urine voiding, larger voided volumes, and similar cystometric pressure values, in comparison to wild-type control animals. Thus, an animal, which does not express the P2X.sub.3 receptor subunit (a KO animal), is useful as a positive control for evaluating potential therapeutic compounds. Compounds that cause wild-type animals or animals having disease states described above to express phenotypic characteristics similar to that of the KO animal should be useful in the treatment of these disease states.

Problems solved by technology

ATP, and to a lesser extent, adenosine, can stimulate sensory nerve endings resulting in intense pain and a pronounced increase in sensory nerve discharge.

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