Novel therapeutic and diagnostic products and methods

Abstract

The present invention relates to the use of p11 as a drug target as well as a tool for the diagnosis, treatment and development of p11/5-HT receptor related disorders. The invention further relates to p11 knock-out animals as well as p11 transgenic animals and their use as models for the development of novel psychotherapeutic agents, and to methods of diagnosis, prophylaxis and treatment of p11/5-HT receptor related disorders.

1 . A method of diagnosing a p11/5-HT receptor related disorders in a subject comprising determining the level of p11 in a biological sample from said subject and comparing said p11 level to a reference, wherein an abnormal level of p11 compared to the reference constitutes a positive diagnosis of p11/5-HT receptor related disorder. 
   
   
       2 . A method according to  claim 1 , wherein said p11/5-HT receptor related disorder is a disorder associated with an abnormally low level of p11, wherein a reduced level of p11 in a subject compared to a control subject constitutes a positive diagnosis of such disorders. 
   
   
       3 . A method according to  claim 2 , wherein said disorder associated with an abnormally low level of p11 is selected from a group consisting of depression, obsessive compulsive disorder, drug addiction, eating disorders, Alzheimer's disease, attention deficit disorder and attention deficit hyperactive disorder. 
   
   
       4 . A method according to  claim 2 , wherein said disorder associated with an abnormally low level of p11 is depression. 
   
   
       5 . A method according to  claim 1 , wherein said p11/5-HT receptor related disorders are disorders associated with an abnormally high level of p11, wherein an elevated level of p11 in a subject compared to that in a control subject constitutes a positive diagnosis of such disorders. 
   
   
       6 . A method according to  claim 5 , wherein said disorder associated with an abnormally high level of p11 is selected from a group consisting of mania, dipolar disorder, anxiety disorders, aggression, sleep disorders, sexual dysfunction and gastrointestinal disorders. 
   
   
       7 . The method according to  claim 1 , wherein said level of p11 is determined by assaying p11 protein level in the monocytes and/or lymphocytes in said biological sample from said subject. 
   
   
       8 . The method according to  claim 1 , wherein said level of p11 is determined by assaying p11 mRNA level in a biological sample from said subject. 
   
   
       9 . A method to identify modulators useful to treat or ameliorate p11/5-HT receptor related disorders comprising the steps of:
 a) providing a first sample and a second sample containing equivalent amounts of p11 gene product;   b) contacting the first sample with the candidate p11 modulator; and   c) determining whether the amounts of p11 gene product in the first sample has increased or decreased relative to the amounts of p11 gene product in the second sample not contacted with the candidate p11 modulator, wherein an increased amount of gene product indicate that the candidate modulators can be useful to treat or ameliorate disorders associated with abnormally low level of p11 while a decreased amount of gene products indicates that the candidate modulators can be useful to treat or ameliorate disorders associated with abnormally high level of p11.   
   
   
       10 . A method to identify modulators useful to treat or ameliorate p11/5-HT receptor related disorders comprising the steps of:
 a) providing a first sample and a second sample containing equivalent number of 5-HT 1B  receptors at cell surface;   b) contacting the first sample with the candidate p11 modulator; and   c) determining whether the number of 5-HT 1B  receptors at cell surface of the first sample has increased relative to the second sample, wherein an increased number of 5-HT 1B  receptors at cell surface indicate that the candidate modulators can be useful to treat or ameliorate disorders associated with abnormally low level of p11 activity while a decreased amount of 5-HT 1B  receptors at cell surface indicates that the candidate modulators can be useful to treat or ameliorate disorders associated with abnormally high level of p11 activity.   
   
   
       11 . The method according to  claim 9 , wherein said modulators are useful to treat or ameliorate p11/5-HT receptor related disorders selected from a group consisting of depression, obsessive compulsive disorder, drug addiction, eating disorders, Alzheimer's disease, attention deficit disorder or attention deficit hyperactive disorder, comprising assaying for the ability of said candidate modulator to up regulate p11 expression. 
   
   
       12 . The method according to  claim 11 , wherein said p11/5-HT receptor related disorder is depression. 
   
   
       13 . The method according to  claim 9  wherein the p11 modulator is a tricyclic antidepressant, a serotonin reuptake inhibitor or a monoamine oxidase inhibitor. 
   
   
       14 . A method to identify p11 mimetics useful to treat or ameliorate p11/5-HT receptor related disorders comprising assaying for the ability of a candidate p11 mimetic to recruit 5-HT 1B  receptors to the neuronal plasma membrane. 
   
   
       15 . The method according to  claim 14 , wherein said p11 mimetics are useful to treat or ameliorate disorders associated with abnormally low level of p11, wherein said candidate p11 mimetics recruit 5-HT 1B  receptors to the neuronal plasma membrane. 
   
   
       16 . A method according to  claim 15 , wherein said disorder is selected from a group consisting of depression, obsessive compulsive disorder, drug addiction, eating disorders, Alzheimer's disease, attention deficit disorder and attention deficit hyperactive disorder. 
   
   
       17 . The method according to  claim 16 , wherein said disorder is depression. 
   
   
       18 . A method of treating or ameliorating p11 dysfunction in a subject diagnosed as suffering from one or more p11/5-HT receptor related disorders comprising administering to said subject a therapeutically effective amount of a p11 modulator or p11 mimetic. 
   
   
       19 . The method according to  claim 18 , wherein p11/5-HT receptor related disorder is selected from a group consisting of depression, obsessive compulsive disorder, drug addiction, eating disorders, Alzheimer's disease, attention deficit disorder and attention deficit hyperactive disorder, comprising administering to said subject a therapeutically effective amount of a p11 modulator or mimetic, wherein said p11 modulator or mimetic up regulate p11 expression or recruits 5-HT 1B  receptors to the neuronal plasma membrane. 
   
   
       20 . The method according to  claim 19 , wherein said p11/5-HT receptor related disorder is depression. 
   
   
       21 . The method according to  claim 18 , wherein p11/5-HT receptor related disorder is selected from a group consisting of mania, dipolar disorder, anxiety disorders, aggression, sleep disorders, sexual dysfunction and gastrointestinal disorders, comprising administering to said subject a therapeutically effective amount of a p11 modulator or mimetic, wherein said p11 modulator or mimetic inhibit p11 expression or down-regulate 5-HT 1B  receptors at the neuronal plasma membrane. 
   
   
       22 . A p11 knock-out non-human mammal wherein said mammal has a defect, mutation or deficiency in the p11 gene compared to wild-type mammals of the same species. 
   
   
       23 . The p11 knockout non-human mammal according to  claim 22 , wherein said p11 knockout non-human mammal is a mouse. 
   
   
       24 . The mouse according to  claim 23 , wherein said mouse under-expresses p11 proteins compared to wild-type mice. 
   
   
       25 . The mouse according to  claim 23 , wherein said mouse has fewer 5-HT 1B  receptors at the neuronal plasma membrane compared to wild-type mice. 
   
   
       26 . The mouse according to any of  claim 23 , wherein said mouse exhibits a depression-like phenotype. 
   
   
       27 . A method of studying p11/5-HT receptor related disorders or to develop novel psychotherapeutic agents useful for the treatment of p11/5-HT receptor related disorders comprising:
 a) administering an effective amount of said psychotropic agent to p11 knock-out mice and control mice;   b) assessing the levels of p11 level and/or behavioral responses to said agent in said p11 knock-out mice and control mice;   c) comparing said p11 level and/or behavioral responses in p11 knock-out mice with control mice.   
   
   
       28 . The method according to  claim 27 , wherein said p11/5-HT receptor related disorder is selected from a group consisting of depression, anxiety disorders, aggression, mania, bipolar disorder, sleep disorders, obsessive compulsive disorder, drug addiction, eating disorders, sexual dysfunction, Alzheimer's disease, attention deficit disorder, attention deficit hyperactive disorder and gastrointestinal disorders. 
   
   
       29 . A non-human mammal comprising a transgene encoding p11 under control of a regulatable promoter. 
   
   
       30 . The mammal of  claim 29  which is a mouse. 
   
   
       31 . The mammal of  claim 29  wherein the promoter is a calmodulin/calmodulin-dependent protein kinase II (CamKII) promoter. 
   
   
       32 . A method to enhance p11 expression in a patient suffering from a p11/5-HT receptor related disorder, comprising the administration of a nucleic acid which enhances the expression of p11 in the brain of said patient. 
   
   
       33 . The method of  claim 32  wherein the nucleic acid encodes p11. 
   
   
       34 . The method of  claims 32 , wherein the p11/5-HT receptor related disorder is a disorder associated with abnormally low levels of p11 selected from depression, obsessive compulsive disorder, drug addiction, eating disorders, attention deficit disorder or attention deficit hyperactive disorder, and Alzheimer's disease. 
   
   
       35 . The method of  claim 32 , wherein the p11/5-HT receptor related disorder is depression. 
   
   
       36 . The method of  claim 32 , wherein said nucleic acid is delivered by a recombinant, replication-deficient adenoviral vector comprising a DNA construct encoding p11. 
   
   
       37 . The method of  claim 36  wherein said DNA construct is under the control of a neural tissue-specific promoter. 
   
   
       38 . The method of  claim 32 , wherein said nucleic acid is delivered by a neural stem cell expressing p11 at levels higher than the levels expressed by the patient's brain cells. 
   
   
       39 . The method of  claim 32 , wherein said nucleic acid encoding p11 is delivered to the hippocampus.