Nonhuman animal reproducing pathogenic conditions of spinal and bulbar muscular atrophy and remedy for spinal and bulbar muscular atrophy

Abstract

It is intended to provide a model animal faithfully reproducing the pathogenic conditions of spinal and bulbar muscular atrophy, a method of screening a remedy for polyglutamine disease using the same, and a remedy for spinal and bulbar muscular atrophy. Namely, a nonhuman animal having the following characteristics (1) to (5) in its conditions or pathological findings: (1) showing progressive myoatrophy; (2) showing lowering in muscular power; (3) in immunostaining with the use of an anti-polyglutamine antibody, showing nuclear diffuse staining and nuclear inclusions; (4) in immunostaining with the use of an anti-androgen receptor antibody, showing nuclear diffuse staining and nuclear inclusions; and (5) showing a neurogenic change. A remedy for polyglutamine disease is screened by administering a test substance to this nonhuman animal and examining changes in its conditions or pathological findings. A remedy for spinal and bulbar muscular atrophy is prepared by using as the active ingredient a compound having an effect of inhibiting the secretion of testosterone.

1 . A non-human animal comprising the following characteristics (1) to (5) in symptoms or pathologic findings: 
 (1) showing progressive muscular atrophy;    (2) showing lowering in muscular power;    (3) showing diffuse nuclear staining and nuclear inclusions in immunostaining with the use of an anti-polyglutamine antibody;    (4) showing diffuse nuclear staining and nuclear inclusions in immunostaining with the use of an anti-androgen receptor antibody; and    (5) showing neurogenic change.    
     
     
         2 . A non-human animal according to  claim 1 , wherein when the animals are females, the (1) to (5) are not found or are found more slightly or mildly as compared with the case in male animals.  
     
     
         3 . A non-human animal according to  claim 1 , wherein the non-human animal is Rodentia.  
     
     
         4 . A non-human animal according to  claim 1 , wherein the non-human animal is a mouse.  
     
     
         5 . A method of screening therapeutic agents for polyglutamine diseases, the method comprising the following steps (a) and (b): 
 (a) administering a test agent to the non-human animal according to  claim 1;  and    (b) examining whether or not at least one of the following (1) to (9) is improved in the non-human animal after the test agent was administered, 
 (1) progressive muscular atrophy;  
 (2) lowering in muscular power;  
 (3) an amount of diffuse nuclear staining and nuclear inclusions found in immunostaining with the use of an anti-polyglutamine antibody;  
 (4) an amount of diffuse nuclear staining and nuclear inclusions found in immunostaining with the use of an anti-androgen receptor antibody;  
 (5) neurogenic change;  
 (6) progressive motor impairment;  
 (7) reduction in body size;  
 (8) short life-span; and  
 (9) reduced activity.  
   
     
     
         6 . A method for screening therapeutic agents for polyglutamine diseases, the method comprising the following steps (A) and (B): 
 (A) administering a test agent to the non-human animal according to  claim 1  and to the wild type thereof; and    (B) comparing and assessing the level of at least one of the following (1) to (9) between the administered non-human animal and the wild type, 
 (1) progressive muscular atrophy;  
 (2) lowering in muscular power;  
 (3) an amount of diffuse nuclear staining and nuclear inclusions found in immunostaining with an anti-polyglutamine antibody;  
 (4) an amount of diffuse nuclear staining and nuclear inclusions found in immunostaining with an anti-androgen receptor antibody;  
 (5) neurogenic change,  
 (6) progressive motor impairment;  
 (7) reduction in body size;  
 (8) short life-span; and  
 (9) reduced activity.  
   
     
     
         7 . The screening method according to  claim 5 , wherein the test agent is selected from compounds having an effect of inhibiting the secretion of testosterone.  
     
     
         8 . A therapeutic agent for polyglutamine diseases, comprising, as an active ingredient, the compound selected by the screening method according to  claim 5 .  
     
     
         9 . A therapeutic agent for spinal and bulbar muscular atrophy, comprising, as an active ingredient, a compound having an effect of inhibiting the secretion of testosterone.  
     
     
         10 . A therapeutic agent for spinal and bulbar muscular atrophy, comprising, as an active ingredient, a compound having an effect of inhibiting the secretion of gonadotropin from the pituitary gland.  
     
     
         11 . A therapeutic agent for spinal and bulbar muscular atrophy, comprising, as an active ingredient, a compound having an effect of reducing luteinizing hormone-releasing hormone receptors by acting on the pituitary gland.  
     
     
         12 . A therapeutic agent for spinal and bulbar muscular atrophy, comprising, as an active ingredient, an analog of luteinizing hormone-releasing hormone.  
     
     
         13 . A therapeutic agent for spinal and bulbar muscular atrophy, comprising, as an active ingredient, Leuprorelin or the derivative thereof.