Recombinant t-cell receptor ligand for the treatment of cognitive and neuropsychiatric impairment induced by substance addiction

Abstract

Methods are provided for the treatment of subjects with cognitive or neuropsychiatric impairment induced by substance addiction and for increasing cognitive function in a subject with substance addiction. In some embodiments, the methods include administering to the subject a therapeutically effective amount of a major histocompatibility complex (MHC) molecule including covalently linked first, second, and third domains; wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain; or wherein the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain; and wherein the third domain is covalently linked to the first domain and comprises an antigen of the central or peripheral nervous system.

We claim: 
     
         1 . A method for treating cognitive or neuropsychiatric impairment induced by substance addiction, comprising
 selecting a subject with a substance addiction; and   administering to the subject a therapeutically effective amount of a Major Histocompatibility Complex (MHC) molecule comprising covalently linked first, second and third domains, wherein:
 a) the first domain is an MHC class II β1 domain and the second domain is an MHC Class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain, wherein the MHC molecule does not comprise an MHC class II α2 domain or an MHC Class II β2 domain; or 
 b) the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain, wherein the amino terminus of the α2 domain is covalently linked to the carboxy terminus of the α1 domain, and wherein the MHC molecule does not comprise an α3 domain, 
 and wherein the third domain is covalently linked to the first domain, wherein the third domain comprises an antigen of the central or peripheral nervous system; 
   
       thereby treating the cognitive or neuropsychiatric impairment in the subject. 
     
     
         2 . The method of  claim 1 , wherein the cognitive or neuropsychiatric impairment induced by substance addiction comprises cognitive impairment, anxiety, depression, fatigue, agitation, pain, sleep disturbance, drug craving, or a combination of two or more thereof. 
     
     
         3 . The method of  claim 1 , wherein the substance addiction comprises methamphetamine or other sympathomimetic addiction, opioid addiction, alcohol addiction, or a combination of two or more thereof. 
     
     
         4 . The method of  claim 1 , wherein the subject with a substance addiction does not have multiple sclerosis, a stroke, or a primary neurological disorder. 
     
     
         5 . The method of  claim 1 , wherein the covalent linkage between the first domain and the second domain is provided by a polypeptide linker, the covalent linkage between the first domain and the third domain is provided by a polypeptide linker or a disulfide bond, or a combination thereof. 
     
     
         6 . The method of  claim 1 , wherein the antigen of the central or peripheral nervous system comprises a myelin protein or antigenic determinant thereof, wherein the antigenic determinant is 8 to 30 amino acids in length and binds the MHC molecule. 
     
     
         7 . The method of  claim 6 , wherein the antigen comprises myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP), or a portion thereof. 
     
     
         8 . The method of  claim 6 , wherein the antigenic determinant comprises or consists of MOG 35-55, MOG 1-25, MOG 94-116, MOG 145-160, MOG 194-208, MBP 10-30; MBP 35-45, MBP 77-91, MBP 85-99, MBP 95-112, MBP 145-164, PLP 139-151, or PLP 95-116. 
     
     
         9 . The method of  claim 1 , wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain. 
     
     
         10 . The method of  claim 9 , wherein the MHC molecule is an HLA-DR, HLA-DP, or HLA-DQ human MHC molecule. 
     
     
         11 . The method of  claim 10 , wherein the MHC molecule is modified by substitution of one or more hydrophobic amino acids within a β-sheet platform of the MHC molecule such that the MHC molecule has reduced aggregation in solution compared to aggregation exhibited by an unmodified MHC molecule with a wild-type β-sheet platform. 
     
     
         12 . The method of  claim 11 , wherein the one or more hydrophobic amino acids comprise one or more of V102, 1104, A106, F108, L110, L9, F19, L28, F32, V45, V51, A133, V138 and L141 and wherein the one or more hydrophobic amino acids are substituted with a non-hydrophobic amino acid. 
     
     
         13 . The method of  claim 12 , wherein the non-hydrophobic amino acid is a polar or a charged amino acid. 
     
     
         14 . The method of  claim 13 , wherein the non-hydrophobic amino acid is serine or aspartic acid. 
     
     
         15 . The method of  claim 1 , further comprising measuring one or more of memory, comprehension, learning capacity, attention, information processing, executive function, visuospatial function, language, motor skills, emotional/affective processing, or impulsivity in the subject. 
     
     
         16 . The method of  claim 1 , wherein the subject has one or more of forgetfulness, poor concentration, confusion, disorientation, dementia, a learning disability, delusion, paranoia, hallucinations, disorganization, indecisiveness, poor judgment, poor memory, difficulties with information processing, or problems with verbal skills or motor skills. 
     
     
         17 . The method of  claim 1 , further comprising administering to the subject a therapeutically effective amount of one or more of an anti-depressant, sedative-hypnotic-anxiolytic, analgesic, anti-psychotic, mood stabilizer, or anti-epileptic, psychotherapy, or a psychosocial intervention. 
     
     
         18 . A method of increasing cognitive function in a subject with a substance addiction, comprising
 administering to the subject a therapeutically effective amount of a Major Histocompatibility Complex (MHC) molecule comprising covalently linked first, second and third domains, wherein:
 a) the first domain is an MHC class II β1 domain and the second domain is an MHC Class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain, wherein the MHC molecule does not comprise an MHC class II α2 domain or an MHC Class II β2 domain; or 
 b) the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain, wherein the amino terminus of the α2 domain is covalently linked to the carboxy terminus of the α1 domain, and wherein the MHC molecule does not comprise an α3 domain, 
 and wherein the third domain is covalently linked to the first domain, wherein the third domain comprises an antigen of the central or peripheral nervous system, 
   
       thereby increasing cognitive function in the subject with the substance addiction. 
     
     
         19 . The method of  claim 18 , wherein the cognitive function comprises memory, attention, information processing, executive function, visuospatial function, language, motor skills, emotional/affective processing, impulsivity, or a combination of two or more thereof. 
     
     
         20 . The method of  claim 18 , wherein the substance addiction comprises methamphetamine or other sympathomimetic addiction, opioid addiction, alcohol addiction, or a combination of two or more thereof. 
     
     
         21 . The method of  claim 18 , wherein the subject with a substance addiction does not have multiple sclerosis, a stroke, or a primary neurological disorder. 
     
     
         22 . The method of  claim 18 , wherein the covalent linkage between the first domain and the second domain is provided by a polypeptide linker, the covalent linkage between the first domain and the third domain is provided by a polypeptide linker or a disulfide bond, or a combination thereof. 
     
     
         23 . The method of  claim 18 , wherein the antigen of the central or peripheral nervous system comprises a myelin protein or antigenic determinant thereof, wherein the antigenic determinant is 8 to 30 amino acids in length and binds the MHC molecule. 
     
     
         24 . The method of  claim 23 , wherein the antigen comprises myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP), or a portion thereof. 
     
     
         25 . The method of  claim 23 , wherein the antigenic determinant comprises or consists of MOG 35-55, MOG 1-25, MOG 94-116, MOG 145-160, MOG 194-208, MBP 10-30; MBP 35-45, MBP 77-91, MBP 85-99, MBP 95-112, MBP 145-164, PLP 139-151, or PLP 95-116. 
     
     
         26 . The method of  claim 18 , wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain. 
     
     
         27 . The method of  claim 26 , wherein the MHC molecule is an HLA-DR, HLA-DP, or HLA-DQ human MHC molecule. 
     
     
         28 . The method of  claim 27 , wherein the MHC molecule is modified by substitution of one or more hydrophobic amino acids within a β-sheet platform of the MHC molecule such that the MHC molecule has reduced aggregation in solution compared to aggregation exhibited by an unmodified MHC molecule with a wild-type β-sheet platform. 
     
     
         29 . The method of  claim 28 , wherein the one or more hydrophobic amino acids comprise one or more of V102, 1104, A106, F108, L110, L9, F19, L28, F32, V45, V51, A133, V138 and L141 and wherein the one or more hydrophobic amino acids are substituted with a non-hydrophobic amino acid. 
     
     
         30 . The method of  claim 29 , wherein the non-hydrophobic amino acid is a polar or a charged amino acid. 
     
     
         31 . The method of  claim 30 , wherein the non-hydrophobic amino acid is serine or aspartic acid. 
     
     
         32 . The method of  claim 18 , further comprising measuring one or more of memory, comprehension, learning capacity, attention, information processing, executive function, visuospatial function, language, motor skills, emotional/affective processing, or impulsivity in the subject. 
     
     
         33 . The method of  claim 18 , wherein the subject has one or more of forgetfulness, poor concentration, confusion, disorientation, dementia, a learning disability, delusion, paranoia, hallucinations, disorganization, indecisiveness, poor judgment, poor memory, difficulties with information processing, or problems with verbal skills or motor skills. 
     
     
         34 . The method of  claim 18 , further comprising administering to the subject a therapeutically effective amount of one or more of an anti-depressant, sedative-hypnotic-anxiolytic, analgesic, anti-psychotic, mood stabilizer, or anti-epileptic, psychotherapy, or a psychosocial intervention.