Treatment of Inflammation, Autoimmune, and Neurodegenerative Disorders with Immunosuppressive Tat Derivative Polypeptides

Abstract

The present specification provides immunosuppressive Tat derivative polypeptides, compositions, and methods of using such polypeptides and compositions to treat an autoimmune disease, an inflammation-associated disease and/or a neurodegenerative disease.

What is claimed is: 
     
         1 . A method of treating a disease characterized by aberrant immune responses, the method comprising:
 administering a therapeutically effective amount of one or more immunosuppressive polypeptides to a subject in need thereof, wherein the immunosuppressive polypeptide comprises:   (A) an amino acid sequence comprising the following domains in the indicated order:
 (i) a transcription factor (TF) domain comprising a sequence from an immunosuppressive human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) transactivator of transcription (Tat) protein, hairless or an artificial immunosuppressive sequence, wherein the TF domain comprises the amino acid sequence of one of SEQ ID NOs: 36, 39, 44, 48, 50, or 54; 
 (ii) a cysteine-rich region from lentiviral Tat or a defensin molecule, wherein the cysteine-rich region comprises the amino acid sequence of one of SEQ ID NOs: 37, 40, 41, 43, 45, 51, 55, 57, 58, 62, 63, 64, or 70; and 
 (iii) a C-terminal region from a lentiviral Tat protein comprising the amino acid sequence of one of SEQ ID NOs: 38, 42, 46, 52, 68, or 71; 
   (B) a transcription factor (TF) domain according to (i), and a cysteine-rich domain and C-terminal domain, in that order, wherein the cysteine-rich domain and C-terminal domain together comprise an amino acid sequence of one of SEQ ID NOs: 47, 49 or 53; or   (C) or a conservative variant of the immunosuppressive polypeptide of (A) or (B) having at least 95% sequence identity thereto;   and thereby treating the disease by suppressing the immune system.   
     
     
         2 . The method of  claim 1 , further comprising an arginine-rich domain from a lentiviral Tat protein. 
     
     
         3 . The method of  claim 1 , wherein the lentiviral Tat is from HIV-1, HIV-2, SIV, feline immunodeficiency virus (FIV), or equine infectious anemia virus (EIAV). 
     
     
         4 . The method of  claim 1 , wherein the TF domain further comprises a repeat sequence comprising (PVDPRLEPWKHPGSQP) n  (SEQ ID NO: 12) at the N-terminus, wherein n=2-10. 
     
     
         5 . The method of  claim 1 , wherein the immunosuppressive Tat derivative polypeptide comprises the amino acid sequence of any of SEQ ID NOs: 9-11, 13-35, or 69. 
     
     
         6 . The method of  claim 1 , wherein the treatment increases the expression of Fas ligand on antigen presenting cell regulatory macrophages (ARegs). 
     
     
         7 . The method of  claim 1 , wherein the disease is an autoimmune, neurodegenerative or inflammation-associated disorder. 
     
     
         8 . The method of  claim 7 , wherein the autoimmune disorder is an acute disseminated encephalomyelitis (ADEM), an Addison's disease, an allergy, allergic rhinitis, an Alzheimer's disease, an anti-phospholipid antibody syndrome (APS), an arthritis, an asthma, an autoimmune deficiency syndrome, an autoimmune hemolytic anemia, an autoimmune hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a celiac disease, a Chagas disease, a chronic obstructive pulmonary disease (COPD), a diabetes mellitus type 1 (IDDM), an eczema, an endometriosis, a gastrointestinal disorder, a Goodpasture's syndrome, a Graves' disease, a Guillain-Barré syndrome (GBS), a Hashimoto's thyroiditis, a hidradenitis suppurativa, an idiopathic thrombocytopenic purpura, an inflammatory bowel disease, an inflammatory dermatologic disease, an interstitial cystitis, a lupus, a morphea, a multiple sclerosis (MS), a myasthenia gravis, a myopathy, a narcolepsy, a neuromyotonia, a pemphigus vulgaris, a pernicious anaemia, a primary biliary cirrhosis, a psoriasis, a recurrent disseminated encephalomyelitis, a rheumatic fever, a schizophrenia, a scleroderma, a Sjögren's syndrome, a skin disorder, a tenosynovitis, a uveitis, a vasculitis, or a vitiligo. 
     
     
         9 . The method of  claim 7 , wherein the disease associated with inflammation is an acne, an acid reflux/heartburn, an allergy, an allergic rhinitis, an Alzheimer's disease, an appendicitis, an arteritis, an arthritis, an asthma, an atherosclerosis, an autoimmune disorder, a balanitis, a blepharitis, a bronchiolitis, a bronchitis, a bursitis, a cancer, a carditis, a celiac disease, a cellulitis, a cervicitis, a cholangitis, a cholecystitis, a chorioamnionitis, a chronic obstructive pulmonary disease (COPD), a cirrhosis, a colitis, a conjunctivitis, a cystitis, a common cold, a dacryoadenitis, a dementia, a dermatitis, a dermatomyositis, an eczema, an emphysema, an encephalitis, an endocarditis, an endometritis, an enteritis, an enterocolitis, an epicondylitis, an epididymitis, a fasciitis, a fibrositis, a gastritis, a gastroenteritis, a gingivitis, a glomerulonephritis, a glossitis, a heart disease, a hepatitis, a hidradenitis suppurativa, a high blood pressure, an ileitis, an insulin resistance, an interstitial cystitis, an iritis, an ischemic heart disease, a keratitis, a keratoconjunctivitis, a laryngitis, a lupus, a mastitis, a mastoiditis, a meningitis, a metabolic syndrome (syndrome X), a migraine, a multiple sclerosis, a myelitis, a myocarditis, a myopathy, a myositis, a nephritis, a neuropathy, an obesity, an omphalitis, an oophoritis, an orchitis, an osteochondritis, an osteopenia, an osteoporosis, an osteitis, an otitis, a pancreatitis, a Parkinson's disease, a parotitis, a pelvic inflammatory disease, a pericarditis, a peritonitis, a pharyngitis, a phlebitis, a pleuritis, a pneumonitis, a proctitis, a prostatitis, a psoriasis, a pulpitis, a pyelonephritis, a pylephlebitis, a rheumatic fever, a rhinitis, a salpingitis, a sialadenitis, a sinusitis, a spastic colon, a stomatitis, a synovitis, a tendonitis, a tendinosis, a tenosynovitis, a thrombophlebitis, a tonsillitis, a trigonitis, a tumor, an urethritis, an uveitis, a vaginitis, a vasculitis, or a vulvitis. 
     
     
         10 . The method of  claim 7 , wherein the neurodegenerative disease is Alexander disease, Alper's disease, Alzheimer's disease, amyloidoses, amyotrophic lateral sclerosis, anxiety, ataxia telangiectasia, attention deficit disorders, Canavan disease, central nervous system injuries, Charcot Marie Tooth disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, depression, encephalitis (e.g., bacterial, parasitic, fungal, or viral), Friedreich's ataxia frontotemporal dementia, hereditary spastic paraparesis, Guillain-Barre syndrome (and its variants acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher syndrome), HIV/AIDS dementia complex, Huntington's disease, ischemic damage to the nervous system, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, meningitis (e.g., bacterial, parasitic, fungal, or viral) multiple sclerosis, multiple system atrophy, neural trauma, e.g., percussive brain damage, spinal cord injury and traumatic damage to the nervous system, a neuropathy such as e.g., chemotherapy-induced neuropathy, diabetes-associated neuropathy, and peripheral neuropathy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disorders, progressive supranuclear palsy, Refsum's disease, Sandhoff disease, schizophrenia, Schilder's disease, spinocerebellar atrophies, Steele-Richardson-Olszewski disease, stroke, tabes dorsalis, or vascular dementia. 
     
     
         11 . The method of  claim 1 , wherein the method further causes the reduction of at least one symptom associated with the autoimmune disease, neurodegenerative disease, or disease associated with inflammation and therein the symptom is inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, infertility or reduced sex drive (low libido), blood sugar changes, and depending on the type of autoimmune disease, an increase in the size of an organ or tissue, or the destruction of an organ or tissue. 
     
     
         12 . The method of  claim 1 , wherein, as a result of the administration, secretion of cytokines by ARegs is decreased. 
     
     
         13 . The method of  claim 1 , wherein the immunosuppressive Tat derivative polypeptide is administered in a plurality of doses. 
     
     
         14 . The method of  claim 13 , wherein the immunosuppressive Tat derivative polypeptide is administered daily, weekly, biweekly, monthly, or bimonthly. 
     
     
         15 . The method of  claim 1 , wherein the administering step comprises a repetitive administration cycle wherein each cycle comprises administering a plurality of doses of the immunosuppressive Tat derivative polypeptide in a defined time period followed by a rest period and wherein the cycle is repeated a plurality of times. 
     
     
         16 . A method of increasing the expression of Fas ligand (FasL) on antigen presenting cell regulatory macrophages (ARegs), the method comprising:
 administering a therapeutically effective amount of one or more immunosuppressive polypeptides to a subject in need thereof, wherein the immunosuppressive polypeptide comprises:   (A) an amino acid sequence comprising the following domains in the indicated order:
 (i) a transcription factor (TF) domain comprising a sequence from an immunosuppressive human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) transactivator of transcription (Tat) protein, hairless or an artificial immunosuppressive sequence, wherein the TF domain comprises the amino acid sequence of one of SEQ ID NOs: 36, 39, 44, 48, 50, or 54; 
 (ii) a cysteine-rich region from lentiviral Tat or a defensin molecule, wherein the cysteine-rich region comprises the amino acid sequence of one of SEQ ID NOs: 37, 40, 41, 43, 45, 51, 55, 57, 58, 62, 63, 64, or 70; and 
 (iii) a C-terminal region from a lentiviral Tat protein comprising the amino acid sequence of one of SEQ ID NOs: 38, 42, 46, 52, 68, or 71; 
   (B) a transcription factor (TF) domain according to (i), and a cysteine-rich domain and C-terminal domain, in that order, wherein the cysteine-rich domain and C-terminal domain together comprise an amino acid sequence of one of SEQ ID NOs: 47, 49 or 53; or   (C) or a conservative variant of the immunosuppressive polypeptide of (A) or (B) having at least 95% sequence identity thereto;   and thereby increasing the expression of FasL on the ARegs.   
     
     
         17 . A method of reducing inflammation, the method comprising:
 administering a therapeutically effective amount of one or more immunosuppressive polypeptides to a subject in need thereof, wherein the immunosuppressive polypeptide comprises:   (A) an amino acid sequence comprising the following domains in the indicated order:
 (i) a transcription factor (TF) domain comprising a sequence from an immunosuppressive human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) transactivator of transcription (Tat) protein, hairless or an artificial immunosuppressive sequence, wherein the TF domain comprises the amino acid sequence of one of SEQ ID NOs: 36, 39, 44, 48, 50, or 54; 
 (ii) a cysteine-rich region from lentiviral Tat or a defensin molecule, wherein the cysteine-rich region comprises the amino acid sequence of one of SEQ ID NOs: 37, 40, 41, 43, 45, 51, 55, 57, 58, 62, 63, 64, or 70; and 
 (iii) a C-terminal region from a lentiviral Tat protein comprising the amino acid sequence of one of SEQ ID NOs: 38, 42, 46, 52, 68, or 71; 
   (B) a transcription factor (TF) domain according to (i), and a cysteine-rich domain and C-terminal domain, in that order, wherein the cysteine-rich domain and C-terminal domain together comprise an amino acid sequence of one of SEQ ID NOs: 47, 49 or 53; or   (C) or a conservative variant of the immunosuppressive polypeptide of (A) or (B) having at least 95% sequence identity thereto;   and thereby increasing reducing inflammation in the subject.