Compositions and Methods for Degradation of Misfolded Proteins

Abstract

The present invention relates to compositions and methods for promoting the degradation of misfolded proteins and protein aggregates. The compositions and methods may be used to treat a disorder associated with misfolded proteins or protein aggregates. In certain instances, the compositions and methods relate to modulators of one or more TRIM proteins or one or more STUbLs.

What is claimed is: 
     
         1 . A composition for treating or preventing a disease or disorder associated with misfolded protein or protein aggregates, the composition comprising a modulator of one or more TRIM proteins. 
     
     
         2 . The composition of  claim 1 , wherein the modulator increases the expression or activity of the one or more TRIM proteins. 
     
     
         3 . The composition of  claim 1 , wherein the modulator is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         4 . The composition of  claim 1 , wherein the modulator increases the expression or activity of at least one selected from the group consisting of human TRIM3, TRIM4, TRIM5, TRIM6, TRIM7, TRIM9, TRIM 11, TRIM13, TRIM14, TRIM15, TRIM16, TRIM17, TRIM19 (also referred to herein as “PML”), TRIM20, TRIM21, TRIM24, TRIM25, TRIM27, TRIM28, TRIM29, TRIM32, TRIM34, TRIM39, TRIM43, TRIM44, TRIM45, TRIM46, TRIM49, TRIM50, TRIM52, TRIM58, TRIM59, TRIM65, TRIM67, TRIM69, TRIM70, TRIM74 and TRIM75; and mouse TRIM30. 
     
     
         5 . The composition of  claim 1 , wherein the composition comprises an isolated peptide comprising one or more TRIM proteins. 
     
     
         6 . The compositing of  claim 5 , wherein the isolated peptide further comprises a cell penetrating peptide (CPP) to allow for entry of the isolated peptide into a cell. 
     
     
         7 . The composition of  claim 6 , wherein the CPP comprises the protein transduction domain of HIV tat. 
     
     
         8 . The composition of  claim 1 , wherein the composition comprises an isolated nucleic acid molecule encoding one or more TRIM proteins. 
     
     
         9 . The composition of  claim 1 , wherein the disease or disorder is a polyQ disorder. 
     
     
         10 . The composition of  claim 1 , wherein the disease or disorder is a neurodegenerative disease or disorder selected from the group consisting of Spinocerebellar ataxia (SCA) Type 1 (SCA1), SCA2, SCA3, SCA6, SCA7, SCA17, Huntington's disease, Dentatorubral-pallidoluysian atrophy (DRPLA), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), a transmissible spongiform encephalopathy (prion disease), a tauopathy, and Frontotemporal lobar degeneration (FTLD). 
     
     
         11 . The composition of  claim 1 , wherein the disease or disorder is selected from the group consisting of AL amyloidosis, AA amyloidosis, Familial Mediterranean fever, senile systemic amyloidosis, familial amyloidotic polyneuropathy, hemodialysis-related amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, Finnish hereditary amyloidosis, lysozyme amyloidosis, fibrinogen amyloidosis, Icelandic hereditary cerebral amyloid angiopathy, type II diabetes, medullary carcinoma of the thyroid, atrial amyloidosis, hereditary cerebral hemorrhage with amyloidosis, pituitary prolactinoma, injection-localized amyloidosis, aortic medial amyloidosis, hereditary lattice corneal dystrophy, corneal amyloidosis associated with trichiasis, cataract, calcifying epithelial odontogenic tumor, pulmonary alveolar proteinosis, inclusion-body myostis, and cuteaneous lichen amyloidosis. 
     
     
         12 . The composition of  claim 1 , wherein the disease or disorder is cancer associated with p53 mutant aggregates. 
     
     
         13 . A method for treating or preventing a disease or disorder associated with misfolded protein or protein aggregates in a subject in need thereof, the method comprising administering to the subject a composition comprising a modulator of one or more TRIM proteins. 
     
     
         14 . The method of  claim 13 , wherein the modulator increases the expression or activity of the one or more TRIM proteins 
     
     
         15 . The method of  claim 13 , wherein the modulator is at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         16 . The method of  claim 13 , wherein the modulator increases the expression or activity of at least one selected from the group consisting of human TRIM3, TRIM4, TRIM5, TRIM6, TRIM7, TRIM9, TRIM 11, TRIM13, TRIM14, TRIM15, TRIM16, TRIM17, TRIM19 (also referred to herein as “PML”), TRIM20, TRIM21, TRIM24, TRIM25, TRIM27, TRIM28, TRIM29, TRIM32, TRIM34, TRIM39, TRIM43, TRIM44, TRIM45, TRIM46, TRIM49, TRIM50, TRIM52, TRIM58, TRIM59, TRIM65, TRIM67, TRIM69, TRIM70, TRIM74 and TRIM75; and mouse TRIM30. 
     
     
         17 . The method of  claim 13 , wherein the composition comprises an isolated peptide comprising one or more TRIM proteins. 
     
     
         18 . The method of  claim 17 , wherein the isolated peptide further comprises a cell penetrating peptide (CPP) to allow for entry of the isolated peptide into a cell. 
     
     
         19 . The method of  claim 18 , wherein the CPP comprises the protein transduction domain of HIV tat. 
     
     
         20 . The method of  claim 13 , wherein the composition comprises an isolated nucleic acid molecule encoding one or more TRIM proteins. 
     
     
         21 . The method of  claim 13 , wherein the disorder is a polyQ disorder. 
     
     
         22 . The method of  claim 13 , wherein the disease or disorder is a neurodegenerative disorder elected from the group consisting of Spinocerebellar ataxia (SCA) Type 1 (SCA1), SCA2, SCA3, SCA6, SCA7, SCA17, Huntington's disease, Dentatorubral-pallidoluysian atrophy (DRPLA), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), a transmissible spongiform encephalopathy (prion disease), a tauopathy, and Frontotemporal lobar degeneration (FTLD). 
     
     
         23 . The method of  claim 13 , wherein the disease or disorder is selected from the group consisting of AL amyloidosis, AA amyloidosis, Familial Mediterranean fever, senile systemic amyloidosis, familial amyloidotic polyneuropathy, hemodialysis-related amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, Finnish hereditary amyloidosis, lysozyme amyloidosis, fibrinogen amyloidosis, Icelandic hereditary cerebral amyloid angiopathy, type II diabetes, medullary carcinoma of the thyroid, atrial amyloidosis, hereditary cerebral hemorrhage with amyloidosis, pituitary prolactinoma, injection-localized amyloidosis, aortic medial amyloidosis, hereditary lattice corneal dystrophy, corneal amyloidosis associated with trichiasis, cataract, calcifying epithelial odontogenic tumor, pulmonary alveolar proteinosis, inclusion-body myostis, and cuteaneous lichen amyloidosis. 
     
     
         24 . The method of  claim 13 , wherein the disease or disorder is cancer associated with p53 mutant aggregates. 
     
     
         25 . The method of  claim 13 , wherein the method comprises administering the composition to at least one neural cell of the subject. 
     
     
         26 . A composition for treating or preventing a disease or disorder associated with degradation of functional mutant protein, the composition comprising a modulator of one or more TRIM proteins. 
     
     
         27 . The composition of  claim 26 , wherein the modulator increases the expression or activity of the one or more TRIM proteins. 
     
     
         28 . The composition of  claim 26 , wherein the modulator is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         29 . The composition of  claim 26 , wherein the disease or disorder is cystic fibrosis. 
     
     
         30 . A method for treating or preventing a disease or disorder associated with degradation of functional mutant protein in a subject in need thereof, the method comprising administering to the subject a composition comprising a modulator of one or more TRIM proteins. 
     
     
         31 . The method of  claim 30 , wherein the modulator increases the expression or activity of the one or more TRIM proteins 
     
     
         32 . The method of  claim 30 , wherein the modulator is at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         33 . The method of  claim 30 , wherein the disease or disorder is cystic fibrosis. 
     
     
         34 . A composition for treating or preventing a disease or disorder associated with misfolded protein or protein aggregates, the composition comprising a modulator of one or more SUMO-targeted ubiquitin ligase (STUbl). 
     
     
         35 . The composition of  claim 34 , wherein the modulator increases the expression or activity of one or more STUbLs. 
     
     
         36 . The composition of  claim 34 , wherein the modulator is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         37 . The composition of  claim 34 , wherein the modulator increases the expression or activity of RNF4. 
     
     
         38 . A method for treating or preventing a disease or disorder associated with misfolded protein or protein aggregates in a subject in need thereof, the method comprising administering to the subject a composition comprising a modulator of one or more STUbLs. 
     
     
         39 . The method of  claim 38 , wherein the modulator increases the expression or activity of one or more STUbLs. 
     
     
         40 . The method of  claim 38 , wherein the modulator is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid. 
     
     
         41 . The method of  claim 38 , wherein the modulator increases the expression or activity of RNF4. 
     
     
         42 . A method for producing a recombinant protein comprising administering a modulator of one or more TRIM proteins to cell modified to express a recombinant protein. 
     
     
         43 . The method of  claim 42 , wherein the modulator comprises an isolated peptide comprising one or more TRIM proteins. 
     
     
         44 . The method of  claim 42 , wherein the modulator comprises an isolated nucleic acid molecule encoding one or more TRIM proteins.