136 results about "Huntingtin" patented technology

Methods and compositions for reducing expression of a mutant huntingtin (mHTT) protein in a cell are provided. Such methods include contacting the cell with an effective amount of a nucleic acid silencing agent targeting a differentiating polymorphism in RNA encoding the mHTT.

The drug action mechanisms and core techniques of the present invention are summarized in figure 1. Specifically, the invention provides malignant denatured proteins, such as mutant Huntingtin proteinor alpha-synuclein, stick together to grow into oligomer aggregates (1, 2), fibrillar aggregates (3), and ultimately inclusion bodies (4). Young neuronal cells produce a large quantity of Nt-Arg through N-terminal arginylation (5) of endoplasmic reticulum chaperones, such as BiP, and thereafter, arginylated BiP (R-BiP) comes into the cytoplasm and binds with denatured proteins (6). Nt-Arg of R-BiP, as a ligand, binds with the ZZ domain of p62 (7) to induce the structural activation of p62 (8) while the ordinarily closed inactive form of p62 is changed with an open form thereof, and thus PB1 and LC3-binding domains are exposed. On the basis of oligomerization (9) by the PB1 domain, p62 binds with the denatured protein aggregates to be concentrated to autophagically degradable aggregates, that is, p62 bodies (10). Thereafter, p62 completes autophagy targeting (11) and lysosomal proteolysis through binding with LC3 protruding on the autophagosomal membranes. In young neuronal cells, theautophagic proteolysis occurring through steps 5-11 is strong, and thus the cytotoxic protein aggregates (1-5) do not accumulate, but in aged neuronal cells, the autophagic proteolysis occurring through steps 5-11 is weakened, and thus the protein aggregates (1-5) accumulate, resulting in a vicious cycle. The present invention attempts to effectively remove Huntingtin and alpha-synuclein protein aggregates and the like by artificially activating p62 using low-mass ligands of the p62 ZZ domain (12, 13). Specifically, p62 binding the ligands through step 12 promotes p62-R-BiP-denatured protein oligomerization (9) and autophagy aggregate formation (10). In addition, the ligand-62 conjugates step 13 act as autophagy activators (14), to promote LC3 synthesis, the conversion of LC3-I into LC3-II, and the like, thereby promoting the formation of autophagosomes (15).

The invention features compositions and methods comprising at least one compound selected from a proteasomal inhibitor, an autophagy inhibitor, a lysosomal inhibitor, an inhibitor of protein transport from the ER to the Golgi, an Hsp90 chaperone inhibitor, a heat shock response activator, a glycosidase inhibitor or histone deacetylase inhibitor that are useful for treating or preventing a protein conformation disease in a subject by correcting misfolded proteins in vivo. The compositions and methods can further comprise an 11-cis-retinal or 9-cis-retinal compound. Examples of protein conformation disorders and / or diseases may include retinitis pigmentosa, age-related macular degeneration, glaucoma, corneal dystrophies, retinoschises, Stargardt's disease, autosomal dominant druzen, Best's macular dystrophy, al -antitrypsin deficiency, cystic fibrosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, nephrogenic diabetes insipidus, cancer and / or Jacob-Creutzfeld disease.