JP-2022531841-A5 -

Dates

Publication Date

20230501

Application Date

20200417

Description

This invention was made with the support of the Government of the United States of America under Grant No. RO1NS100529, granted by the NIH. The Government of the United States of America reserves certain rights in this invention. This invention relates to the treatment of Huntington's disease. According to the U.S. National Library of Medicine, Huntington's disease is a progressive brain disorder that causes motor control problems, emotional problems, and cognitive impairments. Adult-onset Huntington's disease, the most common form of this disorder, typically develops in the 30s or 40s. Early signs and symptoms may include irritability, depression, minor involuntary movements, poor coordination, and difficulty learning new information or making decisions. Many Huntington's disease sufferers experience involuntary muscle reflexes or spasms known as chorea. These movements become more pronounced as the disease progresses. Affected individuals may have difficulty walking, speaking, and swallowing. Personality changes, cognitive decline, and impaired judgment may also occur. Individuals with adult-onset Huntington's disease typically survive for approximately 15 to 20 years after the onset of signs and symptoms. Huntington's disease, a less common form known as the juvenile form, begins in childhood or adolescence. It includes motor problems as well as mental and emotional changes. Further signs of the juvenile form include bradykinesia, clumsiness, frequent falls, rigidity, slurred speech, and drooling. Academic performance declines due to impaired thinking and judgment. Seizures occur in 30 to 50 percent of children with this condition. Juvenile Huntington's disease tends to progress more rapidly than the adult-onset form; the survival time for affected individuals is typically 10 to 15 years after the onset of signs and symptoms. Despite the fact that HD is a neurodegenerative disease (ND) encompassing Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, dentatorubral-pallidoluysian atrophy (DRPLA), frontotemporal dementia (FTD), and spinocerebellar ataxia (SCA), and that many NDs share common characteristics and molecular mechanisms, no link between HD and cellular senescence has been demonstrated. Cellular senescence is a process in which cells are forced to permanently cease proliferating in response to various stressors. Historically, it has been considered to contribute to complex biological processes such as aging and age-related disorders. Cellular senescence is associated with cellular repair, which is an attempt by cells to repair cellular components, particularly DNA damage that may include cell cycle arrest or re-entry into the cell cycle. Cellular senescence can result from prolonged, unsuccessful, or suboptimal cellular repair. The relationship between cellular repair and cellular senescence applies to dividing cells, including but not limited to brain dividing cells such as astrocytes, oligodendrocytes, and microglia, as well as postmittal cells, including but not limited to brain postmittal cells such as neurons. In postmittal cells, cellular senescence is often referred to as a "senescence-like state" or "aging response." In both cases, senescent characteristics may include cellular vulnerability to external stressors and the secretion of molecules harmful to surrounding cells, such as inflammatory cytokines. The primary regulator of cell cycle arrest is p16 INK4a , which is also a major inducer and an important marker of cellular senescence. This invention is the result of the accidental discovery of the role of p16 INK4a in the prevention or treatment of HD. This invention addresses p16 INK4a inhibitors for use in the prevention and/or treatment of Huntington's disease (HD). In certain aspects of the present invention, the inhibitor is a nucleic acid, a peptide, a small molecule compound, or a commercially available drug. In a further aspect of the present invention, the p16 INK4a inhibitor is a nucleic acid that encodes RNA that interferes with p16 INK4a, such as siRNA, shRNA, microRNA, non-coding RNA, deoxyribozyme, antisense oligonucleotide, ribozyme DNAzyme, modified or synthetic DNA or RNA denaturation-resistant polynucleosideamide , peptide nucleic acid (PNA), loc nucleic acid (LNA), other nucleic acid base-containing polymers, aptamers or polynucleotide targeted gene edits or any combination thereof. In a further aspect of the present invention, the p16 INK4a inhibitor is a peptide selected from the group including ligands, kinase inhibitors, small molecule compounds such as PPARγ antagonists or retinoid X receptor (RXR) antagonists, small molecule SIRT1 activators, compounds capable of stimulating the activity of FOXO factor, and AMPK activators. In a further aspect of the present invention, the p16 INK4a inhibitor is a ligand, which is an antibody, Fab, Fab', F(ab')2, Fv, dsFv, scFv, diabody, triabody, tetrabody, aptamer, or VHH d