Uses for prevention or treatment of brain diseases using microRNA
Inventors
Ryu, Jin-Hyeob • Cho, Hyun-Jeong
Assignees
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Publication Number
US-11542503-B2
Publication Date
2023-01-03
Expiration Date
Abstract
The present disclosure relates to a pharmaceutical composition for preventing or treating a brain disease, more particularly to a pharmaceutical composition for preventing or treating a brain disease, which contains a miR-485-3p inhibitor, and a method for screening an agent for preventing or treating a brain disease, which includes a step of measuring the expression level of miR-485-3p. Because the composition for treating a brain disease, which contains a miR-485-3p inhibitor, can restore the ELAVL2 protein unlike the exiting therapeutic agents for Alzheimer's disease, which are limited only to alleviating symptoms by inducing decreased expression of amyloid beta 42, the present disclosure can fundamentally treat various diseases caused by decreased expression of ELAVL2, such as Alzheimer's disease, autism spectrum disorder, mental retardation, amyotrophic lateral sclerosis, etc. Therefore, the present disclosure is useful for treating brain diseases including Alzheimer's disease fundamentally.
Core Innovation
The invention relates to miR-485-3p as a therapeutic target for treating a brain disease in a subject in need thereof. The method comprises administering a miR-485-3p inhibitor comprising a nucleic acid molecule that inhibits expression of miR-485-3p. Reducing miR-485-3p is associated with restoring ELAVL2 expression by blocking miR-485-3p binding to the ELAVL2 3′-UTR.
The described concept links the miR-485-3p/ELAVL2 axis to downstream disease-relevant biomarkers. The reduction of miR-485-3p is stated to decrease Aβ42 production and inhibit APP expression and tau phosphorylation. The target and effect are positioned for treatment of Alzheimer's disease and other ELAVL2-associated disorders including autism spectrum disorder, mental retardation, ALS, seizure, stroke, Parkinson’s disease, and spinal cord injury.
The patent also describes a screening method to identify candidate agents that decrease miR-485-3p expression in miR-485-3p-expressing cells. The provided experimental support includes miRNA expression analysis in Alzheimer patients showing significant miR-485-3p elevation and a 5×FAD mouse model showing increased miR-485-3p with decreased ELAVL2 and increased Aβ42. The document further describes use of an antagomir that increases ELAVL2 and reduces Aβ42, APP, and tau/p-tau changes with improved cognitive performance.
Claims Coverage
The independent claims are clm-00001 and clm-00011. Across these, the claims cover 2 main inventive feature areas: administration of a miR-485-3p inhibitor comprising a nucleic acid molecule for treating selected brain diseases, and administration of a miR-485-3p inhibitor as an antisense oligonucleotide capable of binding to SEQ ID NO: 1 or SEQ ID NO: 2 for brain disease associated with decreased ELAVL2 expression.
MiR-485-3p inhibitor nucleic acid for treating selected brain diseases
A method of treating a brain disease in a subject in need thereof comprising administering a miR-485-3p inhibitor to the subject, wherein the brain disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), autism spectrum disorder, mental retardation, seizure, stroke, Parkinson's disease, spinal cord injury, and combinations thereof, and wherein the miR-485-3p inhibitor comprises a nucleic acid molecule and inhibits expression of miR-485-3p.
Antisense oligonucleotide binding to SEQ ID NO: 1 or SEQ ID NO: 2 for diseases associated with decreased ELAVL2 expression
A method of treating a brain disease in a subject in need thereof comprising administering a miR-485-3p inhibitor to the subject, wherein the brain disease is associated with a decreased expression level of ELAV-like RNA binding protein 2 (ELAVL2), and wherein the miR-485-3p inhibitor comprises an antisense oligonucleotide that is capable of binding to the nucleic acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2.
Claim coverage centers on administering a nucleic-acid miR-485-3p inhibitor to treat specified brain diseases, including diseases listed in the independent claims. A second independent claim narrows treatment to brain diseases associated with decreased ELAVL2 expression by requiring an antisense oligonucleotide capable of binding to nucleic acid sequences set forth in SEQ ID NO: 1 or SEQ ID NO: 2, with dependents further restricting allowable antisense sequences and chemical/nucleotide modifications.
Stated Advantages
Restores ELAVL2 expression by blocking miR-485-3p binding to the ELAVL2 3′-UTR.
Decreases Aβ42 production.
Inhibits APP expression and tau phosphorylation.
Improves cognitive performance in the 5×FAD mouse model.
Documented Applications
Treating brain diseases including Alzheimer's disease and ELAVL2-associated disorders such as autism spectrum disorder, mental retardation, ALS, seizure, stroke, Parkinson’s disease, and spinal cord injury.
Screening method identifying candidate agents that decrease miR-485-3p expression in miR-485-3p-expressing cells.
Use of an antagomir with reported effects including increased ELAVL2 and reduced Aβ42 and APP/tau-related changes, including improved cognitive performance in 5×FAD mice [procedural detail omitted for safety].
Intranasal delivery with imaging and delivery results [procedural detail omitted for safety].
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