WO2022003609A1

WO2022003609A1 - Snp diagnostic methods

Info

Publication number: WO2022003609A1
Application number: PCT/IB2021/055891
Authority: WO
Inventors: Jin-Hyeob RYU; Dae Hoon Kim; Jae Woong Min
Original assignee: Biorchestra Co., Ltd.
Priority date: 2020-07-01
Filing date: 2021-07-01
Publication date: 2022-01-06

Abstract

The present disclosure provides methods and compositions to identify patients suitable for treatment with miRNA-485 inhibitors, e.g., antisense oligonucleotides. The methods disclosed herein can be used to select patients not having pathogenic single nucleotide polymorphisms (SNP) in the biomarker genes CD36, GRIA3, NRXN1, and VLDLR, as candidates for treatment with miRNA-485 inhibitors disclosed herein, and identify patients having such pathogenic SNPs as candidates for alternative therapies. The miRNA-485 inhibitors of the present disclosure can be used for treating a disease or condition associated, e.g., with a decreased level of SIRT1, PGC-1α, CD36, LRRK2, NRG1, and/or STMN2 protein or SIRT1, PGC-1α, CD36, LRRK2, NRG1, and/or STMN2 gene expression. The miRNA-485 inhibitors disclosed herein can inhibit miR-485 expression and/or activity, which in turn can increase the level of SIRT1, PGC-1α, CD36, LRRK2, NRG1, and/or STMN2 protein or gene expression.

Description

SNP DIAGNOSTIC METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the priority benefit of U.S. Provisional Application

No. 63/047,117, filed on July 1, 2020, which is herein incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB

[0002] The content of the electronically submitted sequence listing (Name:

4366_032PC01_Seqlisting_ST25.txt; Size: 9,419 bytes; and Date of Creation: June 30, 2021) is herein incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

[0003] The present disclosure provides the use of a miR-485 inhibitor ( e.g ., polynucleotide encoding a nucleotide molecule comprising at least one miR-485 binding site) for the treatment of diseases and disorders (e.g., neurodegenerative diseases and disorders, e.g, Alzheimer's disease) in a subject is identified as not having at least one pathogenic non- synonymous SNP in a gene targeted by miRNA-485.

BACKGROUND OF THE DISCLOSURE

[0004] Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are common and growing cause of mortality and morbidity worldwide. It is estimated that by 2050, more than 100 million people worldwide will be affected by AD. Gaugler et al, Alzheimer's Dement 12(4): 459-509 (2016); Pan et al, Sci Adv 5(2) (2019). The costs of AD are estimated at more than 800 billion USD globally. Over the past two decades, investigators have been trying to develop compounds and antibodies that can inhibit Ab production and aggregation, or, promote amyloid beta clearance. Unfortunately, these attempts have not achieved successful clinical benefits in large clinical trials with mild AD patients. Panza et al, Nat Rev Neurol 15(2): 73-88 (2019).

[0005] Currently, there are no known cures for neurodegenerative disorders. Available treatment options are generally limited to alleviating the various symptoms, as opposed to addressing the underlying causes of the disorders. Therefore, new and more effective approaches to treating neurodegenerative disorders are highly desirable, e.g., antisense therapies.

[0006] Antisense oligonucleotides (ASOs) can be used to target miRNAs that modulate the expression of genes that are up-regulated or downregulated in patients with neurodegenerative disorders such as Alzheimer’s disease or Parkinson’s disease. However, if the amino acid sequence of the gene to be targeted contains abnormalities, it is impossible to predict the biological response that may occur after drug treatment. For example, in cases where the patient expresses a protein encoded by an abnormal target gene, drug administration can results in a lack of response, a poor response, adverse side effects, or unexpected reactions. Therefore, there is a need for the identification of biomarkers and predictive methods that can be used to determine whether to proceed or not with drug treatment and/or to select an alternative therapy.

BRIEF SUMMARY OF THE DISCFOSURE [0007] The present disclosure provides a method of treating a neurodegenerative disease or disorder in a subject in need thereof comprising administering a mir-485 inhibitor to the subject, wherein the subject is identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 (Cluster of Differentiation 36), GRIA4 (glutamate ionotropic receptor AMP A type subunit 4), NRXN1 (neurexin 1), and VLDLR (very low density lipoprotein receptor). The present disclosure also provides a method of treating a neurodegenerative disease or disorder in a subject in need thereof comprising (i) identifying a subject as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRIA4 , NRXN1 , and VLDLR ; and (ii) administering a mir-485 inhibitor to the subject. Also provided is a method of identifying a human subject afflicted with a neurodegenerative disease or condition as suitable for treatment with a mir-485 inhibitor, comprising determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRIA4 , NRXN1, and VLDLR , wherein: a. the presence of at least one pathogenic non-synonymous SNP in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is not suitable for treatment with a mir- 485 inhibitor; and, b. the absence of pathogenic non-synonymous SNPs in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is suitable for treatment with a mir-485 inhibitor. [0008] In some aspects, the method further comprises administering a mir-485 inhibitor to the subject. In some aspects, at least one pathogenic nonsynonymous SNP is in CD36. In some aspects, the at least one pathogenic nonsynonymous SNP in CD36 comprises 1, 2, 3, 4, 5, 6, 7, 8 or 9 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in CD36 is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c 1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c 1237A>C

(rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), and any combination thereof.

[0009] In some aspects, the at least one pathogenic nonsynonymous SNP is in GRIA4. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises 1, 2, 3, 4 or 5 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 is selected from the group consisting of GRIA4 c.2090G>C (rs765556214), GRIA4 c 1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 c 1931C>T (rsl555050174), and any combination thereof.

[0010] In some aspects, the at least one pathogenic nonsynonymous SNP is in NRXN1. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is selected from the group consisting of NRXN1 C.37570T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del (rsl558925686), NRXN1 c.H9G>A (rs 1064795493), and any combination thereof.

[0011] In some aspects, the at least one pathogenic nonsynonymous SNP is in VLDLR. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises 1, 2, 3, 4, 5, 6 or 7 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR are selected from the group consisting of VLDLR C.1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.l041_1045del (rs!554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof.

[0012] In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2,

3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29

30, 31, or 32 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c,1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c,1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c,1915A>T

(rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.1931C>T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del

(rsl558925686), NRXN1 c.H9G>A (rsl064795493), VLDLR c,1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c,1041_1045del (rsl554621211), VLDLR c,1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof.

[0013] In some aspects, the at least one pathogenic nonsynonymous SNP is a substitution

SNP, a duplication SNP, a deletion SNP, a deletion-insertion SNP, or a combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitution SNPs. In some aspects, the substitution SNPs are selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rsl48910227), CD36 C.1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), GRIA4 c.2090G>C

(rs765556214), GRIA4 c,1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.1928C>G (rsl555050171), GRIA4 C.19310T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 c.2936C>G (rs267606922), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.l 19G>A (rs 1064795493), VLDLR c,1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR c,1342C>T (rs80338905), VLDLR c.2117G>T (rs397514750), and any combinations thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3 or 4 duplication SNPs. In some aspects, the duplication SNPs are selected from the group consisting of CD36 c.949dup (rs70961716), CD36 c.784dup (rs766920034), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.3845dup (rsl553535216), and any combinations thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6 or 7 deletion SNPs. In some aspects, the deletion SNPs are selected from the group consisting of CD36 c.l228_1239del (rs550565800), CD36 c.H55del (rs765809606), NRXN1 c.2888del (rs796052787), NRXN1 c.1551 1555del (rsl558925686), VLDLR c 1041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2339del (rs80338906) and any combinations thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1 deletion-insertion SNP. In some aspects, the deletion-insertion SNP is NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl 553400438).

[0014] In some aspects, the subject exhibits improvement in at least a symptom or sequela of the disease or condition. In some aspects, the subject exhibits improvement in overall survival or progression free survival compared to a subject not treated with a mir-485 inhibitor. In some aspects, the method further comprises measuring the expression of SIRT1 (sirtuin 1), GRIA4 , PPARGC1A (PPARG coactivator 1 alpha), NRG1 (neuregulin 1), NRXN1, NXPH1 (neurexophilin 1), CD36, VLDLR , or a combination thereof.

[0015] In some aspects, the mir-485 inhibitor targets SIRT1 , GRLA4 , PPARGC1A , NRG1,

NPXN1 , NXPH1 , CD36 , VLDLR , or a combination thereof. In some aspects, the neurodegenerative disease or condition is associated with an abnormal level of SIRT1 , GRLA4 , PPARGC1A , NRG1, NRXN1, NXPH1 , CD36 , VLDLR , or a combination thereof. In some aspects, the neurodegenerative disease or condition is Alzheimer’s disease or Parkinson’s disease,

[0016] In some aspects, the mir-485 miRNA inhibitor inhibits miR485-3p. In some aspects, the miR485-3p comprises 5'-gucauacacggcucuccucucu-3' (SEQ ID NO: 1). In some aspects, the mir-485 miRNA inhibitor comprises a nucleotide sequence comprising 5'- UGUAUGA- 3', wherein the miRNA inhibitor comprises about 6 to about 30 nucleotides in length.

[0017] In some aspects, the mir-485 miRNA inhibitor increases transcription of an SIRT1 gene and/or expression of a SIRTl protein.

[0018] In some aspects, the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 5' of the nucleotide sequence. [0019] In some aspects, the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 3' of the nucleotide sequence. [0020] In some aspects, the mir-485 miRNA inhibitor has a sequence selected from the group consisting of: 5'-UGUAUGA-3', 5'-GUGUAUGA-3', 5'-CGUGUAUGA-3', 5'- CCGUGUAUGA-3' (SEQ ID NO:2), 5'-GCCGUGUAUGA-3' (SEQ ID NO:3), 5'-

AGCCGUGUAUGA-3' (SEQ ID NO:4), 5'-GAGCCGUGUAUGA-3' (SEQ ID NO:5), 5'- AGAGCCGUGUAUGA-3' (SEQ ID NO:6), 5'-GAGAGCCGUGUAUGA-3' (SEQ ID NO:7), 5'- GGAGAGCCGUGUAUGA-3 ¹ (SEQ ID NO:8), 5'-AGGAGAGCCGUGUAUGA-3' (SEQ ID NO:9), 5'-GAGGAGAGCCGUGUAUGA-3' (SEQ ID NO: 10), 5'-

AGAGGAGAGCCGUGUAUGA-3 ¹ (SEQ ID NO: 11), 5'-GAGAGGAGAGCCGUGUAUGA-3 ' (SEQ ID NO: 12); 5'-UGUAUGAC-3', 5'-GUGUAUGAC-3', 5'-CGUGUAUGAC-3' (SEQ ID NO: 13), 5'-CCGUGUAUGAC-3' (SEQ ID NO: 14), 5'-GCCGUGUAUGAC-3' (SEQ ID NO: 15), 5'-AGCCGUGUAUGAC-3' (SEQ ID NO: 16), 5'-GAGCCGUGUAUGAC-3' (SEQ ID NO: 17), 5'-AGAGCCGUGUAUGAC-3' (SEQ ID NO: 18), 5'-GAGAGCCGUGUAUGAC-3' (SEQ ID NO: 19), 5'-GGAGAGCCGUGUAUGAC-3' (SEQ ID NO:20), 5'-

AGGAGAGCCGUGUAUGAC-3' (SEQ ID NO:21), 5'-GAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO:22), 5'-AGAGGAGAGCCGUGUAUGAC-3' (SEQ ID NO:23), or 5'- GAGAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO:24).

[0021] In some aspects, the miRNA inhibitor has a sequence selected from the group consisting of: 5'-TGTATGA-3', 5'-GTGTATGA-3', 5'-CGTGTATGA-3', 5'-CCGTGTATGA-3' (SEQ ID NO:25), 5'-GCCGTGTATGA-3' (SEQ ID NO:26), 5'-AGCCGTGTATGA-3' (SEQ ID NO:27), 5'-GAGCCGTGTATGA-3' (SEQ ID NO:28), 5'-AGAGCCGTGTATGA-3' (SEQ ID NO:29), 5'-GAGAGCCGTGTATGA-3' (SEQ ID NO:30), 5'-GGAGAGCCGTGTATGA-3' (SEQ ID NO:31), 5'-AGGAGAGCCGTGTATGA-3' (SEQ ID NO:32), 5'-

GAGGAGAGCCGTGTATGA-3 ' (SEQ ID NO:33), 5 ' - AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:34), 5 ' -G AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:35); 5'-TGTATGAC-3', 5'- GTGTATGAC-3', 5'-CGTGTATGAC-3' (SEQ ID NO:36), 5'-CCGTGTATGAC-3' (SEQ ID NO:37), 5'-GCCGTGTATGAC-3' (SEQ ID NO:38), 5'-AGCCGTGTATGAC-3' (SEQ ID NO:39), 5'-GAGCCGTGTATGAC-3' (SEQ ID NO:40), 5'-AGAGCCGTGTATGAC-3' (SEQ ID N0:41), 5'-GAGAGCCGTGTATGAC-3' (SEQ ID NO:42), 5'-GGAGAGCCGTGTATGAC-3' (SEQ ID NO:43), 5'-AGGAGAGCCGTGTATGAC-3' (SEQ ID NO:44), 5'-

GAGGAGAGCCGTGTATGAC-3' SEQ ID NO:45), 5¹ - AG AGG AG AGC CGT GT AT GAC -3¹ (SEQ ID NO:46), and 5'-GAGAGGAGAGCCGTGTATGAC-3' (SEQ ID NO:47).

[0022] In some aspects, the sequence of the mir-485 miRNA inhibitor is at least about

50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AG AGG AG AGC C GT GT AT GAC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor has a sequence that has at least 90% similarity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AGAGGAGAGCCGT GT ATGAC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'-

AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23) or 5'-

AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO:46) with one substitution or two substitutions. In some aspects, the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'-

AG AGG AG AGC C GT GT AT GAC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23).

[0023] In some aspects, the mir-485 miRNA inhibitor comprises at least one modified nucleotide. In some aspects, the at least one modified nucleotide is a locked nucleic acid (LNA), an unlocked nucleic acid (UNA), an arabino nucleic acid (ABA), a bridged nucleic acid (BNA), and/or a peptide nucleic acid (PNA). In some aspects, the mir-485 miRNA inhibitor comprises a backbone modification. In some aspects, the backbone modification is a phosphorodiamidate morpholino oligomer (PMO) and/or phosphorothioate (PS) modification. In some aspects, the mir-485 miRNA inhibitor is delivered in a delivery agent. In some aspects, the delivery agent is a micelle, an exosome, a lipid nanoparticle, an extracellular vesicle, or a synthetic vesicle. In some aspects, the delivery agent is a micelle comprising a cationic carrier unit of the present disclosure. [0024] The present disclosure also provides a kit comprising a nucleic acid probe or a set of nucleic acid probes to detect at least one pathogenic nonsynonymous SNP in CD36 , GRIA4 , NRXN1 , VLDLR , or a combination thereof. In some aspects of the kit, the at least one pathogenic nonsynonymous SNP in CD36, GRIA4, NRXN1 , VLDLR , or a combination thereof is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rsl48910227), CD36 c 1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c 1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165),

GRIA4 C.1928C>G (rsl555050171), GRIA4 C.19310T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 c.2936C>G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del (rsl558925686), NRXN1 c.H9G>A (rsl064795493), VLDLR c 1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR c 1342C>T (rs80338905), VLDLR c 1041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof. In some aspects, of the kit, the at least one pathogenic nonsynonymous SNP in CD36 , GRIA4 , NRXN1 , VLDLR , or a combination thereof comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 nucleic acid probes to detected pathogenic nonsynonymous SNPs in CD36, GRIA4, NRXN1, VLDLR , or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

[0025] FIG. 1 shows mRNA-485-3p binding genes among Alzheimer’s related genes.

[0026] FIG. 2 shows the number of total SNPs, nonsynonymous SNPs, and pathogenic

SNPs for each one of the genes listed in FIG. 1.

[0027] FIG. 3 shows the pathogenic SNPs identified in the target genes listed in FIG. 2.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] The present disclosure is directed to methods to determine whether a subject is eligible for treatment with a miR-485 inhibitor, e.g., a miR-485 disclosed herein. Based on the presence or absence of specific biomarkers (SNPs in specific genes), it is possible to predict whether a patient will be responsive or nonresponsive to therapy with an antisense therapeutic agent, e.g., a miR485-3p antisense oligonucleotide disclosed herein. Accordingly, the methods disclosed herein can be used to determine whether to commence therapy, suspend therapy or modify the therapy administered to a subject having a neurodegenerative disease such as Alzheimer’s disease of Parkinson’s disease.

[0029] The present disclosure provides methods of treating a neurodegenerative disease or disorder in a subject in need thereof comprising administering a mir-485 inhibitor to the subject, wherein the subject is identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 (Cluster of Differentiation 36), GRIA4 (glutamate ionotropic receptor AMP A type subunit 4), NRXN1 (neurexin 1), and VLDLR (very low density lipoprotein receptor).

[0030] The present disclosure also provides methods of treating a neurodegenerative disease or disorder in a subject in need thereof comprising

(i) identifying a subject as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRIA4 , NRXN1, and VLDLR, and,

(ii) administering a mir-485 inhibitor to the subject.

[0031] Also provided are method of identifying a human subject afflicted with a neurodegenerative disease or condition as suitable for treatment with a mir-485 inhibitor, comprising determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRIA4 , NRXN1 , and VLDLR , wherein: a. the presence of at least one pathogenic non-synonymous SNP in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is not suitable for treatment with a mir-485 inhibitor; and, b. the absence of pathogenic non-synonymous SNPs in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is suitable for treatment with a mir-485 inhibitor.

[0032] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to the particular compositions or process steps described, as such can, of course, vary. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0033] The headings provided herein are not limitations of the various aspects of the disclosure, which can be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

I. Terms

[0034] In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0035] It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a nucleotide sequence," is understood to represent one or more nucleotide sequences. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It is further noted that the claims can be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a negative limitation.

[0036] Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0037] It is understood that wherever aspects are described herein with the language

"comprising," otherwise analogous aspects described in terms of "consisting of and/or "consisting essentially of are also provided.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0039] Units, prefixes, and symbols are denoted in their Systeme International de Unites

(SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10

[0040] Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0041] Nucleotides are referred to by their commonly accepted single-letter codes. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Nucleotides are referred to herein by their commonly known one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Accordingly, 'a' represents adenine, 'c' represents cytosine, 'g' represents guanine, 'f represents thymine, and 'u' represents uracil.

[0042] Amino acid sequences are written left to right in amino to carboxy orientation.

Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. [0043] The term "about" is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower).

[0044] As used herein, the term "adeno-associated virus" (AAV), includes but is not limited to, AAV type 1, AAV type 2, AAV type 3 (including types 3 A and 3B), AAV type 4, AAV type 5, AAV type 6, AAV type 7, AAV type 8, AAV type 9, AAV type 10, AAV type 11, AAV type 12, AAV type 13, AAVrh.74, snake AAV, avian AAV, bovine AAV, canine AAV, equine AAV, ovine AAV, goat AAV, shrimp AAV, those AAV serotypes and clades disclosed by Gao et al. (J. Virol. 75:6381 (2004)) and Moris et al. {Virol. 33: 375 (2004)), and any other AAV now known or later discovered. See, e.g. , FIELDS et al. VIROLOGY, volume 2, chapter 69 (4th ed., Lippincott-Raven Publishers). In some aspects, an "AAV" includes a derivative of a known AAV. In some aspects, an "AAV" includes a modified or an artificial AAV.

[0045] The terms "administration," "administering," and grammatical variants thereof refer to introducing a composition, such as a miRNA inhibitor of the present disclosure, into a subject via a pharmaceutically acceptable route. The introduction of a composition, such as a micelle comprising a miRNA inhibitor of the present disclosure, into a subject is by any suitable route, including intratumorally, orally, pulmonarily, intranasally, parenterally (intravenously, intra-arterially, intramuscularly, intraperitoneally, or subcutaneously), rectally, intralymphatically, intrathecally, periocularly or topically. Administration includes self- administration and the administration by another. A suitable route of administration allows the composition or the agent to perform its intended function. For example, if a suitable route is intravenous, the composition is administered by introducing the composition or agent into a vein of the subject.

[0046] As used herein, the term "approximately," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain aspects, the term "approximately" refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0047] As used herein, the term "conserved" refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.

[0048] In some aspects, two or more sequences are said to be "completely conserved" or

"identical" if they are 100% identical to one another. In some aspects, two or more sequences are said to be "highly conserved" if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some aspects, two or more sequences are said to be "highly conserved" if they are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some aspects, two or more sequences are said to be "conserved" if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some aspects, two or more sequences are said to be "conserved" if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Conservation of sequence can apply to the entire length of a polynucleotide or polypeptide or can apply to a portion, region or feature thereof.

[0049] The term "derived from," as used herein, refers to a component that is isolated from or made using a specified molecule or organism, or information ( e.g ., amino acid or nucleic acid sequence) from the specified molecule or organism. For example, a nucleic acid sequence that is derived from a second nucleic acid sequence can include a nucleotide sequence that is identical or substantially similar to the nucleotide sequence of the second nucleic acid sequence. In the case of nucleotides or polypeptides, the derived species can be obtained by, for example, naturally occurring mutagenesis, artificial directed mutagenesis or artificial random mutagenesis. The mutagenesis used to derive nucleotides or polypeptides can be intentionally directed or intentionally random, or a mixture of each. The mutagenesis of a nucleotide or polypeptide to create a different nucleotide or polypeptide derived from the first can be a random event (e.g., caused by polymerase infidelity) and the identification of the derived nucleotide or polypeptide can be made by appropriate screening methods, e.g, as discussed herein. In some aspects, a nucleotide or amino acid sequence that is derived from a second nucleotide or amino acid sequence has a sequence identity of at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% to the second nucleotide or amino acid sequence, respectively, wherein the first nucleotide or amino acid sequence retains the biological activity of the second nucleotide or amino acid sequence.

[0050] As used herein, a "coding region" or "coding sequence" is a portion of polynucleotide which consists of codons translatable into amino acids. Although a "stop codon" (TAG, TGA, or TAA) is typically not translated into an amino acid, it can be considered to be part of a coding region, but any flanking sequences, for example promoters, ribosome binding sites, transcriptional terminators, introns, and the like, are not part of a coding region. The boundaries of a coding region are typically determined by a start codon at the 5' terminus, encoding the amino terminus of the resultant polypeptide, and a translation stop codon at the 3' terminus, encoding the carboxyl terminus of the resulting polypeptide.

[0051] The terms "complementary" and "complementarity" refer to two or more oligomers (i.e., each comprising a nucleobase sequence), or between an oligomer and a target gene, that are related with one another by Watson-Crick base-pairing rules. For example, the nucleobase sequence "T-G-A (5'- 3')," is complementary to the nucleobase sequence "A-C-T (3'- 5')." Complementarity can be "partial," in which less than all of the nucleobases of a given nucleobase sequence are matched to the other nucleobase sequence according to base pairing rules. For example, in some aspects, complementarity between a given nucleobase sequence and the other nucleobase sequence can be about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. Accordingly, in certain aspects, the term "complementary" refers to at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% match or complementarity to a target nucleic acid sequence (e.g, miR-485 nucleic acid sequence). Or, there can be "complete" or "perfect" (100%) complementarity between a given nucleobase sequence and the other nucleobase sequence to continue the example. In some aspects, the degree of complementarity between nucleobase sequences has significant effects on the efficiency and strength of hybridization between the sequences.

[0052] The term "downstream" refers to a nucleotide sequence that is located 3' to a reference nucleotide sequence. In certain aspects, downstream nucleotide sequences relate to sequences that follow the starting point of transcription. For example, the translation initiation codon of a gene is located downstream of the start site of transcription.

[0053] The terms "excipient" and "carrier" are used interchangeably and refer to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound, e.g., a miRNA inhibitor of the present disclosure.

[0054] The term "expression," as used herein, refers to a process by which a polynucleotide produces a gene product, e.g., RNA or a polypeptide. It includes without limitation transcription of the polynucleotide into micro RNA binding site, small hairpin RNA (shRNA), small interfering RNA (siRNA), or any other RNA product. It includes, without limitation, transcription of the polynucleotide into messenger RNA (mRNA), and the translation of mRNA into a polypeptide. Expression produces a "gene product." As used herein, a gene product can be, e.g, a nucleic acid, such as an RNA produced by transcription of a gene. As used herein, a gene product can be either a nucleic acid, RNA or miRNA produced by the transcription of a gene, or a polypeptide which is translated from a transcript. Gene products described herein further include nucleic acids with post transcriptional modifications, e.g, polyadenylation or splicing, or polypeptides with post translational modifications, e.g, phosphorylation, methylation, glycosylation, the addition of lipids, association with other protein subunits, or proteolytic cleavage.

[0055] As used herein, the term "homology" refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules. Generally, the term "homology" implies an evolutionary relationship between two molecules. Thus, two molecules that are homologous will have a common evolutionary ancestor. In the context of the present disclosure, the term homology encompasses both to identity and similarity.

[0056] In some aspects, polymeric molecules are considered to be "homologous" to one another if at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the monomers in the molecule are identical (exactly the same monomer) or are similar (conservative substitutions). The term "homologous" necessarily refers to a comparison between at least two sequences ( e.g ., polynucleotide sequences).

[0057] In the context of the present disclosure, substitutions (even when they are referred to as amino acid substitution) are conducted at the nucleic acid level, i.e., substituting an amino acid residue with an alternative amino acid residue is conducted by substituting the codon encoding the first amino acid with a codon encoding the second amino acid.

[0058] As used herein, the term "identity" refers to the overall monomer conservation between polymeric molecules, e.g., between polynucleotide molecules. The term "identical" without any additional qualifiers, e.g, polynucleotide A is identical to polynucleotide B, implies the polynucleotide sequences are 100% identical (100% sequence identity). Describing two sequences as, e.g, "70% identical," is equivalent to describing them as having, e.g, "70% sequence identity."

[0059] Calculation of the percent identity of two polypeptide or polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g, gaps can be introduced in one or both of a first and a second polypeptide or polynucleotide sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain aspects, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The amino acids at corresponding amino acid positions, or bases in the case of polynucleotides, are then compared. [0060] When a position in the first sequence is occupied by the same amino acid or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.

[0061] Suitable software programs that can be used to align different sequences (e.g, polynucleotide sequences) are available from various sources. One suitable program to determine percent sequence identity is bl2seq, part of the BLAST suite of program available from the U.S. government's National Center for Biotechnology Information BLAST web site (blast.ncbi.nlm.nih.gov). B12seq performs a comparison between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. Other suitable programs are, e.g., Needle, Stretcher, Water, or Matcher, part of the EMBOSS suite of bioinformatics programs and also available from the European Bioinformatics Institute (EBI) at www.ebi.ac.uk/Tools/psa.

[0062] Sequence alignments can be conducted using methods known in the art such as

MAFFT, Clustal (ClustalW, Clustal X or Clustal Omega), MUSCLE, etc.

[0063] Different regions within a single polynucleotide or polypeptide target sequence that aligns with a polynucleotide or polypeptide reference sequence can each have their own percent sequence identity. It is noted that the percent sequence identity value is rounded to the nearest tenth. For example, 80.11, 80.12, 80.13, and 80.14 are rounded down to 80.1, while 80.15, 80.16, 80.17, 80.18, and 80.19 are rounded up to 80.2. It also is noted that the length value will always be an integer.

[0064] In certain aspects, the percentage identity (%ID) or of a first amino acid sequence

(or nucleic acid sequence) to a second amino acid sequence (or nucleic acid sequence) is calculated as %ID = 100 x (Y/Z), where Y is the number of amino acid residues (or nucleobases) scored as identical matches in the alignment of the first and second sequences (as aligned by visual inspection or a particular sequence alignment program) and Z is the total number of residues in the second sequence. If the length of a first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be higher than the percent identity of the second sequence to the first sequence.

[0065] One skilled in the art will appreciate that the generation of a sequence alignment for the calculation of a percent sequence identity is not limited to binary sequence-sequence comparisons exclusively driven by primary sequence data. It will also be appreciated that sequence alignments can be generated by integrating sequence data with data from heterogeneous sources such as structural data (e.g., crystallographic protein structures), functional data (e.g., location of mutations), or phylogenetic data. A suitable program that integrates heterogeneous data to generate a multiple sequence alignment is T-Coffee, available at www.tcoffee.org, and alternatively available, e.g, from the EBI. It will also be appreciated that the final alignment used to calculate percent sequence identity can be curated either automatically or manually.

[0066] As used herein, the terms "isolated," "purified," "extracted," and grammatical variants thereof are used interchangeably and refer to the state of a preparation of desired composition of the present disclosure, e.g., a miRNA inhibitor of the present disclosure, that has undergone one or more processes of purification. In some aspects, isolating or purifying as used herein is the process of removing, partially removing (e.g, a fraction) of a composition of the present disclosure, e.g., a miRNA inhibitor of the present disclosure from a sample containing contaminants.

[0067] In some aspects, an isolated composition has no detectable undesired activity or, alternatively, the level or amount of the undesired activity is at or below an acceptable level or amount. In other aspects, an isolated composition has an amount and/or concentration of desired composition of the present disclosure, at or above an acceptable amount and/or concentration and/or activity. In other aspects, the isolated composition is enriched as compared to the starting material from which the composition is obtained. This enrichment can be by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.9%, at least about 99.99%, at least about 99.999%, at least about 99.9999%, or greater than 99.9999% as compared to the starting material.

[0068] In some aspects, isolated preparations are substantially free of residual biological products. In some aspects, the isolated preparations are 100% free, at least about 99% free, at least about 98% free, at least about 97% free, at least about 96% free, at least about 95% free, at least about 94% free, at least about 93% free, at least about 92% free, at least about 91% free, or at least about 90% free of any contaminating biological matter. Residual biological products can include abiotic materials (including chemicals) or unwanted nucleic acids, proteins, lipids, or metabolites.

[0069] The term "linked" as used herein refers to a first amino acid sequence or polynucleotide sequence covalently or non-covalently joined to a second amino acid sequence or polynucleotide sequence, respectively. The first amino acid or polynucleotide sequence can be directly joined or juxtaposed to the second amino acid or polynucleotide sequence or alternatively an intervening sequence can covalently join the first sequence to the second sequence. The term "linked" means not only a fusion of a first polynucleotide sequence to a second polynucleotide sequence at the 5'-end or the 3'-end, but also includes insertion of the whole first polynucleotide sequence (or the second polynucleotide sequence) into any two nucleotides in the second polynucleotide sequence (or the first polynucleotide sequence, respectively). The first polynucleotide sequence can be linked to a second polynucleotide sequence by a phosphodiester bond or a linker. The linker can be, e.g., a polynucleotide.

[0070] A "miRNA inhibitor," as used herein, refers to a compound that can decrease, alter, and/or modulate miRNA expression, function, and/or activity. The miRNA inhibitor can be a polynucleotide sequence that is at least partially complementary to the target miRNA nucleic acid sequence, such that the miRNA inhibitor hybridizes to the target miRNA sequence. For instance, in some aspects, a miR-485 inhibitor of the present disclosure comprises a nucleotide sequence encoding a nucleotide molecule that is at least partially complementary to the target miR-485 nucleic acid sequence, such that the miR-485 inhibitor hybridizes to the miR-485 sequence. In further aspects, the hybridization of the miR-485 to the miR-485 sequence decreases, alters, and/or modulates the expression, function, and/or activity of miR-485 ( e.g ., hybridization results in an increase in the expression of SIRTl protein and/or SIRT1 gene).

[0071] The terms "miRNA," "miR," and "microRNA" are used interchangeably and refer to a microRNA molecule found in eukaryotes that is involved in RNA-based gene regulation. The term will be used to refer to the single-stranded RNA molecule processed from a precursor. In some aspects, the term "antisense oligomers" can also be used to describe the microRNA molecules of the present disclosure. Names of miRNAs and their sequences related to the present disclosure are provided herein. MicroRNAs recognize and bind to target mRNAs through imperfect base pairing leading to destabilization or translational inhibition of the target mRNA and thereby downregulate target gene expression. Conversely, targeting miRNAs via molecules comprising a miRNA binding site (generally a molecule comprising a sequence complementary to the seed region of the miRNA) can reduce or inhibit the miRNA-induced translational inhibition leading to an upregulation of the target gene.

[0072] The terms "mismatch" or "mismatches" refer to one or more nucleobases (whether contiguous or separate) in an oligomer nucleobase sequence (e.g., miR-485 inhibitor) that are not matched to a target nucleic acid sequence (e.g, miR-485) according to base pairing rules. While perfect complementarity is often desired, in some aspects, one or more (e.g, 6, 5, 4, 3, 2, or 1 mismatches) can occur with respect to the target nucleic acid sequence. Variations at any location within the oligomer are included. In certain aspects, antisense oligomers of the disclosure (e.g, miR-485 inhibitor) include variations in nucleobase sequence near the termini, variations in the interior, and if present are typically within about 6, 5, 4, 3, 2, or 1 subunits of the 5' and/or 3' terminus. In some aspects, one, two, or three nucleobases can be removed and still provide on- target binding.

[0073] As used herein, the terms "modulate," "modify," and grammatical variants thereof, generally refer when applied to a specific concentration, level, expression, function or behavior, to the ability to alter, by increasing or decreasing, e.g, directly or indirectly promoting/stimulating/up-regulating or interfering with/inhibiting/down-regulating the specific concentration, level, expression, function or behavior, such as, e.g, to act as an antagonist or agonist. In some instances, a modulator can increase and/or decrease a certain concentration, level, activity or function relative to a control, or relative to the average level of activity that would generally be expected or relative to a control level of activity. In some aspects, a miRNA inhibitor disclosed herein, e.g. , a miR-485 inhibitor, can modulate (e.g., decrease, alter, or abolish) miR-485 expression, function, and/or activity, and thereby, modulate SIRT1 protein or gene expression and/or activity.

[0074] "Nucleic acid," "nucleic acid molecule," "nucleotide sequence," "polynucleotide," and grammatical variants thereof are used interchangeably and refer to the phosphate ester polymeric form of ribonucleosides (adenosine, guanosine, uridine or cytidine; "RNA molecules") or deoxyribonucleosides (deoxyadenosine, deoxyguanosine, deoxythymidine, or deoxycytidine; "DNA molecules"), or any phosphoester analogs thereof, such as phosphorothioates and thioesters, in either single stranded form, or a double-stranded helix. Single stranded nucleic acid sequences refer to single-stranded DNA (ssDNA) or single-stranded RNA (ssRNA). Double stranded DNA-DNA, DNA-RNA and RNA-RNA helices are possible. The term nucleic acid molecule, and in particular DNA or RNA molecule, refers only to the primary and secondary structure of the molecule, and does not limit it to any particular tertiary forms. Thus, this term includes double-stranded DNA found, inter alia , in linear or circular DNA molecules (e.g, restriction fragments), plasmids, supercoiled DNA and chromosomes. In discussing the structure of particular double-stranded DNA molecules, sequences can be described herein according to the normal convention of giving only the sequence in the 5' to 3' direction along the non- transcribed strand of DNA (i.e., the strand having a sequence homologous to the mRNA). A "recombinant DNA molecule" is a DNA molecule that has undergone a molecular biological manipulation. DNA includes, but is not limited to, cDNA, genomic DNA, plasmid DNA, synthetic DNA, and semi -synthetic DNA. A "nucleic acid composition" of the disclosure comprises one or more nucleic acids as described herein.

[0075] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," and grammatical variations thereof, encompass any of the agents approved by a regulatory agency of the U.S. Federal government or listed in the U.S. Pharmacopeia for use in animals, including humans, as well as any carrier or diluent that does not cause the production of undesirable physiological effects to a degree that prohibits administration of the composition to a subject and does not abrogate the biological activity and properties of the administered compound. Included are excipients and carriers that are useful in preparing a pharmaceutical composition and are generally safe, non-toxic, and desirable.

[0076] As used herein, the term "pharmaceutical composition" refers to one or more of the compounds described herein, such as, e.g ., a miRNA inhibitor of the present disclosure, mixed or intermingled with, or suspended in one or more other chemical components, such as pharmaceutically acceptable carriers and excipients. One purpose of a pharmaceutical composition is to facilitate administration of preparations comprising a miRNA inhibitor of the present disclosure to a subject.

[0077] The term "polynucleotide," as used herein, refers to polymers of nucleotides of any length, including ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. [0078] In some aspects, the term refers to the primary structure of the molecule. Thus, the term includes triple-, double- and single-stranded deoxyribonucleic acid ("DNA"), as well as triple-, double- and single-stranded ribonucleic acid ("RNA"). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide.

[0079] In some aspects, the term "polynucleotide" includes polydeoxyribonucleotides

(containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), including tRNA, rRNA, shRNA, siRNA, miRNA and mRNA, whether spliced or unspliced, any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing normucleotidic backbones, for example, polyamide (e.g, peptide nucleic acids "PNAs") and polymorpholino polymers, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA.

[0080] In some aspects of the present disclosure, a polynucleotide can be, e.g, an oligonucleotide, such as an antisense oligonucleotide. In some aspects, the oligonucleotide is an RNA. In some aspects, the RNA is a synthetic RNA. In some aspects, the synthetic RNA comprises at least one unnatural nucleobase. In some aspects, all nucleobases of a certain class have been replaced with unnatural nucleobases (e.g, all uridines in a polynucleotide disclosed herein can be replaced with an unnatural nucleobase, e.g, 5-methoxyuridine).

[0081] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length, e.g. , that are encoded by the SIRTl gene. The polymer can comprise modified amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids such as homocysteine, ornithine, p-acetylphenylalanine, D- amino acids, and creatine), as well as other modifications known in the art. The term "polypeptide," as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function.

[0082] Polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing.

[0083] A polypeptide can be a single polypeptide or can be a multi-molecular complex such as a dimer, trimer or tetramer. They can also comprise single chain or multichain polypeptides. Most commonly, disulfide linkages are found in multichain polypeptides. The term polypeptide can also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid. In some aspects, a "peptide" can be less than or equal to about 50 amino acids long, e.g., about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 amino acids long.

[0084] The terms "prevent," "preventing," and variants thereof as used herein, refer partially or completely delaying onset of an disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular disease, disorder, and/or condition; partially or completely delaying progression from a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the disease, disorder, and/or condition. In some aspects, preventing an outcome is achieved through prophylactic treatment. [0085] As used herein, the terms "promoter" and "promoter sequence" are interchangeable and refer to a DNA sequence capable of controlling the expression of a coding sequence or functional RNA. In general, a coding sequence is located 3' to a promoter sequence. Promoters can be derived in their entirety from a native gene, or be composed of different elements derived from different promoters found in nature, or even comprise synthetic DNA segments. It is understood by those skilled in the art that different promoters can direct the expression of a gene in different tissues or cell types, or at different stages of development, or in response to different environmental or physiological conditions. Promoters that cause a gene to be expressed in most cell types at most times are commonly referred to as "constitutive promoters." Promoters that cause a gene to be expressed in a specific cell type are commonly referred to as "cell-specific promoters" or "tissue-specific promoters." Promoters that cause a gene to be expressed at a specific stage of development or cell differentiation are commonly referred to as "developmentally-specific promoters" or "cell differentiation-specific promoters." Promoters that are induced and cause a gene to be expressed following exposure or treatment of the cell with an agent, biological molecule, chemical, ligand, light, or the like that induces the promoter are commonly referred to as "inducible promoters" or "regulatable promoters." It is further recognized that since in most cases the exact boundaries of regulatory sequences have not been completely defined, DNA fragments of different lengths can have identical promoter activity.

[0086] The promoter sequence is typically bounded at its 3' terminus by the transcription initiation site and extends upstream (5' direction) to include the minimum number of bases or elements necessary to initiate transcription at levels detectable above background. Within the promoter sequence will be found a transcription initiation site (conveniently defined for example, by mapping with nuclease SI), as well as protein binding domains (consensus sequences) responsible for the binding of RNA polymerase. In some aspects, a promoter that can be used with the present disclosure includes a tissue specific promoter.

[0087] As used herein, "prophylactic" refers to a therapeutic or course of action used to prevent the onset of a disease or condition, or to prevent or delay a symptom associated with a disease or condition.

[0088] As used herein, a "prophylaxis" refers to a measure taken to maintain health and prevent the onset of a disease or condition, or to prevent or delay a symptom associated with a disease or condition.

[0089] As used herein, the term "gene regulatory region" or "regulatory region" refers to nucleotide sequences located upstream (5' non-coding sequences), within, or downstream (3' non coding sequences) of a coding region, and which influence the transcription, RNA processing, stability, or translation of the associated coding region. Regulatory regions can include promoters, translation leader sequences, introns, polyadenylation recognition sequences, RNA processing sites, effector binding sites, or stem-loop structures. If a coding region is intended for expression in a eukaryotic cell, a polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence. [0090] In some aspects, a miR-485 inhibitor disclosed herein ( e.g ., a polynucleotide encoding a RNA comprising one or more miR-485 binding site) can include a promoter and/or other expression (e.g., transcription) control elements operably associated with one or more coding regions. In an operable association a coding region for a gene product is associated with one or more regulatory regions in such a way as to place expression of the gene product under the influence or control of the regulatory region(s). For example, a coding region and a promoter are "operably associated" if induction of promoter function results in the transcription of mRNA encoding the gene product encoded by the coding region, and if the nature of the linkage between the promoter and the coding region does not interfere with the ability of the promoter to direct the expression of the gene product or interfere with the ability of the DNA template to be transcribed. Other expression control elements, besides a promoter, for example enhancers, operators, repressors, and transcription termination signals, can also be operably associated with a coding region to direct gene product expression.

[0091] As used herein, the term "similarity" refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. miRNA molecules). Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art. It is understood that percentage of similarity is contingent on the comparison scale used, i.e., whether the nucleic acids are compared, e.g, according to their evolutionary proximity, charge, volume, flexibility, polarity, hydrophobicity, aromaticity, isoelectric point, antigenicity, or combinations thereof. [0092] The terms "subject," "patient," "individual," and "host," and variants thereof are used interchangeably herein and refer to any mammalian subject, including without limitation, humans, domestic animals (e.g, dogs, cats and the like), farm animals (e.g, cows, sheep, pigs, horses and the like), and laboratory animals (e.g, monkey, rats, mice, rabbits, guinea pigs and the like) for whom diagnosis, treatment, or therapy is desired, particularly humans. The methods described herein are applicable to both human therapy and veterinary applications.

[0093] As used herein, the phrase "subject in need thereof includes subjects, such as mammalian subjects, that would benefit from administration of a miRNA inhibitor of the disclosure (e.g, miR-485 inhibitor), e.g, to increase the expression level of SIRT1 protein and/or SIRTl gene.

[0094] As used herein, the term "therapeutically effective amount" is the amount of reagent or pharmaceutical compound comprising a miRNA inhibitor of the present disclosure that is sufficient to a produce a desired therapeutic effect, pharmacologic and/or physiologic effect on a subject in need thereof. A therapeutically effective amount can be a "prophylactically effective amount" as prophylaxis can be considered therapy.

[0095] The terms "treat," "treatment," or "treating," as used herein refers to, e.g., the reduction in severity of a disease or condition; the reduction in the duration of a disease course; the amelioration or elimination of one or more symptoms associated with a disease or condition (e.g., diabetes); the provision of beneficial effects to a subject with a disease or condition, without necessarily curing the disease or condition. The term also includes prophylaxis or prevention of a disease or condition or its symptoms thereof.

[0096] The term "upstream" refers to a nucleotide sequence that is located 5' to a reference nucleotide sequence.

[0097] A "vector" refers to any vehicle for the cloning of and/or transfer of a nucleic acid into a host cell. A vector can be a replicon to which another nucleic acid segment can be attached so as to bring about the replication of the attached segment. A "replicon" refers to any genetic element (e.g, plasmid, phage, cosmid, chromosome, virus) that functions as an autonomous unit of replication in vivo , i.e., capable of replication under its own control. The term "vector" includes both viral and nonviral vehicles for introducing the nucleic acid into a cell in vitro, ex vivo or in vivo. A large number of vectors are known and used in the art including, for example, plasmids, modified eukaryotic viruses, or modified bacterial viruses. Insertion of a polynucleotide into a suitable vector can be accomplished by ligating the appropriate polynucleotide fragments into a chosen vector that has complementary cohesive termini.

[0098] Vectors can be engineered to encode selectable markers or reporters that provide for the selection or identification of cells that have incorporated the vector. Expression of selectable markers or reporters allows identification and/or selection of host cells that incorporate and express other coding regions contained on the vector. Examples of selectable marker genes known and used in the art include: genes providing resistance to ampicillin, streptomycin, gentamycin, kanamycin, hygromycin, bialaphos herbicide, sulfonamide, and the like; and genes that are used as phenotypic markers, i.e., anthocyanin regulatory genes, isopentanyl transferase gene, and the like. Examples of reporters known and used in the art include: luciferase (Luc), green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT), b-galactosidase (LacZ), b-glucuronidase (Gus), and the like. Selectable markers can also be considered to be reporters. II. Single Nucleotide Polymorphism (SNP) Biomarkers for Patient Selection [0099] SNP screening can be used for patient screening to identify patients likely to be responsive to the mir-485 inhibitors of the disclosure, and also to identify patients who are not likely to respond to the mir-485 inhibitor of the disclosure, to respond poorly, or to present adverse reactions or side effects. Accordingly, the present disclosure provides a method of treating a neurodegenerative disease or disorder (e.g., Alzheimer’s disease or Parkinson’s disease) in a subject in need thereof comprising administering a mir-485 inhibitor disclosed herein to the subject, wherein the subject is identified as not having at least one pathogenic non- synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 (Cluster of Differentiation 36), GRIA4 (glutamate ionotropic receptor AMP A type subunit 4), NRXN1 (neurexin 1), and VLDLR (very low density lipoprotein receptor).

[0100] As used herein, the term "pathogenic non-synonymous SNP" refers to a non- synonymous SNP, i.e., an SNP that changes the protein sequence, that has been linked to a particular neurodegenerative disease (e.g., Alzheimer’s disease or Parkinson’s disease) by at least one peer reviewed study.

[0101] CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), Illb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.

[0102] GRIA4 (Glutamate receptor 4) is a protein that in humans is encoded by the

GRIA4 gene. This gene is a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA). Some haplotypes of this gene show a positive association with schizophrenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

[0103] NRXN1 (Neurexin- 1 -alpha) is a protein that in humans is encoded by the NRXN1 gene. Neurexins are a family of proteins that function in the vertebrate nervous system as cell adhesion molecules and receptors. They are encoded by several unlinked genes of which two, NRXN1 and NRXN3, are among the largest known human genes. Three of the genes (NRXN1- 3) utilize two alternate promoters and include numerous alternatively spliced exons to generate thousands of distinct mRNA transcripts and protein isoforms. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms; a much smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins.

[0104] VLDLR (very-low-density-lipoprotein receptor) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family encoded by the VLDRL gene. VLDLR shows considerable homology with the members of this lineage. VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. Mutations of the VLDRL gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

[0105] The present disclosure also provides a method of treating a neurodegenerative disease or disorder (e.g., Alzheimer’s disease or Parkinson’s disease) in a subject in need thereof comprising (i) identifying a subject as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRLA4 , NRXN1 , and VLDLR ; and (ii) administering a mir-485 inhibitor to the subject, e.g., a mir-485 inhibitor disclosed herein.

[0106] Also provided is a method of identifying a human subject afflicted with a neurodegenerative disease or condition (e.g., Alzheimer’s disease or Parkinson’s disease) as suitable for treatment with a mir-485 inhibitor, e.g., a mir-485 inhibitor disclosed herein, comprising determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRLA4 , NRXN1 , and VLDLR , wherein (a) the presence of at least one pathogenic non-synonymous SNP in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is not suitable for treatment with a mir-485 inhibitor; and, (b) the absence of pathogenic non-synonymous SNPs in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is suitable for treatment with a mir-485 inhibitor. In some aspects, the method further comprises administering a mir-485 inhibitor to the subject. [0107] In some aspects, at least one pathogenic nonsynonymous SNP is in CD36. Thus, in some aspects, the at least one pathogenic nonsynonymous SNP in CD36 can comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pathogenic nonsynonymous SNPs. In some aspects, the method disclosed comprises determining the absence or presence of one pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of two pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of three pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of four pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of five pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of six pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of seven pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of eight pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of nine pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of ten pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 11 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 12 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 13 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 14 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 15 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 16 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 17 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 18 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 19 pathogenic nonsynonymous SNP in CD36. In some aspects, the method disclosed comprises determining the absence or presence of 20 pathogenic nonsynonymous SNP in CD36. [0108] For clarity, the SNPs disclosed herein have been named using the source gene

(e.g., CD36 ), followed by the SNP description (e.g., c.330_331C>A), and between parenthesis the dbSNP database identifier, e.g., CD36 c.H55del (rs765809606).

[0109] Accordingly, in some aspects, the at least one pathogenic nonsynonymous SNP in

CD36 is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 c.H56C>T (rsl48910227), CD36 c 1228_1239del

(rs550565800), CD36 c.949dup (rs70961716), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), and any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in CD36 is a substitution SNP, e.g., CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rsl48910227), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), or a combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in CD36 is a deletion SNP, e.g., CD36 c 1228_1239del (rs550565800), and/or CD36 c.H55del (rs765809606). In some aspects, the at least one pathogenic nonsynonymous SNP in CD36 is a duplication SNP, e.g., CD36 c.949dup (rs70961716) and/or CD36 c.784dup (rs766920034),

[0110] In some aspects, the at least one pathogenic nonsynonymous SNP is in GRIA4. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises 1, 2, 3, 4 or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises one pathogenic nonsynonymous SNP. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises two pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises three pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises four pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 comprises five pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 is selected from the group consisting of GRIA4 c.2090G>C (rs765556214), GRIA4 c 1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.19310T (rsl555050174), and any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in GRIA4 is substitution SNP, e.g., GRIA4 c.2090G>C (rs765556214), GRIA4 C.1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.19310T (rsl555050174), or a combination thereof. [0111] In some aspects, the at least one pathogenic nonsynonymous SNP is in NRXN1. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises one pathogenic nonsynonymous SNP. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises two pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises three pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises four pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises five pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises six pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises seven pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises eight pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises nine pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises ten pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 comprises eleven pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is selected from the group consisting of NRXN1 C.37570T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA

(rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 C.37690T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del (rsl558925686), NRXN1 c.H9G>A (rs 1064795493), and any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is a substitution SNP, e.g., NRXN1 C.37570T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 C.37690T (rs 1002820022), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.H9G>A (rs 1064795493), or any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is a duplication SNP, e.g., NRXN1 c.4291_4294dup (rsl558507406) and/or NRXN1 c.3845dup (rsl553535216). In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is a deletion-insertion SNP, e.g., NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438). In some aspects, the at least one pathogenic nonsynonymous SNP in NRXN1 is a deletion SNP, e.g., NRXN1 c.1551 1555del (rsl558925686) and/or NRXN1 c.2888del (rs796052787).

[0112] In some aspects, the at least one pathogenic nonsynonymous SNP is in VLDLR. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises one pathogenic nonsynonymous SNP. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises two pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises three pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises four pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises five pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises six pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR comprises seven pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR are selected from the group consisting of VLDLR c 1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.l041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR is a substitution SNP, e.g., VLDLR C.1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.2117G>T (rs397514750), or a combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP in VLDLR is a deletion SNP, e.g., VLDLR c.l041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2339del (rs80338906), or a combination thereof.

[0113] In some aspects the at least one pathogenic nonsynonymous SNP comprises 1, 2,

3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

31, or 32 pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP comprises between about 5 and about 10, between about 10 and about 15, between about 15 and about 20, between about 20 and about 25, between about 25 and about 30, between about 5 and about 15, between about 10 and about 20, between about 20 and about 30, between about 5 and about 20, between about 10 and about 25, between about 15 and about 30, between about 5 and about 25, between about 10 and about 30, or between about 5 and about 30, pathogenic nonsynonymous SNPs. In some aspects, the at least one pathogenic nonsynonymous SNP comprises at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30, e.g., 32, pathogenic nonsynonymous SNPs.

[0114] In some aspects, the at least one pathogenic nonsynonymous SNP is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c,1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c,1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 C.1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 c,1928C>G (rsl555050171), GRIA4 c,1931C>T (rsl555050174), NRXNl c.3757C>T (rsl201575289), NRXN1 c.2936C>G (rs267606922), NRXNl c.4291_4294dup (rsl558507406), NRXNl c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXNl c.3845dup (rsl553535216), NRXNl c.3769C>T (rs 1002820022), NRXNl c.2888del (rs796052787), NRXNl c.2832T>G (rsl057521798), NRXNl c.2085G>A (rsl553759318), NRXNl c.1551 1555del

(rsl558925686), NRXNl c.H9G>A (rsl064795493), VLDLR c,1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR c,1342C>T (rs80338905), VLDLR c.l041_1045del (rsl554621211), VLDLR c,1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 , pathogenic nonsynonymous SNPs selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rsl48910227), CD36 c,1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c,1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c,1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165),

GRIA4 C.19280G (rsl555050171), GRIA4 c,1931C>T (rsl555050174), NRXNl c.3757C>T (rsl201575289), NRXNl c.2936C>G (rs267606922), NRXNl c.4291_4294dup (rsl558507406), NRXNl c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXNl c.3845dup (rsl553535216), NRXNl c.3769C>T (rs 1002820022), NRXNl c.2888del (rs796052787), NRXNl c.2832T>G (rsl057521798), NRXNl c.2085G>A (rsl553759318), NRXNl c.1551 1555del (rsl558925686), NRXNl c.H9G>A (rsl064795493), VLDLR c,1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.l041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906),

[0115] In some aspects, the at least one pathogenic nonsynonymous SNP is a substitution

SNP, a duplication SNP, a deletion SNP, a deletion-insertion SNP, or a combination thereof. In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitution SNPs. In some aspects, the substitution SNPs are selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), GRIA4 c.2090G>C (rs765556214), GRIA4 c 1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.1931C>T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.3769C>T (rs 1002820022), NRXNl c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXNl c.H9G>A (rsl064795493), VLDLR c 1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.2117G>T (rs397514750), and any combinations thereof.

[0116] In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2,

3 or 4 duplication SNPs. In some aspects, the duplication SNP are selected from the group consisting of CD36 c.949dup (rs70961716), CD36 c.784dup (rs766920034), NRXNl c.4291_4294dup (rsl558507406), NRXNl c.3845dup (rsl553535216), and any combinations thereof.

[0117] In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1, 2,

3, 4, 5, 6 or 7 deletion SNPs. In some aspects, the deletion SNPs are selected from the group consisting of CD36 c 1228_1239del (rs550565800), CD36 c.H55del (rs765809606), NRXNl c.2888del (rs796052787), NRXNl c.1551 1555del (rsl558925686), VLDLR c.l041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2339del (rs80338906) and any combinations thereof.

[0118] In some aspects, the at least one pathogenic nonsynonymous SNP comprises 1 deletion-insertion SNP. In some aspects, the deletion-insertion SNP is NRXNl c.4173_4188delinsGTGTCCCTAA (rsl 553400438).

[0119] In some aspects of the methods disclosed herein, the subject selected for treatment with a mir-485 miRNA inhibitor of the present disclosure (or a combination thereof) exhibits improvement in at least a symptom or sequela of the disease or condition (e.g., a symptom of Alzheimer’s disease or Parkinson’s disease) compared to a subject not treated with the mir-485 miRNA inhibitor of the present disclosure (or a combination thereof). In some aspects of the methods disclosed herein, the subject selected for treatment with a mir-485 miRNA inhibitor of the present disclosure (or a combination thereof) exhibits improvement in at least a symptom or sequela of the disease or condition (e.g., a symptom of Alzheimer’s disease or Parkinson’s disease) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to a subject not treated with the mir-485 miRNA inhibitor of the present disclosure (or a combination thereof). In some aspects of the methods disclosed herein, the subject selected for treatment with a mir-485 miRNA inhibitor of the present disclosure (or a combination thereof) exhibits improvement in at least a symptom or sequela of the disease or condition (e.g., a symptom of Alzheimer’s disease or Parkinson’s disease) by at least about 1- fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10- fold compared to a subject not treated with the mir-485 miRNA inhibitor of the present disclosure (or a combination thereof).

[0120] In some aspects, the subject selected for treatment with a mir-485 miRNA inhibitor of the present disclosure (or a combination thereof) exhibits improvement in overall survival or progression free survival compared to a subject not treated with a mir-485 miRNA inhibitor of the present disclosure (or a combination thereof).

[0121] In some aspects, the methods disclosed herein further comprises measuring, e.g., the expression level (e.g., mRNA levels and/or protein levels) of SIRT1 (sirtuin 1), GRIA4 , PPARGC1A (PPARG coactivator 1 alpha), NRG1 (neuregulin 1), NRXN1, NXPH1 (neurexophilin 1), CD36 , VLDLR , or a combination thereof. In some aspects, the methods disclosed herein further comprises measuring, e.g., the expression level (e.g., mRNA levels and/or protein levels) of a mir-485 miRNA inhibitor target disclosed herein, e.g., SIRT1, PGC- la, CD36, LRRK2, NRGl, STMN2, or a combination. In some aspects, expression levels (e.g., mRNA levels and/or protein levels) are measured prior to the administration of a mir-485 miRNA inhibitor of the present disclosure, for example, to determine whether the subject is eligible for administration of a mir-485 miRNA inhibitor of the present disclosure (for example, to determine if a gene is down-regulated in the subject may benefit by up-regulating the gene via administration of a mir-485 mRNA inhibitor). In some aspects, expression levels (e.g., mRNA levels and/or protein levels) are measured after the administration of a mir-485 miRNA inhibitor of the present disclosure, for example, to determine whether downregulation of mir-485 mRNA via administration of a mir-485 mRNA inhibitor up-regulates the expression a target gene. If administration of the mir-485 mRNA inhibitor causes the intended effect, treatment would continue. If despite administration of the mir-485 mRNA inhibitor, the intended effect is not observed, or undesirable side effects (adverse effects) are observed, treatment with the mir-485 mRNA inhibitor may be suspended or modified, and, e.g., be replaced with an alternative therapy o co-therapy. In some aspects, expression levels (e.g., mRNA levels and/or protein levels) are measured before and after the administration of the mir-485 mRNA inhibitor. Expression levels, e.g., levels of mRNA or levels of protein of the genes disclosed herein can be determined using methods known in the art, for example, using commercial kits and following the manufacturer’s instructions.

[0122] In some aspects, the mir-485 inhibitor targets SIRT1 , GRIA4 , PPARGC1A ( PGC - la), NRG1 , NRXN1, NXPH1, CD 36, VLDLR, LRRK2, STMN2, or a combination thereof.

[0123] In some aspects, the neurodegenerative disease or condition is associated with an abnormal level of SIRT1, GRIA4, PPARGC1A , NRG1, NRXN1, NXPH1, CD36, VLDLR, or a combination thereof, e.g., Alzheimer’s disease, or Parkinson’s disease.

[0124] In some aspects, the mir-485 miRNA inhibitor inhibits miR485-3p, wherein the miR485-3p comprises the sequence 5'-gucauacacggcucuccucucu-3' (SEQ ID NO:l). In some aspects, the mir-485 miRNA inhibitor comprises a nucleotide sequence comprising 5'- UGUAUGA- 3', wherein the miRNA inhibitor comprises about 6 to about 30 nucleotides in length. In some aspects, the mir-485 miRNA inhibitor increases transcription of an SIRT1 gene and/or expression of a SIRT1 protein. In some aspects, the mir-485 miRNA inhibitor increases SIRT1, PGC-la, CD36, LRRK2, NRG1, and/or STMN2 protein or gene expression, as disclosed more in detail below.

[0125] In some aspects, the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 5' of the 5'- UGUAUGA-3' nucleotide sequence. In some aspects, the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 3' of the 5'- UGUAUGA-3' nucleotide sequence.

[0126] In some aspects, the mir-485 miRNA inhibitor comprises a sequence selected from the group consisting of: 5'-UGUAUGA-3', 5'-GUGUAUGA-3', 5'-CGUGUAUGA-3', 5'- CCGUGUAUGA-3' (SEQ ID NO:2), 5'-GCCGUGUAUGA-3' (SEQ ID NO:3), 5'-

[0127] In some aspects, the miR-485 miRNA inhibitor comprises a sequence selected from the group consisting of: 5'-TGTATGA-3', 5'-GTGTATGA-3', 5'-CGTGTATGA-3', 5'- CCGTGTATGA-3' (SEQ ID NO:25), 5'-GCCGTGTATGA-3' (SEQ ID NO:26), 5'- AGCCGTGTATGA-3' (SEQ ID NO:27), 5'-GAGCCGTGTATGA-3' (SEQ ID NO:28), 5'- AGAGCCGTGTATGA-3' (SEQ ID NO:29), 5'-GAGAGCCGTGTATGA-3' (SEQ ID NO:30), 5'-GGAGAGCCGTGTATGA-3' (SEQ ID NO:31), 5 ' - AGGAGAGCC GT GT AT GA-3 ' (SEQ ID NO:32), 5'-GAGGAGAGCCGTGTATGA-3' (SEQ ID NO:33), 5'-

AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:34), 5 ' -G AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:35); 5'-TGTATGAC-3', 5'-GTGTATGAC-3', 5'-CGTGTATGAC-3' (SEQ ID NO:36), 5'-CCGTGTATGAC-3' (SEQ ID NO:37), 5'-GCCGTGTATGAC-3' (SEQ ID NO:38), 5'-AGCCGTGTATGAC-3' (SEQ ID NO:39), 5'-GAGCCGTGTATGAC-3' (SEQ ID NO:40), 5'- AGAGCCGTGTATGAC-3' (SEQ ID NO:41), 5'-GAGAGCCGTGTATGAC-3' (SEQ ID NO:42), 5'-GGAGAGCCGTGTATGAC-3' (SEQ ID NO:43), 5 ' - AGGAGAGCCGT GT AT GAC -3 ' (SEQ ID NO:44), 5'-GAGGAGAGCCGTGTATGAC-3' SEQ ID NO:45), 5'-

AGAGGAGAGCCGTGTATGAC-3 ' (SEQ ID NO:46), and 5'- G AG AGG AG AGC C GT GT AT GAC - 3 ' (SEQ ID NO:47).

[0128] In some aspects, the mir-485 miRNA inhibitor consists or consists essentially of a sequence selected from the group consisting of: 5'-UGUAUGA-3', 5'-GUGUAUGA-3', 5'- CGUGUAUGA-3', 5'-CCGUGUAUGA-3' (SEQ ID NO:2), 5'-GCCGUGUAUGA-3' (SEQ ID NO:3), 5'-AGCCGUGUAUGA-3' (SEQ ID NO:4), 5'-GAGCCGUGUAUGA-3' (SEQ ID NO:5), 5'-AGAGCCGUGUAUGA-3' (SEQ ID NO:6), 5'-GAGAGCCGUGUAUGA-3' (SEQ ID NO:7), 5'-GGAGAGCCGUGUAUGA-3' (SEQ ID NO: 8), 5'-AGGAGAGCCGUGUAUGA-3' (SEQ ID NO:9), 5'-GAGGAGAGCCGUGUAUGA-3' (SEQ ID NO: 10), 5'-

[0129] In some aspects, mir-485 miRNA inhibitor consists or consists essentially of a sequence selected from the group consisting of: 5'-TGTATGA-3', 5'-GTGTATGA-3', 5'- CGTGTATGA-3', 5'-CCGTGTATGA-3' (SEQ ID NO:25), 5'-GCCGTGTATGA-3' (SEQ ID NO:26), 5'-AGCCGTGTATGA-3' (SEQ ID NO:27), 5 '-GAGCCGT GT AT GA-3 ' (SEQ ID NO:28), 5'-AGAGCCGTGTATGA-3' (SEQ ID NO:29), 5'-GAGAGCCGTGTATGA-3' (SEQ ID NO:30), 5'-GGAGAGCCGTGTATGA-3' (SEQ ID NO:31), 5 ' - AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:32), 5'-GAGGAGAGCCGT GT AT GA-3 ' (SEQ ID NO:33), 5'-

AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:34), 5 ' -GAG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:35); 5'-TGTATGAC-3', 5'-GTGTATGAC-3', 5'-CGTGTATGAC-3' (SEQ ID NO:36), 5'-CCGTGTATGAC-3' (SEQ ID NO:37), 5'-GCCGTGTATGAC-3' (SEQ ID NO:38), 5'-AGCCGTGTATGAC-3' (SEQ ID NO:39), 5'-GAGCCGTGTATGAC-3' (SEQ ID NO:40), 5'- AGAGCCGTGTATGAC-3' (SEQ ID NO:41), 5'-GAGAGCCGTGTATGAC-3' (SEQ ID NO:42), 5'-GGAGAGCCGTGTATGAC-3' (SEQ ID NO:43), 5 ' - AGGAGAGCCGT GT AT GAC -3 ' (SEQ ID NO:44), 5'-GAGGAGAGCCGTGTATGAC-3' SEQ ID NO:45), 5'-

AGAGGAGAGCCGTGTATGAC-3 ' (SEQ ID NO:46), and 5'-

G AG AGG AG AGC C GT GT AT G AC - 3 ' (SEQ ID NO:47)

[0130] In some aspects, the sequence of the mir-485 miRNA inhibitor is at least about

50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AG AGG AG AGC C GT GT AT G AC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor has a sequence that has at least 90% similarity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AG AGG AG AGC C GT GT AT G AC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'-

AG AGG AG AGC C GT GT AT G AC -3' (SEQ ID NO:46). In some aspects, the mir-485 miRNA inhibitor consists or consist essentially of the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'-

AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO:46). In some aspects, the the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23). In some aspects, the miR-485 miRNA inhibitor consists or consist essentially of the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:46). Additional mir-485 miRNA inhibitor compositions and method of use are disclosed more in detail below.

[0131] In some aspects, the mir-485 miRNA inhibitor comprises at least one modified nucleotide, e.g., a locked nucleic acid (LNA), an unlocked nucleic acid (UNA), an arabino nucleic acid (ABA), a bridged nucleic acid (BNA), and/or a peptide nucleic acid (PNA). In some aspects, the mir-485 miRNA inhibitor comprises a backbone modification. In some aspects, the backbone modification is a phosphorodiamidate morpholino oligomer (PMO) and/or phosphorothioate (PS) modification. Additional mir-485 miRNA inhibitor modifications are disclosed more in detail below.

[0132] In some aspects, the mir-485 miRNA inhibitor is delivered in a delivery agent. In some aspects, the delivery agent is a micelle, an exosome, a lipid nanoparticle, an extracellular vesicle, or a synthetic vesicle. In some aspects, the micelle comprises a cationic carrier disclosed herein. Delivery systems comprising, e.g., cationic carriers, are disclosed more in detail below.

III. Methods of Use of miR-485 inhibitors

[0133] In some aspects, miR-485 inhibitors of the present disclosure can exert therapeutic effects (e.g., in a subject suffering from a neurodegenerative disease) by regulating the expression and/or activity of one or more genes. As described herein, in some aspects, miR-485 inhibitors disclosed herein are capable of regulating the expression and/or activity of a gene selected from SIRT1, CD36, PGC1, LRRK2, NRG1, STMN2, or combinations thereof. Not to be bound by any one theory, through such regulation, the miR-485 inhibitors can affect many biological processes, including, but not limited to, cellular homeostasis (e.g, CD36, SIRTl, PGCla), protein homeostasis (e.g, LRRK2 and SIRTl), those associated with the autophagy- lysosomal pathway (e.g, SIRTl and CD36), phagocytosis (e.g, CD36), glial biology (e.g, CD36 and SIRTl), neurogenesis/synaptogenesis (e.g, SIRTl, PGCla, STMN2, and NRGl) neuroinflammation (e.g, CD36 and SIRTl), those associated with the mitochondria (e.g, PGCla), and combinations thereof (e.g, SIRTl and PGCla).

SIRTl Regulation

[0134] In some aspects, the present disclosure provides a method of increasing an expression of a SIRTl protein and/or a SIRTl gene in a subject in need thereof, comprising administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a SIRTl protein and/or SIRTl gene in the subject. In some aspects, the method comprises determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1, and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of SIRTl prior and/or after the administration of the miR-485 inhibitor.

[0135] Sirtuin 1 (SIRTl), also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRTl gene. The SIRTl gene is located on chromosome 10 in humans (nucleotides 67,884,656 to 67,918,390 of GenBank Accession Number NC_000010.11, plus strand orientation). Synonyms of the SIRTl gene, and the encoded protein thereof, are known and include "regulatory protein SIR2 homolog 1," "silent mating-type information regulation 2 homolog 1," "SIR2," "SIR2-Like Protein 1," "SIR2L1," "SIR2alpha," "Sirtuin Type 1," "hSIRTl," or "hSIR2." [0136] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of SIRT1 protein and/or SIRT1 gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference (e.g, expression of SIRT1 protein and/or SIRT1 gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor).

[0137] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of SIRT1 protein and/or SIRT1 gene by reducing the expression and/or activity of miR-485, e.g., miR-485-3p. In some aspects, a miR-485 inhibitor of the present disclosure can reduce the expression and/or activity of miR-485-3p.

[0138] As described herein, a miR-485 inhibitor of the present disclosure can increase the expression of SIRT1 protein and/or SIRT1 gene when administered to a subject. Accordingly, in some aspects, the present disclosure provides a method of treating a disease or condition associated with an abnormal (e.g, reduced) level of a SIRTl protein and/or SIRTl gene in a subject in need thereof. In certain aspects, the method comprises administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor), wherein the miR-485 inhibitor increases the level of the SIRTl protein and/or SIRTl gene.

CD 36 Regulation

[0139] As described herein, Applicant has identified that the human CD36 3'-UTR comprises a target site for miR-485-3p and that the binding of miR-485-3p can decrease CD36 expression (see, e.g, Examples 7 and 8). Accordingly, in some aspects, the present disclosure provides a method of increasing an expression of a CD36 protein and/or a CD36 gene in a subject in need thereof, comprising administering to the subject a compound that inhibits miR- 485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a CD36 protein and/or CD36 gene in the subject. In some aspects, the method comprises determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1, and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of CD36 prior and/or after the administration of the miR-485 inhibitor.

[0140] Cluster determinant 36 (CD36) is also known as platelet glycoprotein 4, is a protein that in humans is encoded by the CD36 gene. The CD36 gene is located on chromosome 7 (nucleotides 80,602,656 to 80,679,277 of GenBank Accession Number NC_000007.14, plus strand orientation). Synonyms of the CD36 gene, and the encoded protein thereof, are known and include "platelet glycoprotein IV," "fatty acid translocase," "scavenger receptor class B member 3," "glycoprotein 88," "glycoprotein Illb," "glycoprotein IV," "thrombospondin receptor," "GPIIIB," "PAS IV," "GP3B," "GPIV," "FAT," "GP4," "BDPLT10," "SCARB3," "CHDS7," "PASIV," or "PAS-4."

[0141] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of CD36 protein and/or CD36 gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference (e.g, expression of CD36 protein and/or CD36 gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor).

[0142] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of CD36 protein and/or CD36 gene by reducing the expression and/or activity of miR-485. There are two known mature forms of miR-485: miR-485-3p and miR-485-5p. As disclosed herein, in some aspects, a miR-485 inhibitor of the present disclosure can reduce the expression and/or activity of miR-485-3p. In some aspects, a miR-485 inhibitor can reduce the expression and/or activity of miR-485-5p. In further aspects, a miR-485 inhibitor disclosed herein can reduce the expression and/or activity of both miR-485-3p and miR-485-5p. PGC1 Regulation

[0143] The disclosures provided herein demonstrates that the miR-485 inhibitors of the present disclosure can further regulate the expression of PGC-Ia, e.g. , in a subject suffering from a disease or disorder disclosed herein (see, e.g, Example 3). Therefore, in some aspects, the present disclosure provides a method of increasing an expression of a PGC-Ia protein and/or a PGC-Ia gene in a subject in need thereof, comprising administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a PGC-Ia protein and/or PGC-Ia gene in the subject. In some aspects, the method comprises determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1, and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of PGC-Ia prior and/or after the administration of the miR-485 inhibitor. [0144] Peroxisome proliferator-activated receptor gamma coactivator 1 -alpha (PGCl-a), also known as PPARG Coactivator 1 Alpha or Ligand Effect Modulator-6, is a protein that in humans is encoded by the PPARGC1A gene. The PGCl-a gene is located on chromosome 4 in humans (nucleotides 23,792,021 to 24,472,905 of GenBank Accession Number NC_000004.12, plus strand orientation). Synonyms of the PGCl-a gene, and the encoded protein thereof, are known and include "PPARGC1A," "LEM6," "PGC1," "PGC1A," "PGC-lv," "PPARGCl, "PGC1 alpha," or "PGC-l(alpha)."

[0145] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of PGCl-a protein and/or PGCl-a gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference (e.g, expression of PGCl-a protein and/or PGCl-a gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor).

[0146] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of PGCl-a protein and/or PGCl-a gene by reducing the expression and/or activity of miR-485. There are two known mature forms of miR-485: miR- 485-3p and miR-485-5p. In some aspects, a miR-485 inhibitor of the present disclosure can reduce the expression and/or activity of miR-485-3p. In some aspects, a miR-485 inhibitor can reduce the expression and/or activity of miR-485-5p. In further aspects, a miR-485 inhibitor disclosed herein can reduce the expression and/or activity of both miR-485-3p and miR-485-5p. LRRK2 Regulation

[0147] In some aspects, the disclosures provided herein demonstrates that the miR-485 inhibitors of the present disclosure can further regulate the expression of LRRK2, e.g. , in a subject suffering from a disease or disorder disclosed herein (e.g, Parkinson's disease). Therefore, in some aspects, the present disclosure provides a method of increasing an expression of a LRRK2 protein and/or a LRRK2 gene in a subject in need thereof, comprising administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a LRRK2 protein and/or LRRK2 gene in the subject. . In some aspects, the method comprises determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1 , and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of LRRK2 prior and/or after the administration of the miR-485 inhibitor.

[0148] Leucine-rich repeat kinase 2 (LRRK2) is a kinase enzyme that in humans is encoded by the LRRK2 gene. The LRRK2 gene is located on chromosome 12 in humans (nucleotides 40,224,890 to 40,369,285 of GenBank Accession Number NC_000012.12, plus strand orientation). Synonyms of the LRRK2 gene, and the encoded protein thereof, are known and include PARK8, RIPK7, ROC02, AURA 17, and DARDARIN.

[0149] As used herein, the term "LRRK2" includes any variants or isoforms of LRRK2 which are naturally expressed by cells.

[0150] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of LRRK2 protein and/or LRRK2 gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference (e.g., expression of LRRK2 protein and/or LRRK2 gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor).

[0151] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of LRRK2 protein and/or LRRK2 gene by reducing the expression and/or activity of miR-485, e.g, miR-485-3p.

NRG1 Regulation

[0152] The disclosures provided herein demonstrates that the miR-485 inhibitors of the present disclosure can further regulate the expression of NRGl, e.g, in a subject suffering from a disease or disorder disclosed herein (see, e.g, Parkinson's disease). Therefore, in some aspects, the present disclosure provides a method of increasing an expression of a NRGl protein and/or a NRGl gene in a subject in need thereof, comprising administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a NRGl protein and/or NRGl gene in the subject. . In some aspects, the method comprises determining the presence or absence of at least one pathogenic non- synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1, and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of NRGl prior and/or after the administration of the miR-485 inhibitor. [0153] Neuregulin 1 is a cell adhesion molecule that in humans is encoded by the NRGl gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. The NRG1 gene is located on chromosome 8 in humans (nucleotides 31,639,245 to 32,774,046 of GenBank Accession Number NC_000008.11). Synonyms of the NRG1 gene, and the encoded protein thereof, are known and include "GGF," "HGL," "HRG," "NDF," "ARIA," "GGF2," "HRG1," "HRGA," "SMDF," "MST131," "MSTP131," and "NRG1-IT2."

[0154] As used herein, the term "NRGl" includes any variants or isoforms of NRG 1 which are naturally expressed by cells. Accordingly, in some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 1 (i.e., canonical sequence). In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 2. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 3. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 4. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 6. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 7. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 8. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 9. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 10. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 11. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 12. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of NRGl isoform 1, NRGl isoform 2, NRGl isoform 3, NRGl isoform 4, NRGl isoform 6, NRGl isoform 7, NRGl isoform 8, NRGl isoform 9, NRGl isoform 10, NRGl isoform 11, and NRGl isoform 12. Unless indicated otherwise, the above-described isoforms of NRGl are collectively referred to herein as "NRGl."

[0155] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of NRGl protein and/or NRGl gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference ( e.g ., expression of NRGl protein and/or NRGl gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor). [0156] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of NRGl protein and/or NRGl gene by reducing the expression and/or activity of miR-485, e.g., miR-485-3p.

STMN2 Regulation

[0157] The disclosures provided herein demonstrates that the miR-485 inhibitors of the present disclosure can further regulate the expression of STMN2, e.g. , in a subject suffering from a disease or disorder disclosed herein (see, e.g, Parkinson's disease). Therefore, in some aspects, the present disclosure provides a method of increasing an expression of a STMN2 protein and/or a STMN2 gene in a sub _ ject in need thereof, comprising administering to the subject a compound that inhibits miR-485 activity (i.e., miR-485 inhibitor). In certain aspects, inhibiting miR-485 activity increases the expression of a STMN2 protein and/or STMN2 gene in the subject. . In some aspects, the method comprises determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36, GRIA4, NRXN1, and VLDLR. In some aspects, the method comprises measuring the expression level (e.g., mRNA and/or protein) of STMN2 prior and/or after the administration of the miR-485 inhibitor.

[0158] Stathmin-2 is a member of the stathmin family of phosphoproteins and in humans is encoded by the STMN2 gene. Stathmin proteins function in microtubule dynamics and signal transduction. The encoded protein plays a regulatory role in neuronal growth and is also thought to be involved in osteogenesis. The STMN2 gene is located on chromosome 8 in humans (nucleotides 79,611,117 to 79, 666,162 of NC_000008.11). Synonyms of the STMN2 gene, and the encoded protein thereof, are known and include "SCG10" and "SCGN10."

[0159] As used herein, the term "STMN2" includes any variants or isoforms of TMN2 which are naturally expressed by cells. Accordingly, in some aspects, a miR-485 inhibitor disclosed herein can increase the expression of STMN2 isoform 1 (i.e., canonical sequence). In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of STMN2 isoform 2. In some aspects, a miR-485 inhibitor disclosed herein can increase the expression of STMN2 isoform 1 and STMN2 isoform 2. Unless indicated otherwise, the above-described isoforms of STMN2 are collectively referred to herein as "STMN2."

[0160] In some aspects, a miR-485 inhibitor of the present disclosure increases the expression of STMN2 protein and/or STMN2 gene by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% compared to a reference (e.g., expression of STMN2 protein and/or STMN2 gene in a corresponding subject that did not receive an administration of the miR-485 inhibitor).

[0161] Not to be bound by any one theory, in some aspects, a miR-485 inhibitor disclosed herein increases the expression of STMN2 protein and/or STMN2 gene by reducing the expression and/or activity of miR-485, e.g. , miR-485-3p.

[0162] In some aspects, a disease or condition associated with abnormal (e.g, reduced) level of such proteins and/or genes comprises a neurodegenerative disease or disorder. As used herein, the term "neurodegenerative disease or disorder" refers to a disease or disorder caused by the progressive pathologic changes within the nervous system, particularly within the neurons of the brain. In some aspects, such progressive destruction of the nervous system can result in physical (e.g, ataxias) and/or mental (e.g, dementia) impairments. Non-limiting examples of neurodegenerative diseases or disorders that can be treated with the present disclosure include Alzheimer's disease, Parkinson's disease, or any combination thereof. Other diseases or conditions that can be treated with the present disclosure include, but are not limited to, autism spectrum disorder, mental retardation, seizure, stroke, spinal cord injury, or any combination thereof.

[0163] In some aspects, a disease or disorder that can be treated with the present disclosure comprises Alzheimer's disease. In certain aspects, Alzheimer's disease comprises pre dementia Alzheimer's disease, early Alzheimer's disease, moderate Alzheimer's disease, advanced Alzheimer's disease, early onset familial Alzheimer's disease, inflammatory Alzheimer's disease, non-inflammatory Alzheimer's disease, cortical Alzheimer's disease, early- onset Alzheimer's disease, late-onset Alzheimer's disease, or any combination thereof.

[0164] In some aspects, a disease or disorder that can be treated comprises a parkinsonism. As used herein, the term "parkinsonism" refers to a group of neurological disorders that causes a combination of the movement abnormalities seen in Parkinson's disease. Non-limiting examples of such movement abnormalities include tremor, slow movement (bradykinesia), postural instability, loss of postural reflexes, flexed posture, freezing phenomen (when the feet are transiently "glued" to the ground), impaired speech, muscle stiffness (rigidity), or combinations thereof. In some aspects, parkinsonism comprises a Parkinson's disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticalbasal degeneration (CBD), normal pressure hydrocephalus (NSA), vascular parkinsonism (also known as cerebrovascular disease), diffuse Lewy body disease, Parkinson-dementia, X-linked dystonia- parkinsonism, secondary Parkinsonism (resulting from environmental etiology, e.g, toxins, drugs, post encephalitic, brain tumors, head trauma, normal pressure hydrocephalus), or combinations thereof.

[0165] In some aspects, a parkinsonism that can be treated with the present disclosure is a

Parkinson's disease. As used herein, the term "Parkinson's disease" (PD) refers to neurodegenerative disorder leading to motor and non-motor manifestations (i.e., symptoms) and characterized by extensive degeneration of dopaminergic neurons in the nigrostriatal system. Non-limiting examples of motor and non-motor manifestations of PD are provided elsewhere in the present disclosure. Proteinopathy (a-synuclein abnormal aggregation) is a hallmark of PD. Other exemplary features of PD include dopaminergic neuron damage, mitochondrial dysfunction, neuroinflammation, protein homeostasis (e.g, autophagic clearance of damaged proteins and organelles glial cell dysfunction), and combinations thereof. Not to be bound by any one theory, in some aspects, miR-485 inhibitors of the present disclosure can teat PD by improving one or more of these features of PD.

[0166] In some aspects, administering a miR-485 inhibitor of the present disclosure reduces an amyloid beta (Ab) plaque load in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, amyloid beta (Ab) plaque load in the subject prior to the administering). As used herein, "amyloid beta plaque" refers to all forms of aberrant deposition of amyloid beta including large aggregates and small associations of a few amyloid beta peptides and can contain any variation of the amyloid beta peptides. Amyloid beta (Ab) plaque is known to cause neuronal changes, e.g, aberrations in synapse composition, synapse shape, synapse density, loss of synaptic conductivity, changes in dendrite diameter, changes in dendrite length, changes in spine density, changes in spine area, changes in spine length, or changes in spine head diameter. In some aspects, administering a miR-485 inhibitor of the present disclosure reduces an amyloid beta plaque load in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 85%, at least about 90%, at least about 95%, or about 100% compared to a reference (e.g., subjects that did not receive an administration of the miR-485 inhibitor).

[0167] In some aspects, administering a miR-485 inhibitor disclosed herein increases neurogenesis in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, neurogenesis in the subject prior to the administering). As used herein, the term "neurogenesis" refers to the process by which neurons are created. Neurogenesis encompasses proliferation of neural stem and progenitor cells, differentiation of these cells into new neural cell types, as well as migration and survival of the new cells. The term is intended to cover neurogenesis as it occurs during normal development, predominantly during pre-natal and peri-natal development, as well as neural cells regeneration that occurs following disease, damage or therapeutic intervention. Adult neurogenesis is also termed "nerve" or "neural" regeneration. In some aspects, administering a miR-485 inhibitor of the present disclosure increases neurogenesis in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0168] In some aspects, increasing and/or inducing neurogenesis is associated with increased proliferation, differentiation, migration, and/or survival of neural stem cells and/or progenitor cells. Accordingly, in some aspects, administering a miR-485 inhibitor of the present disclosure can increase the proliferation of neural stem cells and/or progenitor cells in the subject. In certain aspects, the proliferation of neural stem cells and/or progenitor cells is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor). In some aspects, the survival of neural stem cells and/or progenitor cells is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0169] In some aspects, increasing and/or inducing neurogenesis is associated with an increased number of neural stem cells and/or progenitor cells. In certain aspects, the number of neural stem cells and/or progenitor cells is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference ( e.g ., subjects that did not receive an administration of the miR-485 inhibitor).

[0170] In some aspects, increasing and/or inducing neurogenesis is associated with increased axon, dendrite, and/or synapse development. In certain aspects, axon, dendrite, and/or synapse development is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g., subjects that did not receive an administration of the miR-485 inhibitor).

[0171] In some aspects, administering a miR-485 inhibitor disclosed herein prevents and/or inhibits the development of an amyloid beta plaque load in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485). In some aspects, administering a miR-485 inhibitor disclosed herein delays the onset of the development of an amyloid beta plaque load in a subject (e.g, suffering from a neurodegenerative disease). In some aspects, administering a miR-485 inhibitor of the present disclosure lowers the risk of development an amyloid beta plaque load in a subject (e.g, suffering from a neurodegenerative disease).

[0172] In some aspects, administering a miR-485 inhibitor of the present disclosure increases dendritic spine density of a neuron in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, dendritic spine density of a neuron in the subject prior to the administering). In some aspects, administering a miR-485 inhibitor of the present disclosure increases dendritic spine density of a neuron in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0173] In some aspects, administering a miR-485 inhibitor disclosed herein decreases the loss of dendritic spines of a neuron in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g., loss of dendritic spines of a neuron in the subject prior to the administering). In certain aspects, administering a miR-485 inhibitor decreases the loss of dendritic spines of a neuron in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0174] In some aspects, administering a miR-485 inhibitor of the present disclosure decreases neuroinflammation (e.g, by increasing the expression of SIRT1 protein and/or SIRTl gene) in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, neuroinflammation in the subject prior to the administering). In certain aspects, administering a miR-485 inhibitor decreases neuroinflammation in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor). In some aspects, decreased neuroinflammation comprises glial cells producing decreased amounts of inflammatory mediators. Accordingly, in certain aspects, administering a miR-485 inhibitor disclosed herein to a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) decreases the amount of inflammatory mediators produced by glial cells by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor). In some aspects, an inflammatory mediator produced by glial cells comprises TNF-a. In some aspects, the inflammatory mediator comprises IL-Ib. In some aspects, an inflammatory mediator produced by glial cells comprises both TNF-a and IL-Ib. [0175] In some aspects, administering a miR-485 inhibitor disclosed herein increases autophagy ( e.g ., by increasing the expression of a SIRT1 protein and/or SIRTl gene) in a subject ( e.g ., subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485). As used herein, the term "autophagy" refers to cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis.

Not surprisingly, abnormalities of autophagy have been associated with number of diseases, including many neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease). In some aspects, administering a miR-485 inhibitor disclosed herein to a subject (e.g, suffering from a degenerative disease) increases autophagy by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, or at least about 300% or more, compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0176] As is known in the art, many neurodegenerative diseases exhibit certain motor and/or non-motor symptoms. For instance, non-limiting examples of motor symptoms associated with Parkinson's disease include resting tremor, reduction of spontaneous movement (bradykinesia), rigidity, postural instability, freezing of gait, impaired handwriting (micrographia), decreased facial expression, and uncontrolled rapid movements. Non-limiting examples of non-motor symptoms associated with Parkinson's disease include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior, or thought alterations), sensory alterations (especially altered sense of smell), and sleep difficulties.

[0177] In some aspects, administering a miR-485 inhibitor of the present disclosure improves one or more motor symptoms in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, corresponding motor symptoms in the subject prior to the administering).

In certain aspects, administering a miR-485 inhibitor of the present disclosure improves one or more motor symptoms in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference ( e.g ., subjects that did not receive an administration of the miR-485 inhibitor). [0178] In some aspects, administering a miR-485 inhibitor of the present disclosure improves one or more non-motor symptoms in a subject (e.g., subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, corresponding non-motor symptom in the subject prior to the administering). In certain aspects, administering a miR-485 inhibitor disclosed herein improves one or more non motor symptoms in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor). [0179] In some aspects, administering a miR-485 inhibitor disclosed herein improves synaptic function in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, synaptic function in the subject prior to the administering). As used herein, the term "synaptic function," refers to the ability of the synapse of a cell (e.g, a neuron) to pass an electrical or chemical signal to another cell (e.g, a neuron). In some aspects, administering a miR-485 inhibitor of the present disclosure improves synaptic function in a subject (e.g, suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% or more compared to a reference (e.g, subjects that did not receive an administration of the miR-485 inhibitor).

[0180] In some aspects, administering a miR-485 inhibitor of the present disclosure can prevent, delay, and/or ameliorate the loss of synaptic function in a subject (e.g, subject identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485) compared to a reference (e.g, loss of synaptic function in the subject prior to the administering). In some aspects, administering a miR-485 inhibitor prevents, delays, and/or ameliorates the loss of synaptic function in a subject ( e.g ., suffering from a neurodegenerative disease) by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% compared to a reference (e.g., subjects that did not receive an administration of the miR-485 inhibitor). [0181] In some aspects, a miR-485 inhibitor disclosed herein can be administered by any suitable route known in the art. In certain aspects, a miR-485 inhibitor is administered parenthetically, intramuscularly, subcutaneously, ophthalmic, intravenously, intraperitoneally, intradermally, intraorbitally, intracerebrally, intracranially, intracerebroventricularly, intraspinally, intraventricular, intrathecally, intracistemally, intracapsularly, intratumorally, or any combination thereof. In certain aspects, a miR-485 inhibitor is administered intracerebroventricularly (ICV). In certain aspects, a miR-485 inhibitor is administered intravenously.

[0182] In some aspects, a miR-485 inhibitor of the present disclosure can be used in combination with one or more additional therapeutic agents. In some aspects, the additional therapeutic agent and the miR-485 inhibitor are administered concurrently. In certain aspects, the additional therapeutic agent and the miR-485 inhibitor are administered sequentially.

[0183] In some aspects, the administration of a miR-485 inhibitor disclosed herein does not result in any adverse effects. In certain aspects, miR-485 inhibitors of the present disclosure does not adversely affect body weight when administered to a subject. In some aspects, miR-485 inhibitors disclosed herein do not result in increased mortality or cause pathological abnormalities when administered to a subject.

IV miRNA-485 Inhibitors Useful for the Present Disclosure

[0184] Disclosed herein are compounds that can inhibit miR-485 activity (miR-485 inhibitor). In some aspects, a miR-485 inhibitor of the present disclosure comprises a nucleotide sequence encoding a nucleotide molecule that comprises at least one miR-485 binding site, wherein the nucleotide molecule does not encode a protein. As described herein, in some aspects, the miR-485 binding site is at least partially complementary to the target miRNA nucleic acid sequence (i.e., miR-485), such that the miR-485 inhibitor hybridizes to the miR-485 nucleic acid sequence. [0185] In some aspects, the miR-485 binding site of a miR inhibitor disclosed herein has at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence complementarity to the nucleic acid sequence of a miR-485. In certain aspects, the miR-485 binding site is fully complementary to the nucleic acid sequence of a miR-485.

[0186] The miR-485 hairpin precursor can generate both miR-485-5p and miR-485-3p. In the context of the present disclosure "miR-485" encompasses both miR-485-5p and miR-485-3p unless specified otherwise. The human mature miR-485-3p has the sequence 5'- GUCAUACACGGCUCUCCUCUCU-3' (SEQ ID NO: 1; miRBase Acc. No. MIMAT0002176). A 5' terminal subsequence of miR-485-3p 5'-UCAUACA-3' is the seed sequence. The human mature miR-485-5p has the sequence 5'-AGAGGCUGGCCGUGAUGAAUUC-3' (SEQ ID NO: 48; miRBase Acc. No. MIMAT0002175). A 5' terminal subsequence of miR-485-5p 5'- GAGGCUG-3' is the seed sequence.

[0187] As will be apparent to those in the art, the human mature miR-485-3p has significant sequence similarity to that of other species. For instance, the mouse mature miR-485- 3p differs from the human mature miR-485-3p by a single amino acid at each of the 5'- and 3'- ends (i.e., has an extra "A" at the 5'-end and missing "C" at the 3'-end). The mouse mature miR- 485-3p has the following sequence: 5'-AGUCAUACACGGCUCUCCUCUC-3' (SEQ ID NO: 49; miRBase Acc. No. MTMAT0003129; underlined portion corresponds to overlap to human mature miR-485-3p). The sequence for the mouse mature miR-485-5p is identical to that of the human: 5'-agaggcuggccgugaugaauuc-3' (SEQ ID NO: 48; miRBase Acc. No. MTMAT0003128). Because of the similarity in sequences, in some aspects, a miR-485 inhibitor of the present disclosure is capable of binding miR-485-3p and/or miR-485-5p from one or more species. In certain aspects, a miR-485 inhibitor disclosed herein is capable of binding to miR-485-3p and/or miR-485-5p from both human and mouse.

[0188] In some aspects, the miR-485 binding site is a single-stranded polynucleotide sequence that is complementary ( e.g ., fully complementary) to a sequence of a miR-485-3p (or a subsequence thereof). In some aspects, the miR-485-3p subsequence comprises the seed sequence. Accordingly, in certain aspects, the miR-485 binding site has at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence complementarity to the nucleic acid sequence 5'-UCAUACA-3'. In certain aspects, the miR-485 binding site is complementary to miR-485-3p except for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mismatches. In further aspects, the miR-485 binding site is fully complementary to the nucleic acid sequence set forth in SEQ ID NO: 1.

[0189] In some aspects, the miR-485 binding site is a single-stranded polynucleotide sequence that is complementary ( e.g ., fully complementary) to a sequence of a miR-485-5p (or a subsequence thereof). In some aspects, the miR-485-5p subsequence comprises the seed sequence. In certain aspects, the miR-485 binding site has at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence complementarity to the nucleic acid sequence 5'-GAGGCUG-3'. In certain aspects, the miR-485 binding site is complementary to miR-485-5p except for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mismatches. In further aspects, the miR- 485 binding site is fully complementary to the nucleic acid sequence set forth in SEQ ID NO: 48. [0190] The seed region of a miRNA forms a tight duplex with the target mRNA. Most miRNAs imperfectly base-pair with the 3' untranslated region (UTR) of target mRNAs, and the 5' proximal "seed" region of miRNAs provides most of the pairing specificity. Without being bound to any theory, it is believed that the first nine miRNA nucleotides (encompassing the seed sequence) provide greater specificity whereas the miRNA ribonucleotides 3' of this region allow for lower sequence specificity and thus tolerate a higher degree of mismatched base pairing, with positions 2-7 being the most important. Accordingly, in specific aspects of the present disclosure, the miR-485 binding site comprises a subsequence that is fully complementary (i.e., 100% complementary) over the entire length of the seed sequence of miR-485.

[0191] miRNA sequences and miRNA binding sequences that can be used in the context of the disclosure include, but are not limited to, all or a portion of those sequences in the sequence listing provided herein, as well as the miRNA precursor sequence, or complement of one or more of these miRNAs. Any aspects of the disclosure involving specific miRNAs or miRNA binding sites by name is contemplated also to cover miRNAs or complementary sequences thereof whose sequences are at least about at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the mature sequence of the specified miRNA sequence or complementary sequence thereof.

[0192] In some aspects, miRNA binding sequences of the present disclosure can include additional nucleotides at the 5', 3', or both 5' and 3' ends of those sequences in the sequence listing provided herein, as long as the modified sequence is still capable of specifically binding to miR-485. In some aspects, miRNA binding sequences of the present disclosure can differ in at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides with respect to those sequence in the sequence listing provided, as long as the modified sequence is still capable of specifically binding to miR- 485.

[0193] It is also specifically contemplated that any methods and compositions discussed herein with respect to miRNA binding molecules or miRNA can be implemented with respect to synthetic miRNAs binding molecules. It is also understood that the disclosures related to RNA sequences in the present disclosure are equally applicable to corresponding DNA sequences. [0194] In some aspects, a miRNA-485 inhibitor of the present disclosure comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 5' of the nucleotide sequence. In some aspects, a miRNA-485 inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 3' of the nucleotide sequence. [0195] In some aspects, a miR-485 inhibitor disclosed herein is about 6 to about 30 nucleotides in length. In certain aspects, a miR-485 inhibitor disclosed herein is 7 nucleotides in length. In further aspects, a miR-485 inhibitor disclosed herein is 8 nucleotides in length. In some aspects, a miR-485 inhibitor is 9 nucleotides in length. In some aspects, a miR-485 inhibitor of the present disclosure is 10 nucleotides in length. In certain aspects, a miR-485 inhibitor is 11 nucleotides in length. In further aspects, a miR-485 inhibitor is 12 nucleotides in length. In some aspects, a miR-485 inhibitor disclosed herein is 13 nucleotides in length. In certain aspects, a miR-485 inhibitor disclosed herein is 14 nucleotides in length. In some aspects, a miR-485 inhibitor disclosed herein is 15 nucleotides in length. In further aspects, a miR-485 inhibitor is 16 nucleotides in length. In certain aspects, a miR-485 inhibitor of the present disclosure is 17 nucleotides in length. In some aspects, a miR-485 inhibitor is 18 nucleotides in length. In some aspects, a miR-485 inhibitor is 19 nucleotides in length. In certain aspects, a miR-485 inhibitor is 20 nucleotides in length. In further aspects, a miR-485 inhibitor of the present disclosure is 21 nucleotides in length. In some aspects, a miR-485 inhibitor is 22 nucleotides in length.

[0196] In some aspects, a miR-485 inhibitor disclosed herein comprises a nucleotide sequence that is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a sequence selected from SEQ ID NOs: 2 to 24. In certain aspects, a miR-485 inhibitor comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 2 to 24, wherein the nucleotide sequence can optionally comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mismatches.

[0197] In some aspects, a miRNA inhibitor comprises 5'-UGUAUGA-3', 5'-

GUGUAUGA-3', 5'-CGUGUAUGA-3', 5'-CCGUGUAUGA-3' (SEQ ID NO: 2), 5'-

GCCGUGUAUGA-3' (SEQ ID NO: 3), 5'-AGCCGUGUAUGA-3' (SEQ ID NO: 4), 5'- GAGCCGUGUAUGA-3 ¹ (SEQ ID NO: 5), 5'-AGAGCCGUGUAUGA-3' (SEQ ID NO: 6), 5'- GAGAGCCGUGUAUGA-3' (SEQ ID NO: 7), 5'-GGAGAGCCGUGUAUGA-3' (SEQ ID NO: 8), 5'-AGGAGAGCCGUGUAUGA-3' (SEQ ID NO: 9), 5'-GAGGAGAGCCGUGUAUGA-3' (SEQ ID NO: 10), 5¹ - AG AGG AG AGC C GU GU AU G A-3¹ (SEQ ID NO: 11), or 5'- GAGAGGAGAGCCGUGUAUGA-3 ¹ (SEQ ID NO: 12).

[0198] In some aspects, the miRNA inhibitor has the sequence 5'-UGUAUGAC-3', 5'-

GUGUAUGAC-3', 5'-CGUGUAUGAC-3' (SEQ ID NO: 13), 5'-CCGUGUAUGAC-3' (SEQ ID NO: 14), 5'-GCCGUGUAUGAC-3' (SEQ ID NO: 15), 5'-AGCCGUGUAUGAC-3' (SEQ ID NO: 16), 5'-GAGCCGUGUAUGAC-3' (SEQ ID NO: 17), 5'-AGAGCCGUGUAUGAC-3' (SEQ ID NO: 18), 5'-GAGAGCCGUGUAUGAC-3' (SEQ ID NO: 19), 5'-

GGAGAGCCGUGUAUGAC-3 ¹ (SEQ ID NO: 20), 5'-AGGAGAGCCGUGUAUGAC-3' (SEQ ID NO: 21), 5'-GAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO: 22), 5'-

AGAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO: 23), or 5'-

GAGAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO: 24). [0199] In some aspects, the miRNA inhibitor has a sequence selected from the group consisting of: 5'-TGTATGA-3', 5'-GTGTATGA-3', 5'-CGTGTATGA-3', 5'-CCGTGTATGA-3' (SEQ ID NO: 25), 5'-GCCGTGTATGA-3' (SEQ ID NO: 26), 5'-AGCCGTGTATGA-3' (SEQ ID NO: 27), 5'-GAGCCGTGTATGA-3' (SEQ ID NO: 28), 5'-AGAGCCGTGTATGA-3' (SEQ ID NO: 29), 5'-GAGAGCCGTGTATGA-3' (SEQ ID NO: 30), 5'-GGAGAGCCGTGTATGA-3' (SEQ ID NO: 31), 5'-AGGAGAGCCGTGTATGA-3' (SEQ ID NO: 32), 5'-

GAGGAGAGCCGTGTATGA-3 ' (SEQ ID NO: 33), 5'-AGAGGAGAGCCGTGTATGA-3 ' (SEQ ID NO: 34), 5 ' -G AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO: 35); 5'-TGTATGAC- 3', 5'-GTGTATGAC-3', 5'-CGTGTATGAC-3' (SEQ ID NO: 36), 5'-CCGTGTATGAC-3' (SEQ ID NO: 37), 5'-GCCGTGTATGAC-3' (SEQ ID NO: 38), 5'-AGCCGTGTATGAC-3' (SEQ ID NO: 39), 5'-GAGCCGTGTATGAC-3' (SEQ ID NO: 40), 5'-AGAGCCGTGTATGAC-3' (SEQ ID NO: 41), 5'-GAGAGCCGTGTATGAC-3' (SEQ ID NO: 42), 5'-

GGAGAGCCGTGTATGAC-3' (SEQ ID NO: 43), 5'-AGGAGAGCCGTGTATGAC-3' (SEQ ID NO: 44), 5¹ - G AGG AG AGC C GT GT AT G AC -3¹ (SEQ ID NO: 45), 5'-

AGAGGAGAGCCGTGTATGAC-3 ¹ (SEQ ID NO: 46), and 5'-

GAGAGGAGAGCCGTGTATGAC-3' (SEQ ID NO: 47)

[0200] In some aspects, a miRNA inhibitor disclosed herein (i.e., miR-485 inhibitor) comprises a nucleotide sequence that is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to 5'-

AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23) or 5'-

AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO: 46). In some aspects, the miRNA inhibitor comprises a nucleotide sequence that has at least 90% similarity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23) or 5'-

AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO: 46). In some aspects, the miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23) or 5'- AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO: 46) with one substitution or two substitutions. In certain aspects, the miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23) or 5'-

AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO: 46). In certain aspects, the miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO: 23). [0201] In some aspects, a miR-485 inhibitor of the present disclosure comprises the sequence disclosed herein, e.g., any one of SEQ ID NOs: 2 to 24, and at least one, at least two, at least three, at least four or at least five additional nucleic acid at the N terminus, at least one, at least two, at least three, at least four, or at least five additional nucleic acid at the C terminus, or both. In some aspects, a miR-485 inhibitor of the present disclosure comprises the sequence disclosed herein, e.g., any one of SEQ ID NOs: 2 to 24, and one additional nucleic acid at the N terminus and/or one additional nucleic acid at the C terminus. In some aspects, a miR-485 inhibitor of the present disclosure comprises the sequence disclosed herein, e.g., any one of SEQ ID NOs: 2 to 24, and one or two additional nucleic acids at the N terminus and/or one or two additional nucleic acids at the C terminus. In some aspects, a miR-485 inhibitor of the present disclosure comprises the sequence disclosed herein, e.g., any one of SEQ ID NOs: 2 to 24, and one to three additional nucleic acids at the N terminus and/or one to three additional nucleic acids at the C terminus. In some aspects, a miR-485 inhibitor comprises 5'- GAGAGGAGAGCCGUGUAUGAC-3' (SEQ ID NO: 24).

[0202] In some aspects, a miR-485 inhibitor of the present disclosure comprises one miR-

485 binding site. In further aspects, a miR-485 inhibitor disclosed herein comprises at least two miR-485 binding sites. In certain aspects, a miR-485 inhibitor comprises three miR-485 binding sites. In some aspects, a miR-485 inhibitor comprises four miR-485 binding sites. In some aspects, a miR-485 inhibitor comprises five miR-485 binding sites. In certain aspects, a miR-485 inhibitor comprises six or more miR-485 binding sites. In some aspects, all the miR-485 binding sites are identical. In some aspects, all the miR-485 binding sites are different. In some aspects, at least one of the miR-485 binding sites is different. In some aspects, all the miR-485 binding sites are miR-485-3p binding sites. In other aspects, all the miR-485 binding sites are miR-485-5p binding sites. In further aspects, a miR-485 inhibitor comprises at least one miR-485-3p binding site and at least one miR-485-5p binding site.

III. a. Chemically Modified Polynucleotides

[0203] In some aspects, a miR-485 inhibitor disclosed herein comprises a polynucleotide which includes at least one chemically modified nucleoside and/or nucleotide. When the polynucleotides of the present disclosure are chemically modified the polynucleotides can be referred to as "modified polynucleotides."

[0204] A "nucleoside" refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g, a purine or pyrimidine) or a derivative thereof (also referred to herein as "nucleobase"). A "nucleotide" refers to a nucleoside including a phosphate group. Modified nucleotides can be synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides.

[0205] Polynucleotides can comprise a region or regions of linked nucleosides. Such regions can have variable backbone linkages. The linkages can be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides.

[0206] The modified polynucleotides disclosed herein can comprise various distinct modifications. In some aspects, the modified polynucleotides contain one, two, or more (optionally different) nucleoside or nucleotide modifications. In some aspects, a modified polynucleotide can exhibit one or more desirable properties, e.g., improved thermal or chemical stability, reduced immunogenicity, reduced degradation, increased binding to the target microRNA, reduced non-specific binding to other microRNA or other molecules, as compared to an unmodified polynucleotide.

[0207] In some aspects, a polynucleotide of the present disclosure (e.g, a miR-485 inhibitor) is chemically modified. As used herein, in reference to a polynucleotide, the terms "chemical modification" or, as appropriate, "chemically modified" refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribo- or deoxyribonucleosides in one or more of their position, pattern, percent or population, including, but not limited to, its nucleobase, sugar, backbone, or any combination thereof.

[0208] In some aspects, a polynucleotide of the present disclosure (e.g, a miR-485 inhibitor) can have a uniform chemical modification of all or any of the same nucleoside type or a population of modifications produced by downward titration of the same starting modification in all or any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation In further aspects, the polynucleotide of the present disclosure (e.g, a miR-485 inhibitor) can have a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and/or all cytidines, etc. are modified in the same way).

[0209] Modified nucleotide base pairing encompasses not only the standard adenine- thymine, adenine-uracil, or guanine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. One example of such non-standard base pairing is the base pairing between the modified nucleobase inosine and adenine, cytosine or uracil. Any combination of base/sugar or linker can be incorporated into polynucleotides of the present disclosure.

[0210] The skilled artisan will appreciate that, except where otherwise noted, polynucleotide sequences set forth in the instant application will recite "T"s in a representative DNA sequence but where the sequence represents RNA, the "T"s would be substituted for "U"s. For example, TD's of the present disclosure can be administered as RNAs, as DNAs, or as hybrid molecules comprising both RNA and DNA units.

[0211] In some aspects, the polynucleotide ( e.g ., a miR-485 inhibitor) includes a combination of at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20 or more) modified nucleobases.

[0212] In some aspects, the nucleobases, sugar, backbone linkages, or any combination thereof in a polynucleotide are modified by at least about 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100%.

(i) Base Modification

[0213] In certain aspects, the chemical modification is at nucleobases in a polynucleotide of the present disclosure (e.g, a miR-485 inhibitor). In some aspects, the at least one chemically modified nucleoside is a modified uridine (e.g, pseudouridine (y), 2-thiouridine (s2U), 1- methyl-pseudouridine (ihΐy), 1 -ethyl-pseudouridine (el y), or 5 -m ethoxy -uridine (mo5U)), a modified cytosine (e.g, 5-methyl-cytidine (m5C)) a modified adenosine (e.g, 1 -methyl-adenosine (ml A), N6-methyl-adenosine (m6A), or 2-methyl-adenine (m2A)), a modified guanosine (e.g, 7- methyl-guanosine (m7G) or 1-methyl-guanosine (mlG)), or a combination thereof.

[0214] In some aspects, the polynucleotide of the present disclosure (e.g, a miR-485 inhibitor) is uniformly modified (e.g, fully modified, modified throughout the entire sequence) for a particular modification. For example, a polynucleotide can be uniformly modified with the same type of base modification, e.g, 5-methyl-cytidine (m5C), meaning that all cytosine residues in the polynucleotide sequence are replaced with 5-methyl-cytidine (m5C). Similarly, a polynucleotide can be uniformly modified for any type of nucleoside residue present in the sequence by replacement with a modified nucleoside such as any of those set forth above. [0215] In some aspects, the polynucleotide of the present disclosure ( e.g ., a miR-485 inhibitor) includes a combination of at least two (e.g., 2, 3, 4 or more) of modified nucleobases. In some aspects, at least about 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100% of a type of nucleobases in a polynucleotide of the present disclosure (e.g, a miR-485 inhibitor) are modified nucleobases.

(ii) Backbone modifications

[0216] In some aspects, the polynucleotide of the present disclosure (i.e., miR-485 inhibitor) can include any useful linkage between the nucleosides. Such linkages, including backbone modifications, that are useful in the composition of the present disclosure include, but are not limited to the following: 3'-alkylene phosphonates, 3'-amino phosphoramidate, alkene containing backbones, aminoalkylphosphoramidates, aminoalkylphosphotriesters, boranophosphates, -CH₂-0-N(CH3)-CH₂-, -CH₂-N(CH3)-N(CH₃)-CH₂-, -CH₂-NH-CH₂-, chiral phosphonates, chiral phosphorothioates, formacetyl and thioformacetyl backbones, methylene (methylimino), methylene formacetyl and thioformacetyl backbones, methyleneimino and methylenehydrazino backbones, morpholino linkages, -N(CH3)-CH₂-CH₂-, oligonucleosides with heteroatom internucleoside linkage, phosphinates, phosphoramidates, phosphorodithioates, phosphorothioate internucleoside linkages, phosphorothioates, phosphotriesters, PNA, siloxane backbones, sulfamate backbones, sulfide sulfoxide and sulfone backbones, sulfonate and sulfonamide backbones, thionoalkylphosphonates, thionoalkylphosphotriesters, and thionophosphoramidates.

[0217] In some aspects, the presence of a backbone linkage disclosed above increase the stability and resistance to degradation of a polynucleotide of the present disclosure (i.e., miR-485 inhibitor).

[0218] In some aspects, at least about 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100% of the backbone linkages in a polynucleotide of the present disclosure (i.e., miR-485 inhibitor) are modified (e.g., all of them are phosphorothioate). [0219] In some aspects, a backbone modification that can be included in a polynucleotide of the present disclosure {i.e., miR-485 inhibitor) comprises phosphorodiamidate morpholino oligomer (PMO) and/or phosphorothioate (PS) modification.

(iii) Sugar modifications

[0220] The modified nucleosides and nucleotides which can be incorporated into a polynucleotide of the present disclosure {i.e., miR-485 inhibitor) can be modified on the sugar of the nucleic acid. In some aspects, the sugar modification increases the affinity of the binding of a miR-485 inhibitor to miR-485 nucleic acid sequence. Incorporating affinity-enhancing nucleotide analogues in the miR-485 inhibitor, such as LNA or 2'-substituted sugars, can allow the length and/or the size of the miR-485 inhibitor to be reduced.

[0221] In some aspects, at least about 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100% of the nucleotides in a polynucleotide of the present disclosure {i.e., miR-485 inhibitor) contain sugar modifications {e.g, LNA).

[0222] In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,

21, or 22 nucleotide units in a polynucleotide of the present disclosure are sugar modified {e.g, LNA).

[0223] Generally, RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary, non-limiting modified nucleotides include replacement of the oxygen in ribose {e.g, with S, Se, or alkylene, such as methylene or ethylene); addition of a double bond {e.g, to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose {e.g, to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose {e.g, to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone); multi cyclic forms {e.g, tricyclo; and "unlocked" forms, such as glycol nucleic acid (GNA) {e.g, R-GNA or S-GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), threose nucleic acid (TNA, where ribose is replace with a-L- threofuranosyl-(3' 2')) , and peptide nucleic acid (PNA, where 2-amino-ethyl-glycine linkages replace the ribose and phosphodiester backbone). The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a polynucleotide molecule can include nucleotides containing, e.g., arabinose, as the sugar.

[0224] The 2' hydroxyl group (OH) of ribose can be modified or replaced with a number of different substituents. Exemplary substitutions at the 2'-position include, but are not limited to, H, halo, optionally substituted Ci-₆ alkyl; optionally substituted Ci-₆ alkoxy; optionally substituted C6-10 aryloxy; optionally substituted C3-8 cycloalkyl; optionally substituted C3-8 cycloalkoxy; optionally substituted C6-10 aryloxy; optionally substituted C6-10 aryl-Ci-₆ alkoxy, optionally substituted Ci-12 (heterocyclyl)oxy; a sugar (e.g., ribose, pentose, or any described herein); a polyethyleneglycol (PEG), -0(CH2CH20)nCH2CH20R, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g, from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from 1 to 20, from 2 to 4, from 2 to 8, from 2 to 10, from 2 to 16, from 2 to 20, from 4 to 8, from 4 to 10, from 4 to 16, and from 4 to 20); "locked" nucleic acids (LNA) in which the 2'-hydroxyl is connected by a Ci-₆ alkylene or Ci-₆ heteroalkylene bridge to the 4'-carbon of the same ribose sugar, where exemplary bridges include methylene, propylene, ether, amino bridges, aminoalkyl, aminoalkoxy, amino, and amino acid.

[0225] In some aspects, nucleotide analogues present in a polynucleotide of the present disclosure (i.e., mir-485 inhibitor) comprise, e.g, 2'-0-alkyl-RNA units, 2'-OMe-RNA units, 2'- O-alkyl-SNA, 2'-amino-DNA units, 2'-fluoro-DNA units, LNA units, arabino nucleic acid (ANA) units, 2'-fluoro-ANA units, HNA units, INA (intercalating nucleic acid) units, 2'MOE units, or any combination thereof. In some aspects, the LNA is, e.g, oxy-LNA (such as beta-D- oxy-LNA, or alpha-L-oxy-LNA), amino-LNA (such as beta-D-amino-LNA or alpha-L-amino- LNA), thio-LNA (such as beta-D-thioO-LNA or alpha-L-thio-LNA), ENA (such a beta-D-ENA or alpha-L-ENA), or any combination thereof. In further aspects, nucleotide analogues that can be included in a polynucleotide of the present disclosure (i.e., miR-485 inhibitor) comprises a locked nucleic acid (LNA), an unlocked nucleic acid (UNA), an arabino nucleic acid (ABA), a bridged nucleic acid (BNA), and/or a peptide nucleic acid (PNA).

[0226] In some aspects, a polynucleotide of the present disclosure (i.e., miR-485 inhibitor) can comprise both modified RNA nucleotide analogues (e.g, LNA) and DNA units. In some aspects, a miR-485 inhibitor is a gapmer. See, e.g, U.S. Pat. Nos. 8,404,649; 8,580,756; 8,163,708; 9,034,837; all of which are herein incorporated by reference in their entireties. In some aspects, a miR-485 inhibitor is a micromir. See U.S. Pat. Appl. Publ. No. US20180201928, which is herein incorporated by reference in its entirety.

[0227] In some aspects, a polynucleotide of the present disclosure (i.e., miR-485 inhibitor) can include modifications to prevent rapid degradation by endo- and exo-nucleases. Modifications include, but are not limited to, for example, (a) end modifications, e.g., 5' end modifications (phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.), 3' end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), (b) base modifications, e.g., replacement with modified bases, stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, or conjugated bases, (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar, as well as (d) intemucleoside linkage modifications, including modification or replacement of the phosphodiester linkages.

V Vectors and Delivery Systems

[0228] In some aspects, the miR-485 inhibitors of the present disclosure can be administered, e.g., to a subject suffering from a disease or condition associated with abnormal (e.g, reduced) level of a SIRT1 protein and/or SIRT1 gene, using any relevant delivery system known in the art. In certain aspects, the delivery system is a vector. Accordingly, in some aspects, the present disclosure provides a vector comprising a miR-485 inhibitor of the present disclosure.

[0229] In some aspects, the vector is viral vector. In some aspects, the viral vector is an adenoviral vector or an adenoassociated viral vector. In certain aspects, the viral vector is an AAV that has a serotype of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or any combination thereof. In some aspects, the adenoviral vector is a third generation adenoviral vector. ADEASY™ is by far the most popular method for creating adenoviral vector constructs. The system consists of two types of plasmids: shuttle (or transfer) vectors and adenoviral vectors. The transgene of interest is cloned into the shuttle vector, verified, and linearized with the restriction enzyme Pmel. This construct is then transformed into ADEASIER- 1 cells, which are BJ5183 E. coll cells containing P ADEASY™. P ADEASY™ is a ~33Kh adenoviral plasmid containing the adenoviral genes necessary for virus production. The shuttle vector and the adenoviral plasmid have matching left and right homology arms which facilitate homologous recombination of the transgene into the adenoviral plasmid. One can also co- transform standard BJ5183 with supercoiled P ADEASY™ and the shuttle vector, but this method results in a higher background of non-recombinant adenoviral plasmids. Recombinant adenoviral plasmids are then verified for size and proper restriction digest patterns to determine that the transgene has been inserted into the adenoviral plasmid, and that other patterns of recombination have not occurred. Once verified, the recombinant plasmid is linearized with Pad to create a linear dsDNA construct flanked by ITRs. 293 or 911 cells are transfected with the linearized construct, and virus can be harvested about 7-10 days later. In addition to this method, other methods for creating adenoviral vector constructs known in the art at the time the present application was filed can be used to practice the methods disclosed herein.

[0230] In some aspects, the viral vector is a retroviral vector, e.g., a lentiviral vector (e.g., a third or fourth generation lentiviral vector). Lentiviral vectors are usually created in a transient transfection system in which a cell line is transfected with three separate plasmid expression systems. These include the transfer vector plasmid (portions of the HIV provirus), the packaging plasmid or construct, and a plasmid with the heterologous envelop gene ( env ) of a different virus. The three plasmid components of the vector are put into a packaging cell which is then inserted into the HIV shell. The virus portions of the vector contain insert sequences so that the virus cannot replicate inside the cell system. Current third generation lentiviral vectors encode only three of the nine HIV-1 proteins (Gag, Pol, Rev), which are expressed from separate plasmids to avoid recombination-mediated generation of a replication-competent virus. In fourth generation lentiviral vectors, the retroviral genome has been further reduced (see, e.g., TAKARA® LENTI- X™ fourth-generation packaging systems).

[0231] Any AAV vector known in the art can be used in the methods disclosed herein.

The AAV vector can comprise a known vector or can comprise a variant, fragment, or fusion thereof. In some aspects, the AAV vector is selected from the group consisting of AAV type 1 (AAV1), AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, bovine AAV, shrimp AVV, snake AVV, and any combination thereof.

[0232] In some aspects, the AAV vector is derived from an AAV vector selected from the group consisting of AAV1, AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV 12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, ovine AAV, shrimp AVV, snake AVV, and any combination thereof.

[0233] In some aspects, the AAV vector is a chimeric vector derived from at least two

AAV vectors selected from the group consisting of AAV1, AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, ovine AAV, shrimp AVV, snake AVV, and any combination thereof.

[0234] In certain aspects, the AAV vector comprises regions of at least two different

AAV vectors known in the art.

[0235] In some aspects, the AAV vector comprises an inverted terminal repeat from a first AAV (e.g, AAV1, AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV 12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, ovine AAV, shrimp AVV, snake AVV, or any derivative thereof) and a second inverted terminal repeat from a second AAV (e.g. , AAV1, AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, ovine AAV, shrimp AVV, snake AVV, or any derivative thereof).

[0236] In some aspects, the AVV vector comprises a portion of an AAV vector selected from the group consisting of AAV1, AAV2, AAV3A, AVV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AVV9, AVV10, AVV11, AVV 12, AVV13, AAVrh.74, avian AAV, bovine AAV, canine AAV, equine AAV, goat AVV, primate AAV, non-primate AAV, ovine AAV, shrimp AVV, snake AVV, and any combination thereof. In some aspects, the AAV vector comprises AAV2. [0237] In some aspects, the AVV vector comprises a splice acceptor site. In some aspects, the AVV vector comprises a promoter. Any promoter known in the art can be used in the AAV vector of the present disclosure. In some aspects, the promoter is an RNA Pol III promoter. In some aspects, the RNA Pol III promoter is selected from the group consisting of the U6 promoter, the HI promoter, the 7SK promoter, the 5S promoter, the adenovirus 2 (Ad2) VAI promoter, and any combination thereof. In some aspects, the promoter is a cytomegalovirus immediate-early gene (CMV) promoter, an EFla promoter, an SV40 promoter, a PGK1 promoter, a Ubc promoter, a human beta actin promoter, a CAG promoter, a TRE promoter, a UAS promoter, a Ac5 promoter, a polyhedrin promoter, a CaMKIIa promoter, a GALl promoter, a GAL 10 promoter, a TEF promoter, a GDS promoter, a ADH1 promoter, a CaMV35S promoter, or a Ubi promoter. In a specific aspect, the promoter comprises the U6 promoter.

[0238] In some aspects, the AAV vector comprises a constitutively active promoter

(constitutive promoter). In some aspects, the constitutive promoter is selected from the group consisting of hypoxanthine phosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase, beta-actin promoter, cytomegalovirus (CMV), simian virus ( e.g SV40), papilloma virus, adenovirus, human immunodeficiency virus (HIV), Rous sarcoma virus, a retrovirus long terminal repeat (LTR), Murine stem cell virus (MSCV) and the thymidine kinase promoter of herpes simplex virus.

[0239] In some aspects, the promoter is an inducible promoter. In some aspects, the inducible promoter is a tissue specific promoter. In certain aspects, the tissue specific promoter drives transcription of the coding region of the AVV vector in a neuron, a glial cell, or in both a neuron and a glial cell.

[0240] In some aspects, the AVV vector comprises one or more enhancers. In some aspects, the one or more enhancer are present in the AAV alone or together with a promoter disclosed herein. In some aspects, the AAV vector comprises a 3'UTR poly(A) tail sequence. In some aspects, the 3'UTR poly(A) tail sequence is selected from the group consisting of bGH poly(A), actin poly(A), hemoglobin poly(A), and any combination thereof. In some aspects, the 3'UTR poly(A) tail sequence comprises bGH poly(A).

[0241] In some aspects, a miR-485 inhibitor disclosed herein is administered with a delivery agent. Non-limiting examples of delivery agents that can be used include a lipidoid, a liposome, a lipoplex, a lipid nanoparticle, a polymeric compound, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, a micelle, or a conjugate.

[0242] Thus, in some aspects, the present disclosure also provides a composition comprising a miRNA inhibitor of the present disclosure (i.e., miR-485 inhibitor) and a delivery agent. In some aspects, the deliver}_' agent comprises a cationic carrier unit comprising

[WP]-L1-[CC]-L2-[AM] (formula I) or

[WP]-L1-[AM]-L2-[CC] (formula II) wherein

WP is a water-soluble biopolymer moiety;

CC is a positively charged carrier moiety;

AM is an adjuvant moiety; and,

LI and L2 are independently optional linkers, and wherein when mixed with a nucleic acid at an ionic ratio of about 1:1, the cationic carrier unit forms a micelle. [0243] In some aspects, composition comprising a miRNA inhibitor of the present disclosure (i.e., miR-485 inhibitor) interacts with the cationic carrier unit via an ionic bond.

[0244] In some aspects, the water-soluble polymer comprises po!yia!ky!ene glycols), poly(oxyethylated polyol), poly(olefmic alcohol), polyvinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly (saccharides), poly(a- hydroxy acid), poly(vinyl alcohol), polyglycerol, polyphosphazene, polyoxazolines ("POZ") poly(N-acryloylmorpholine), or any combinations thereof. In some aspects, the water-soluble polymer comprises polyethylene glycol ("PEG"), polyglycerol, or polypropylene glycol) ("PPG"). In some aspects, the water-soluble polymer comprises:

wherein n is 1-1000.

[0245] In some aspects, the n is at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, at least about 124, at least about 125, at least about 126, at least about 127, at least about 128, at least about 129, at least about 130, at least about 131, at least about 132, at least about 133, at least about 134, at least about 135, at least about 136, at least about 137, at least about 138, at least about 139, at least about 140, or at least about 141. In some aspects, the n is about 80 to about 90, about 90 to about 100, about 100 to about 110, about 110 to about 120, about 120 to about 130, about 140 to about 150, about 150 to about 160.

[0246] In some aspects, the water-soluble polymer is linear, branched, or dendritic. In some aspects, the cationic carrier moiety comprises one or more basic amino acids. In some aspects, the cationic carrier moiety comprises at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 13, at least 14, at last 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, or at least 50 basic amino acids. In some aspects, the cationic carrier moiety comprises about 30 to about 50 basic amino acids. In some aspects, the basic amino acid comprises arginine, lysine, histidine, or any combination thereof. In some aspects, the cationic carrier moiety comprises about 40 lysine monomers.

[0247] In some aspects, the adjuvant moiety is capable of modulating an immune response, an inflammatory response, and/or a tissue microenvironment. In some aspects, the adjuvant moiety comprises an imidazole derivative, an amino acid, a vitamin, or any combination thereof. In some aspects, the adjuvant moiety comprises:

(formula IV), wherein each of G1 and G2 is H, an aromatic ring, or 1-10 alkyl, or G1 and G2 together form an aromatic ring, and wherein n is 1-10.

[0248] In some aspects, the adjuvant moiety comprises nitroimidazole. In some aspects, the adjuvant moiety comprises metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azanidazole, benznidazole, or any combination thereof. In some aspects, the adjuvant moiety comprises an amino acid.

[0249] In some aspects, the adjuvant moiety comprises

(formula V), wherein

wherein each of Z1 and Z2 is H or OH.

[0250] In some aspects, the adjuvant moiety comprises a vitamin. In some aspects, the vitamin comprises a cyclic ring or cyclic hetero atom ring and a carboxyl group or hydroxyl group. In some aspects, the vitamin comprises: (formula VI), wherein each of Y1 and Y2 is C, N, O, or S, and wherein n is 1 or 2.

[0251] In some aspects, the vitamin is selected from the group consisting of vitamin A, vitamin Bl, vitamin B2, vitamin B3, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin M, vitamin H, and any combination thereof. In some aspects, the vitamin is vitamin B3.

[0252] In some aspects, the adjuvant moiety comprises at least about two, at least about three, at least about four, at least about five, at least about six, at least about seven, at least about eight, at least about nine, at least about ten, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, or at least about 20 vitamin B3. In some aspects, the adjuvant moiety comprises about 10 vitamin B3.

[0253] In some aspects, the composition comprises a water-soluble biopolymer moiety with about 120 to about 130 PEG units, a cationic carrier moiety comprising a poly-lysine with about 30 to about 40 lysines, and an adjuvant moiety with about 5 to about 10 vitamin B3.

[0254] The present disclosure also provides a micelle comprising a miRNA inhibitor of the present disclosure (i.e., miR-485 inhibitor) wherein the miRNA inhibitor and the delivery agent are associated with each other.

[0255] In some aspects, the association is a covalent bond, a non-covalent bond, or an ionic bond. In some aspects, the positive charge of the cationic carrier moiety of the cationic carrier unit is sufficient to form a micelle when mixed with the miR-485 inhibitor disclosed herein in a solution, wherein the overall ionic ratio of the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the miR-485 inhibitor (or vector comprising the inhibitor) in the solution is about 1: 1.

[0256] In some aspects, the cationic carrier unit is capable of protecting the miRNA inhibitor of the present disclosure (i.e., miR-485 inhibitor) from enzymatic degradation. See U.S. Prov. Appl. 62/867,097, which is herein incorporated by reference in its entirety.

VI. Pharmaceutical compositions

[0257] In some aspects, the present disclosure also provides pharmaceutical compositions comprising a miR-485 inhibitor disclosed herein ( e.g ., a polynucleotide or a vector comprising the miR-485 inhibitor) that are suitable for administration to a subject. The pharmaceutical compositions generally comprise a miR-485 inhibitor described herein ( e.g ., a polynucleotide or a vector) and a pharmaceutically-acceptable excipient or carrier in a form suitable for administration to a subject. Pharmaceutically acceptable excipients or carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition.

[0258] Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions comprising a miR-485 inhibitor of the present disclosure. (See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 18th ed. (1990)). The pharmaceutical compositions are generally formulated sterile and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.

VII. Kits

[0259] The present disclosure provides kits or products of manufacture comprising a nucleic acid probe or a set of nucleic acid probes to detect at least one pathogenic nonsynonymous SNP in CD36, GRIA4, NRXN1, VLDLR, or a combination thereof. In some aspects, the kit or product of manufacture can comprise probes to detect the presence of at least one pathogenic nonsynonymous SNP in CD36, GRIA4, NRXN1, VLDLR, or a combination thereof is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rsl48910227), CD36 c 1228_1239del

(rs550565800), CD36 c.949dup (rs70961716), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c 1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.19310T (rsl555050174), NRXN1 C.37570T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del (rsl558925686), NRXN1 c.H9G>A (rsl064795493), VLDLR c.l586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR c 1342C>T (rs80338905), VLDLR c 1041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof. [0260] In some aspects, the kit or product of manufacture comprises 1, 2, 3, 4, 5, 6, 7, 8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 nucleic acid probes to detected pathogenic nonsynonymous SNPs in CD36 , GRIA4 , NRXN1 , VLDLR , or a combination thereof, and optionally instruction for use. In some aspects, the kit or product of manufacture further comprises a miR-485 inhibitor (e.g, vector, e.g, an AAV vector, a polynucleotide, or a pharmaceutical composition of the present disclosure) in one or more containers

[0261] The present disclosure also provides kits or products of manufacture, comprising a miRNA inhibitor of the present disclosure (e.g., a polynucleotide, vector, or pharmaceutical composition disclosed herein) and optionally instructions for use, e.g., instructions for use according to the methods disclosed herein. In some aspects, the kit or product of manufacture comprises a miR-485 inhibitor (e.g, vector, e.g, an AAV vector, a polynucleotide, or a pharmaceutical composition of the present disclosure) in one or more containers. In some aspects, the kit or product of manufacture comprises miR-485 inhibitor (e.g, a vector, e.g, an AAV vector, a polynucleotide, or a pharmaceutical composition of the present disclosure) and a brochure. One skilled in the art will readily recognize that miR-485 inhibitors disclosed herein (e.g, vectors, polynucleotides, and pharmaceutical compositions of the present disclosure, or combinations thereof) can be readily incorporated into one of the established kit formats which are well known in the art.

[0262] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections can set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.

[0263] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0264] The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0265] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

[0266] The contents of all cited references (including literature references, patents, patent applications, and websites) that can be cited throughout this application are hereby expressly incorporated by reference in their entirety for any purpose, as are the references cited therein. [0267] The sequences of biomolecules (e.g., proteins, genes, miRNAs, SNPs) disclosed herein and identified by either database accession number or gene name are incorporated by reference. The database accession numbers disclosed herein (e.g, Genbak accession numbers) refer to the database version that in effect on July 1, 2020. The nucleic acid sequences of genes identified by name as well as their official names and alternative names correspond to those in the version of the Genbank database active on July 1, 2020, and are herein incorporated by reference. The amino acid sequences of proteins identified by name or translation products of genes identified by name as well as their official and alternative names correspond to those in the version of the UniProt database active on July 1, 2020, and are herein incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a neurodegenerative disease or disorder in a subject in need thereof comprising administering a mir-485 inhibitor to the subject, wherein the subject is identified as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 (Cluster of Differentiation 36), GRIA4 (glutamate ionotropic receptor AMPA type subunit 4), NRXN1 (neurexin 1), and VLDLR (very low density lipoprotein receptor).

2. A method of treating a neurodegenerative disease or disorder in a subject in need thereof comprising (i) identifying a subject as not having at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRIA4 , NRXN1 , and VLDLR ; and (ii) administering a mir-485 inhibitor to the subject.

3. A method of identifying a human subject afflicted with a neurodegenerative disease or condition as suitable for treatment with a mir-485 inhibitor, comprising determining the presence or absence of at least one pathogenic non-synonymous SNP in a gene targeted by miRNA-485 selected from the group consisting of CD36 , GRLA4 , NRXN1 , and VLDLR , wherein: a. the presence of at least one pathogenic non-synonymous SNP in CD36 , GRLA4 , NRXN1 , or VLDLR indicates that the patient is not suitable for treatment with a mir-485 inhibitor; and, b. the absence of pathogenic non-synonymous SNPs in CD36 , GRIA4 , NRXN1 , or VLDLR indicates that the patient is suitable for treatment with a mir-485 inhibitor.

4. The method of claim 3, further comprising administering a mir-485 inhibitor to the subject.

5. The method of any one of claims 1 to 4, wherein at least one pathogenic nonsynonymous SNP is in CD36.

6. The method of claim 5, wherein the at least one pathogenic nonsynonymous SNP in CD36 comprises 1, 2, 3, 4, 5, 6, 7, 8 or 9 pathogenic nonsynonymous SNPs.

7. The method of claims 5 or 6, wherein the at least one pathogenic nonsynonymous SNP in

(rs550565800), CD36 c.949dup (rs70961716), CD36 c 1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), and any combination thereof.

8. The method of any one of claims 1 to 7, wherein the at least one pathogenic nonsynonymous SNP is in GRIA4.

9. The method of claim 9, wherein the at least one pathogenic nonsynonymous SNP in GRIA4 comprises 1, 2, 3, 4 or 5 pathogenic nonsynonymous SNPs.

10. The method of claims 8 or 9, wherein the at least one pathogenic nonsynonymous SNP in GRIA4 is selected from the group consisting of GRIA4 c.2090G>C (rs765556214), GRIA4 C.1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 c 1931C>T (rsl555050174), and any combination thereof.

11. The method of any one of claims 1 to 10, wherein the at least one pathogenic nonsynonymous SNP is in NRXN1.

12. The method of claim 11, wherein the at least one pathogenic nonsynonymous SNP in NRXN1 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 pathogenic nonsynonymous SNPs.

13. The method of claim 11 or 12, wherein the at least one pathogenic nonsynonymous SNP in NRXN1 is selected from the group consisting of NRXN1 C.37570T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 C.37690T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del

(rsl558925686), NRXN1 c.H9G>A (rs 1064795493), and any combination thereof.

14. The method of any one of claims 1 to 13, wherein the at least one pathogenic nonsynonymous SNP is in VLDLR.

15. The method of claim 14, wherein the at least one pathogenic nonsynonymous SNP in VLDLR comprises 1, 2, 3, 4, 5, 6 or 7 pathogenic nonsynonymous SNPs.

16. The method of claim 14 or 15, wherein the at least one pathogenic nonsynonymous SNP in VLDLR are selected from the group consisting of VLDLR c,1586G>A (rs745973997), VLDLR C.7690T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.l041_1045del (rsl554621211), VLDLR c,1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof.

17. The method of any one of claims 1 to 4, wherein the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 pathogenic nonsynonymous SNPs.

18. The method of any one of claims 1 to 4, wherein the at least one pathogenic nonsynonymous SNP is selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c,1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 c,1237A>C

(rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c,1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 C.1931C>T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 C.29360G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del

19. The method of any one of claims 1 to 4, wherein the at least one pathogenic nonsynonymous SNP is a substitution SNP, a duplication SNP, a deletion SNP, a deletion- insertion SNP, or a combination thereof.

20. The method of claim 19, wherein the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitution SNPs.

21. The method of claim 20, wherein the substitution SNPs are selected from the group consisting of CD36 c.330_331C>A (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c,1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), GRIA4 c.2090G>C (rs765556214), GRIA4 c,1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 C.19280G (rsl555050171), GRIA4 c,1931C>T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 c.2936C>G (rs267606922), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.l 19G>A (rs 1064795493), VLDLR c,1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR C.13420T (rs80338905), VLDLR c.2117G>T (rs397514750), and any combinations thereof.

22. The method of claim 19, wherein the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3 or 4 duplication SNPs.

23. The method of claim 22, wherein the duplication SNP are selected from the group consisting of CD36 c.949dup (rs70961716), CD36 c.784dup (rs766920034), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.3845dup (rsl553535216), and any combinations thereof.

24. The method of claim 19, wherein the at least one pathogenic nonsynonymous SNP comprises 1, 2, 3, 4, 5, 6 or 7 deletion SNPs.

25. The method of claim 24, wherein the deletion SNPs are selected from the group consisting of CD36 c,1228_1239del (rs550565800), CD36 c.H55del (rs765809606), NRXN1 c.2888del (rs796052787), NRXN1 c.1551 1555del (rsl558925686), VLDLR c,1041_1045del (rsl554621211), VLDLR c 1249_1255del (rs398122380), VLDLR c.2339del (rs80338906) and any combinations thereof.

26. The method of claim 24, wherein the at least one pathogenic nonsynonymous SNP comprises 1 deletion-insertion SNP.

27. The method of claim 26, wherein the deletion-insertion SNP is NRXNl c.4173_4188delinsGTGTCCCTAA (rsl 553400438).

28. The method of any one of claims 1 to 27, wherein the subject exhibits improvement in at least a symptom or sequela of the disease or condition.

29. The method of any one of claims 1 to 28, wherein the subject exhibits improvement in overall survival or progression free survival compared to a subject not treated with a mir-485 inhibitor.

30. The method of any one of claim 1 to 29, wherein the method further comprises measuring the expression of SIRT1 (sirtuin 1), GRIA4, PPARGC1A (PPARG coactivator 1 alpha), NRG1 (neuregulin 1), NRXNl, NXPH1 (neurexophilin 1), CD36, VLDLR, or a combination thereof.

31. The method of any one of claim 1 to 30, wherein the mir-485 inhibitor targets SIRT1, GRIA4, PPARGC1A, NRG1, NRXNl, NXPH1, CD36, VLDLR, or a combination thereof.

32. The method of any one of claims 1 to 31, wherein the neurodegenerative disease or condition is associated with an abnormal level of SIRT1, GRLA4, PPARGC1A, NRG1, NRXNl, NXPH1, CD36, VLDLR, or a combination thereof.

33. The method of any one of claims 1 to 32, wherein the neurodegenerative disease or condition is Alzheimer’s disease, Parkinson’s disease.

34. The method of any one of claims 1 to 33, wherein the mir-485 miRNA inhibitor inhibits miR485-3p.

35. The method of claim 34, wherein the miR485-3p comprises 5'-gucauacacggcucuccucucu- 3' (SEQ ID NO:l).

36. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor comprises a nucleotide sequence comprising 5'- UGUAUGA-3' and wherein the miRNA inhibitor comprises about 6 to about 30 nucleotides in length.

37. The method of any one of claims 1 to 36, wherein the mir-485 miRNA inhibitor increases transcription of an SIRT1 gene and/or expression of a SIRTl protein.

38. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 5' of the nucleotide sequence.

39. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor comprises at least 1 nucleotide, at least 2 nucleotides, at least 3 nucleotides, at least 4 nucleotides, at least 5 nucleotides, at least 6 nucleotides, at least 7 nucleotides, at least 8 nucleotides, at least 9 nucleotides, at least 10 nucleotides, at least 11 nucleotides, at least 12 nucleotides, at least 13 nucleotides, at least 14 nucleotides, at least 15 nucleotides, at least 16 nucleotides, at least 17 nucleotides, at least 18 nucleotides, at least 19 nucleotides, or at least 20 nucleotides at the 3' of the nucleotide sequence.

40. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor has a sequence selected from the group consisting of: 5'-UGUAUGA-3', 5'-GUGUAUGA-3', 5'- CGUGUAUGA-3', 5'-CCGUGUAUGA-3' (SEQ ID NO:2), 5'-GCCGUGUAUGA-3' (SEQ ID NO:3), 5'-AGCCGUGUAUGA-3' (SEQ ID NO:4), 5'-GAGCCGUGUAUGA-3' (SEQ ID NO:5), 5'-AGAGCCGUGUAUGA-3' (SEQ ID NO:6), 5'-GAGAGCCGUGUAUGA-3' (SEQ ID NO:7), 5'-GGAGAGCCGUGUAUGA-3' (SEQ ID NO:8), 5'-AGGAGAGCCGUGUAUGA-3' (SEQ ID NO:9), 5'-GAGGAGAGCCGUGUAUGA-3' (SEQ ID NO: 10), 5'-

AGAGGAGAGCCGUGUAUGA-3 ' (SEQ ID NO: 11), 5'-GAGAGGAGAGCCGUGUAUGA-3 ' (SEQ ID NO: 12); 5'-UGUAUGAC-3', 5'-GUGUAUGAC-3', 5'-CGUGUAUGAC-3' (SEQ ID NO: 13), 5'-CCGUGUAUGAC-3' (SEQ ID NO: 14), 5'-GCCGUGUAUGAC-3' (SEQ ID NO: 15), 5'-AGCCGUGUAUGAC-3' (SEQ ID NO: 16), 5'-GAGCCGUGUAUGAC-3' (SEQ ID NO: 17), 5'-AGAGCCGUGUAUGAC-3' (SEQ ID NO: 18), 5'-GAGAGCCGUGUAUGAC-3' (SEQ ID NO: 19), 5'-GGAGAGCCGUGUAUGAC-3' (SEQ ID NO:20), 5'-

AGGAGAGCCGUGUAUGAC-3' (SEQ ID NO:21), 5'-GAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO:22), 5 ' - AG AGG AG AGC C GU GU AU G AC -3 ' (SEQ ID NO:23), and 5'- GAGAGGAGAGCCGUGUAUGAC-3 ' (SEQ ID NO:24).

41. The method of any one of claims 1 to 17 and 20 to 22, wherein the miRNA inhibitor has a sequence selected from the group consisting of: 5'-TGTATGA-3', 5'-GTGTATGA-3', 5'- CGTGTATGA-3', 5'-CCGTGTATGA-3' (SEQ ID NO:25), 5'-GCCGTGTATGA-3' (SEQ ID NO:26), 5'-AGCCGTGTATGA-3' (SEQ ID NO:27), 5 '-GAGCCGT GT AT GA-3 ' (SEQ ID NO:28), 5'-AGAGCCGTGTATGA-3' (SEQ ID NO:29), 5'-GAGAGCCGTGTATGA-3' (SEQ ID NO:30), 5'-GGAGAGCCGTGTATGA-3' (SEQ ID NO:31), 5 ' - AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:32), 5'-GAGGAGAGCCGT GT AT GA-3 ' (SEQ ID NO:33), 5'- AG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:34), 5 ' -GAG AGG AG AGC C GT GT AT G A- 3 ' (SEQ ID NO:35); 5'-TGTATGAC-3', 5'-GTGTATGAC-3', 5'-CGTGTATGAC-3' (SEQ ID NO:36), 5'-CCGTGTATGAC-3' (SEQ ID NO:37), 5'-GCCGTGTATGAC-3' (SEQ ID NO:38), 5'-AGCCGTGTATGAC-3' (SEQ ID NO:39), 5'-GAGCCGTGTATGAC-3' (SEQ ID NO:40), 5'- AGAGCCGTGTATGAC-3' (SEQ ID NO:41), 5'-GAGAGCCGTGTATGAC-3' (SEQ ID NO:42), 5'-GGAGAGCCGTGTATGAC-3' (SEQ ID NO:43), 5'-AGGAGAGCCGTGTATGAC- 3' (SEQ ID NO:44), 5'-GAGGAGAGCCGTGTATGAC-3' SEQ ID NO:45), 5'-

AGAGGAGAGCCGTGTATGAC-3 ¹ (SEQ ID NO:46), and 5'-

G AG AGG AG AGC C GT GT AT G AC - 3¹ (SEQ ID NO:47).

42. The method of any one of claims 1 to 34, wherein the sequence of the mir-485 miRNA inhibitor is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AGAGGAGAGCCGT GT AT GAC -3' (SEQ ID NO:46).

43. The method of claim 41, wherein the mir-485 miRNA inhibitor has a sequence that has at least 90% similarity to 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO:46).

44. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO:46) with one substitution or two substitutions.

45. The method of any one of claims 1 to 34, wherein the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23) or 5'- AGAGGAGAGCCGTGTATGAC -3' (SEQ ID NO:46).

46. The method of claim 45, wherein the mir-485 miRNA inhibitor comprises the nucleotide sequence 5'- AGAGGAGAGCCGUGUAUGAC -3' (SEQ ID NO:23).

47. The method of any one of claims 1 to 46, wherein the mir-485 miRNA inhibitor comprises at least one modified nucleotide.

48. The method of claim 47, wherein the at least one modified nucleotide is a locked nucleic acid (LNA), an unlocked nucleic acid (UNA), an arabino nucleic acid (ABA), a bridged nucleic acid (BNA), and/or a peptide nucleic acid (PNA).

49. The method of any one of claims 1 to 48, wherein the mir-485 miRNA inhibitor comprises a backbone modification.

50. The method of claim 49, wherein the backbone modification is a phosphorodiamidate morpholino oligomer (PMO) and/or phosphorothioate (PS) modification.

51. The method of any one of claims 1 to 50, wherein the mir-485 miRNA inhibitor is delivered in a delivery agent.

52. The method of claim 51, wherein the delivery agent is a micelle, an exosome, a lipid nanoparticle, an extracellular vesicle, or a synthetic vesicle.

53. The method of claim 51, wherein the micelle comprises a cationic carrier unit.

54. A kit comprising a nucleic acid probe or a set of nucleic acid probes to detect at least one pathogenic nonsynonymous SNP in CD36, GRIA4, NRXN1 , VLDLR , or a combination thereof.

55. The kit of claim 54, wherein the at least one pathogenic nonsynonymous SNP in CD36, GRIA4 , NRXN1, VLDLR , or a combination thereof is selected from the group consisting of CD36 c.330_331OA (rs572295823), CD36 C.2680T (rs75326924), CD36 C.11560T (rs 148910227), CD36 c,1228_1239del (rs550565800), CD36 c.949dup (rs70961716), CD36 C.1237A>C (rsl21918035), CD36 c.760T>C (rs 142186404), CD36 c.784dup (rs766920034), CD36 c.H55del (rs765809606), GRIA4 c.2090G>C (rs765556214), GRIA4 c,1915A>T (rsl555050158), GRIA 4c.l921A>G (rsl555050165), GRIA4 c,1928C>G (rsl555050171), GRIA4 C.19310T (rsl555050174), NRXN1 c.3757C>T (rsl201575289), NRXN1 c.2936C>G (rs267606922), NRXN1 c.4291_4294dup (rsl558507406), NRXN1 c.4173_4188delinsGTGTCCCTAA (rsl553400438), NRXN1 c.3845dup (rsl553535216), NRXN1 c.3769C>T (rs 1002820022), NRXN1 c.2888del (rs796052787), NRXN1 c.2832T>G (rsl057521798), NRXN1 c.2085G>A (rsl553759318), NRXN1 c.1551 1555del

(rsl558925686), NRXN1 c.H9G>A (rsl064795493), VLDLR c,1586G>A (rs745973997), VLDLR c.769C>T (rs80338907), VLDLR c,1342C>T (rs80338905), VLDLR c,1041_1045del (rsl554621211), VLDLR c,1249_1255del (rs398122380), VLDLR c.2117G>T (rs397514750), VLDLR c.2339del (rs80338906), and any combination thereof.

56. The kit of claims 54 or 55, wherein the at least one pathogenic nonsynonymous SNP in CD36, GRLA4, NRXN1 , VLDLR , or a combination thereof comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 nucleic acid probes to detected pathogenic nonsynonymous SNPs in CD36 , GRLA4 , NRXN1 , VLDLR , or a combination thereof.