WO2023208028A1 - 用于治疗牛皮癣或阿尔兹海默症的具有16bp-26bp双链茎环结构的环形RNA - Google Patents
用于治疗牛皮癣或阿尔兹海默症的具有16bp-26bp双链茎环结构的环形RNA Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to the field of biomedicine, and in particular, to a method for treating psoriasis or Alzheimer's disease in a subject, which includes administering to the subject a therapeutically effective amount of circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Psoriasis is a chronic skin disease that mostly lasts for 10 to 20 years after the onset. Even if it temporarily improves after treatment, you have to live with the risk of possible recurrence throughout your life. Psoriasis is characterized by erythematous skin lesions covered with well-defined silvery white scales. It mainly occurs in the elbows, knees, buttocks, scalp and other places that are more irritated. In addition, psoriasis is often accompanied by a variety of complications. Among them, psoriatic arthritis is a specific type of arthritis that occurs in patients with psoriasis. There is currently no method that can directly prevent the onset of this type of psoriasis. Preventing its worsening is the best way.
- AD Alzheimer's disease
- PKR as a type of double-stranded RNA-binding protein, plays a role in many innate immune signaling pathways.
- PKR can act as a Tau phosphorylation kinase and directly affect Tau phosphorylation levels.
- PKR knockout can improve the learning and memory abilities of Alzheimer's disease (AD) model mice.
- circular RNA with a specific double-stranded structure can be used as a new target for the intervention and treatment of autoimmune diseases such as psoriasis.
- circular RNA with a 16bp-26bp double-stranded stem-loop structure can alleviate abnormal activation of PKR and reduce psoriasis-related inflammatory cytokines (especially in B lymphocytes and monocytes) by inhibiting PKR dimerization.
- the expression levels of inflammatory cytokines such as IFN ⁇ , IL6, IL17A, IL23, RIG-I and TNF ⁇ , thereby treating or preventing psoriasis.
- the invention provides use of circPOLR2A in the preparation of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides the use of circPOLR2A in the preparation of a medicament for alleviating or reducing symptoms associated with psoriasis in a subject suffering from psoriasis.
- the invention also provides the use of circPOLR2A in the preparation of a medicament for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides the use of circPOLR2A in the preparation of medicaments for preventing psoriasis.
- the present invention provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for preventing or delaying the occurrence or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides the use of circular RNA with a 16-26 bp double-stranded stem-loop structure in the preparation of drugs for preventing psoriasis.
- the present invention provides use of a PKR inhibitor for the manufacture of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides the use of a PKR inhibitor in the preparation of a medicament for alleviating or reducing symptoms associated with psoriasis in a subject suffering from psoriasis.
- the present invention also provides the use of a PKR inhibitor in the manufacture of a medicament for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides the use of a PKR inhibitor in the preparation of a medicament for preventing psoriasis.
- the invention provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for use in treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for preventing psoriasis in a subject.
- the present invention provides a circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for use in treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides a circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides a circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for preventing or delaying the occurrence or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides a circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for preventing psoriasis in a subject.
- the present invention provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in preventing psoriasis in a subject.
- the invention provides a method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- the present invention also provides a method of alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- the present invention also provides a method of preventing or delaying the occurrence or progression of psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- Book The invention also provides a method for preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- the present invention provides a method for treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or comprising the circular RNA.
- RNA pharmaceutical compositions The present invention also provides a method for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or comprising the circular RNA.
- the present invention also provides a method for preventing or delaying the occurrence or progression of psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or Pharmaceutical compositions containing the circular RNA.
- the present invention also provides a method for preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a pharmaceutical composition containing the circular RNA.
- the invention provides a method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor.
- the present invention also provides a method of alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor.
- the present invention also provides a method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor.
- the present invention also provides a method of preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor.
- circular RNA with a 16bp-26bp double-stranded stem-loop structure can alleviate the abnormal activation of PKR by inhibiting PKR dimerization, thereby alleviating the disease phenotype of Alzheimer's disease to a certain extent, indicating that circular RNA RNA is expected to become a new early intervention and treatment method for Alzheimer's disease.
- the present invention provides use of circPOLR2A in the preparation of a medicament for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- the present invention also provides the use of circPOLR2A in the preparation of a medicament for alleviating or alleviating symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- the present invention also provides the use of circPOLR2A in the preparation of a medicament for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides the use of circPOLR2A in the preparation of drugs for preventing Alzheimer's disease.
- the present invention provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in preparing a medicament for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- the present invention also provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides the use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in preparing a medicament for preventing or delaying the occurrence or progression of symptoms related to Alzheimer's disease in a subject suffering from Alzheimer's disease. .
- the present invention also provides the use of circular RNA with a 16-26 bp double-stranded stem-loop structure in preparing drugs for preventing Alzheimer's disease.
- the present invention provides a PKR inhibitor for use in the treatment of Alzheimer's disease or Alzheimer's disease in a subject. Use in medications to treat symptoms associated with Alzheimer's disease.
- the present invention also provides the use of a PKR inhibitor in the preparation of a medicament for alleviating or reducing symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- the present invention also provides the use of a PKR inhibitor in the preparation of a medicament for preventing or delaying the onset or progression of symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- the present invention also provides the use of a PKR inhibitor in the preparation of a medicament for preventing Alzheimer's disease.
- the invention provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for use in treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- the present invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for preventing or delaying the occurrence or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides circPOLR2A or a pharmaceutical composition comprising circPOLR2A for preventing Alzheimer's disease in a subject.
- the present invention provides a circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA for treating Alzheimer's disease or Alzheimer's disease in a subject Related symptoms.
- the present invention also provides a circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA, which is used to alleviate or alleviate Alzheimer's disease-related symptoms in subjects suffering from Alzheimer's disease. symptom.
- the present invention also provides a circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA, which is used to prevent or delay Alzheimer's disease-related symptoms in subjects suffering from Alzheimer's disease. The onset or progression of symptoms.
- the present invention also provides a circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for preventing Alzheimer's disease in a subject.
- the present invention provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in alleviating or reducing Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- the present invention also provides a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in preventing Alzheimer's disease in a subject.
- the present invention provides a method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A .
- the present invention also provides a method for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- the present invention also provides a method for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A or a circPOLR2A-containing circPOLR2A.
- Pharmaceutical compositions The present invention also provides a method for preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of circPOLR2A or a pharmaceutical composition comprising circPOLR2A.
- the present invention provides a method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a double-stranded stem-loop having a 16bp-26bp Structure of circular RNA or pharmaceutical compositions comprising said circular RNA.
- the present invention also provides a method for alleviating or alleviating symptoms related to Alzheimer's disease in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a double-stranded stem-loop structure of 16bp-26bp. circular RNA or a pharmaceutical composition comprising the circular RNA.
- the present invention also provides a method for preventing or delaying the occurrence or progression of symptoms related to Alzheimer's disease in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a doublet with 16bp-26bp. Circular RNA with a chain-stem-loop structure or a pharmaceutical composition containing the circular RNA.
- the present invention also provides a method for preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a pharmaceutical combination comprising the circular RNA. things.
- the invention provides a method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or comprising a PKR inhibitor pharmaceutical compositions.
- the present invention also provides a method for alleviating or alleviating symptoms related to Alzheimer's disease in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or a drug containing a PKR inhibitor.
- Pharmaceutical compositions are provided.
- the present invention also provides a method for preventing or delaying the occurrence or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor or a method comprising: Pharmaceutical compositions of PKR inhibitors.
- the present invention also provides a method for preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor.
- Figure 1 The circPOLR2A sequence is conserved between humans and mice.
- the cis-acting element that promotes the formation of circular RNA is not conserved between humans and mice. Therefore, circPOLR2A is usually not expressed in mice.
- Figure 2 Detection of overexpressed circPOLR2A sequence knocked in at the ROSA26 site by CRISPR/CAS9.
- Figure 3 Construction of transgenic mice stably expressing circPOLR2A and the corresponding linearPOLR2A.
- Figure 4 Expression of circPOLR2A/linearPOLR2A in different tissues of transgenic mouse models.
- Figure 5 Expression of circPOLR2A or linearPOLR2A in spleen tissue of transgenic mice.
- Figure 6 Expression of circPOLR2A in various tissues in transgenic mice.
- Figure 7 Imiquimod-induced mouse model mimics psoriasis disease phenotype.
- Figure 8 Transient expression of cytokines in spleen cells induced by imiquimod.
- Figure 9 Changes in circular RNA expression levels in spleen cells of mouse models induced by imiquimod.
- Figure 10 Changes in PKR protein expression and PKR phosphorylation level after imiquimod treatment.
- Figure 11 Imiquimod-induced changes in different immune cell subtypes in mouse spleen cells.
- Figure 12 Changes in psoriasis phenotype and cytokine expression in mouse models overexpressing circular RNA or linear RNA treated with imiquimod.
- Figure 13 Changes in the expression of psoriasis markers and cytokines in cells of different immune subtypes in the imiquimod-treated circRNA overexpression mouse model.
- Figure 14 Changes in cytokine expression levels in cells of different immune subtypes in poly(I:C)-treated mouse models overexpressing circular RNA or linear RNA.
- Figure 15 PKR expression in spleen cells of mouse models overexpressing circPOLR2A and overexpressing linear POLR2A.
- Figure 16 In vitro synthesis of circPOLR2A and inhibition of PKR activity.
- Figure 17 The introduction of in vitro synthesized circular RNA with a specific double-stranded structure can alleviate the psoriasis disease phenotype induced by imiquimod.
- Figure 18 Schematic diagram of the secondary structure of circPOLR2A and 26 circular RNAs of the same type with a specific double-stranded structure and a circular RNA without a specific double-stranded structure, circSMARCA5.
- Figure 19 Delivery of in vitro synthesized circPOLR2 via LNP inhibits PKR phosphorylation and alleviates imiquimod-induced psoriasis disease phenotypes.
- Figure 20 Changes in PKR background protein expression and activation levels after imiquimod treatment, and analysis of genes with increased expression.
- Figure 21 Changes in circular RNA and linear RNA expression in imiquimod-treated PKR KO mice.
- Figure 22 The activation level of IFN-alpha pathway is inhibited to a certain extent in imiquimod-treated PKR KO mice.
- Figure 23 Changes in IFN-alpha pathway expression in the imiquimod-treated circRNA overexpression mouse model.
- Figure 24 Construction of POLR2A linear and circular AAV overexpression plasmids and localization of mouse hippocampus. GFP expression can be detected 3 weeks after AAV injection.
- Figure 25 Northern blot hybridization detected successful expression of circPOLR2A in AAV-injected mice.
- Figure 26 AAV injection of 5 ⁇ FAD mice overexpressing circPOLR2A showed reduced expression of p-Tau and amyloid protein and weakened inflammatory response compared with linear overexpression mice.
- Figure 27 AAV-overexpressing circPOLR2A mice have reduced levels of p-Tau and amyloid in hippocampal tissue compared to linear-overexpressing mice.
- FIG. 28 AAV-PHPeB-circPOLR2A successfully infected the whole brain of mice through tail vein injection and expressed GFP.
- Figure 29 Tail vein injection of AAV overexpressing circPOLR2A reduces neuroinflammation and the expression levels of A ⁇ and p-PKR.
- Figure 30 Tail vein injection of AAV overexpressing circPOLR2A reduces the accumulation of A ⁇ amyloid in hippocampal tissue.
- Figure 31 Water maze experiment detects that the spatial learning and memory abilities of circPOLR2A overexpressing mice are significantly improved compared to 5 ⁇ FAD AAV-GFP mice.
- Nucleic acid sequence is used interchangeably and are single- or double-stranded RNA or DNA polymers, optionally containing synthetic, non-natural or altered nucleotide bases.
- Nucleotides are referred to by their single-letter names as follows: “A” for adenosine or deoxyadenosine (for RNA or DNA, respectively), “C” for cytidine or deoxycytidine, and “G” for guanosine or Deoxyguanosine, "U” represents uridine, “T” represents deoxythymidine, “R” represents purine (A or G), “Y” represents pyrimidine (C or T), “K” represents G or T, “ H” represents A or C or T, “D” represents A, T or G, “I” represents inosine, and “N” represents any nucleotide.
- nucleotide sequences may be represented herein as DNA sequences (including T), when referring to RNA, one skilled in the art can readily determine the corresponding RNA sequence (i.e., substituting U for T).
- Sequence "identity” has an art-recognized meaning, and the percentage of sequence identity between two nucleic acid or polypeptide molecules or regions can be calculated using published techniques. Sequence identity can be measured along the entire length of a polynucleotide or polypeptide or along a region of the molecule.
- BLAST Basic Local Alignment Search Tool
- NCBI National Center for Biotechnology Information
- “about” may mean plus or minus less than 1% or 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12 %, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30% or greater than 30%, depending on what is known or knowable by those skilled in the art.
- operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleic acid sequence, resulting in the expression of the latter.
- a first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence and the second nucleic acid sequence are in a functional relationship.
- a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
- Operably linked DNA sequences may be adjacent to each other and, for example, in the same reading frame when it is desired to join two coding regions.
- Double-stranded (ds)RNA-dependent protein kinase (PKR) inhibitors Double-stranded (ds)RNA-dependent protein kinase (PKR) inhibitors
- PTK refers to proteins known as: “double-stranded RNA-dependent protein kinase”, “double-stranded RNA-dependent protein kinase” “stranded RNA-dependent eIF-2 ⁇ kinase", “DAI” (Jimenez-Garcia, et al., J. Cell Sci. 106:11-12, 1993), “dSI”, “p68 (human) or p65 (murine) kinase “ (Lee, et al., J. Interferon Cytokine Res. 16: 1073-1078, 1996) or dsRNA-PK, or a protein having the function of the above protein. See also: Clemens, et al., J.
- PKR is an interferon-induced RNA-dependent serine/threonine protein kinase that is responsible for controlling antiviral defense pathways. Activation of this enzyme requires dimerization and subsequent autophosphorylation (Galabru, J. & Hovanessian, A. ., J. Biol. Chem. 262: 15538-15544, 1987; Meurs, E. et al., Cell, 62: 379-390, 1990). PKR has been reported to interact with activating stimuli (such as insulin, IGF, BCAA) After action, homodimers can be formed and autophosphorylated.
- activating stimuli such as insulin, IGF, BCAA
- PKR can catalyze the phosphorylation of target substrates, and the most fully identified PKR substrate in vivo is the ⁇ subunit of eukaryotic initiation factor-2 (eIF-2 ⁇ ).
- eIF-2 ⁇ eukaryotic initiation factor-2
- eIF2B eukaryotic initiation factor-2
- Other Biology of PKR The function is to presume its role as a signal transducer. Kumar et al. confirmed that PKR can phosphorylate I ⁇ B ⁇ , leading to the release and activation of nuclear factor- ⁇ B (NF- ⁇ B) (Kumar, A.
- PKR can physically bind to the I ⁇ K complex and stimulate NF- ⁇ B-inducing kinase (NIK), while phosphorylating I ⁇ K, leading to its subsequent degradation.
- NIK NF- ⁇ B-inducing kinase
- PKR Activation of PKR involves the binding of two molecules in tandem to double-stranded RNA (i.e., PKR dimerization) and then phosphorylate each other in events that occur in the molecule (Wu et al. 1997, J. Biol. Chem 272: 1291-1296).
- PKR is involved in a variety of cellular processes, including signal transduction, differentiation and Apoptosis, particularly as it relates to the process of apoptosis as an in vivo control mechanism, includes antiviral activity, cell growth regulation, and tumor growth (Donze et al. EMBO J., 14:3828-3834, 1995; Lee et al., Virology, 199:491-496, 1994; Jagus et al. Int. J. Biochem. Cell. Biol. 1989, vol. 9: 1576-86).
- PKR may also be referred to as EIF2AK1; MGC126524; PRKR; OTTHUMP00000201320; P1/eIF2 ⁇ protein kinase; double-stranded RNA-activated protein kinase; eIF2 ⁇ protein kinase 2; interferon-induced double-stranded RNA-activated protein kinase; interferon Inducible RNA-dependent protein kinase; interferon-inducible eIF2 ⁇ kinase; p68 kinase; RNA-activated protein kinase; protein kinase, interferon-inducible double-stranded RNA-dependent or eukaryotic translation initiation factor 2- ⁇ kinase 2.
- the PKR protein sequence is provided in NP_002750, which is incorporated by reference in this application, and the PKR mRNA sequence is provided in NM_002759.
- PTK expression refers to the transcription and translation of a nucleic acid sequence encoding PKR, and its products include precursor RNA, mRNA, polypeptides, post-translationally processed polypeptides and their derivatives.
- Assays for PKR expression include, for example, autophosphorylation assay (Der and Lau, Proc. Natl. Acad. Sci. USA, 92:8841-8845, 1995), eIF2 ⁇ phosphorylation assay (Zamanian-Daryoush, M.
- Typical analyzes of PKR expression and/or products include protein analysis (e.g., Western blotting) and PKR mRNA analysis (e.g., reverse transcription polymerase chain reaction (RT-PCR) analysis), Northern blot analysis, dot blot analysis, or analysis of PKR-encoding DNA. In situ hybridization analysis of nucleic acid sequences using appropriately labeled probes.
- abnormal activation of PKR or "abnormal activation of PKR” as used in this application refers to normal activation or activation of PKR caused by recognition of natural immune stimulators and PKR downstream antiviral responses, etc., in diseases such as autoimmune diseases (such as psoriasis). chronic skin diseases) or Alzheimer's disease, unnecessary activation or activation of the natural immune factor PKR and unnecessary activation or activation that may cause and aggravate related disease phenotypes.
- diseases such as autoimmune diseases (such as psoriasis). chronic skin diseases) or Alzheimer's disease, unnecessary activation or activation of the natural immune factor PKR and unnecessary activation or activation that may cause and aggravate related disease phenotypes.
- PTK inhibitor refers to a substance, agent or composition that inhibits at least part of PKR activity or inhibits at least part of PKR expression. In some embodiments, the inhibitor at least partially interferes with PKR kinase activity. Kinase activity can be detected by any method in the art, including, for example, analysis for PKR expression, phospho-specific antibodies to PKR or its major downstream target eIF2 ⁇ , and in vitro assays.
- the PKR inhibitor targets the PKR protein, and preferably is specific for PKR.
- the PKR inhibitor can function by, for example, directly reducing the activity of PKR (e.g., preventing PKR autophosphorylation, preventing PKR dimerization), providing a PKR pseudoactivator, or providing a PKR pseudobasal substances, inhibit eIF2 ⁇ phosphorylation, dephosphorylate eIF2- ⁇ or indirectly promote the activity of PKR or eIF2 ⁇ phosphatase.
- the term "reducing the activity of PKR” relates to means leading to a lower degree of dimerization of PKR compared to the normal situation, in particular in cells, in which the activity of PKR is not reduced/artificially reduced. ylation, lower autophosphorylation of PKR, and/or lower phosphorylation that targets a kinase substrate of PKR (e.g., eIF2- ⁇ ).
- the term includes all means leading to a lower degree of dimerization of PKR.
- reducing the activity of PKR in, e.g., a cell includes treating, e.g., the cell with an inhibitor of the expression and/or activity of PKR.
- the term "inhibition of PKR expression and/or activity” includes complete, substantially complete or partial inhibition of PKR expression and/or activity as well as reduction of expression and/or activity, for example, PKR expression and/or activity is not. 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of PKR expression and/or activity inhibited.
- PKR inhibitors can be used to treat psoriasis.
- PKR inhibitors can be used to treat Alzheimer's disease.
- PKR inhibitors that may be suitable for use in the medicaments, pharmaceutical compositions, kits, uses and methods of the present invention include those described in: Shimazawa et al., Neurosci. Lett., 409: 192-195, 2006; Peel, J and Chang et al., J. Neurochem. 83:1215-1225, 2002.
- the PKR inhibitor is a decoy dsRNA, such as adenovirus VAI RNA, Epstein-Barr virus EBER, HIV TAR.
- bait RNA is a pseudosubstrate RNA whose structure is similar to the RNA substrate of the enzyme. The purpose is to make the enzyme bind to the pseudosubstrate instead of the true substrate, thereby blocking the activity of the enzyme.
- the PKR inhibitor is a compound or agent that affects PKR degradation, such as poliovirus 2Apro.
- a PKR inhibitor is a compound or agent that inhibits PKR activation, e.g., a compound that inhibits PKR activation by hiding viral dsRNA (e.g., vaccinia virus E3/E3L, reovirus sigma3, influenza virus NS1 , herpes simplex virus type 1 (herpes simplex virustype 1, HSV-1) US11).
- the PKR inhibitor blocks PKR dimerization Compounds or reagents, such as influenza virus p58IPK, hepatitis C virus NS5A, and the circular RNA with a specific structure of the present invention (such as circPOLR2A).
- the PKR inhibitor is a compound or agent that inhibits eIF2-alpha phosphorylation.
- inhibiting eIF2- ⁇ phosphorylation includes inhibiting PKR and/or providing a pseudosubstrate that mimics eIF2- ⁇ .
- the pseudosubstrate that mimics eIF2- ⁇ is a viral pseudosubstrate that mimics eIF2- ⁇ .
- the viral pseudosubstrate that mimics eIF2-alpha is vaccinia virus K3.
- the PKR inhibitor is a pseudosubstrate, such as vaccinia virus K3/K3L; adenovirus VAI RNA; HIV Tat; Epstein-Barr virus EBER1 RNA.
- the pseudosubstrate is provided to the cell in the form of a nucleic acid encoding a viral pseudosubstrate, wherein said nucleic acid is preferably RNA.
- the PKR inhibitor is a dephosphorylated substrate, such as herpes simplex virus ICP34.5.
- the PKR inhibitor is a compound or agent that inhibits PKR autophosphorylation, such as an ATP binding site-directed inhibitor of PKR.
- the compound or agent that inhibits PKR autophosphorylation is an imidazo-oxindole compound.
- the compound or agent that inhibits PKR autophosphorylation is 6,8-dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzene Thiazol-7-one, 2-aminopurine or C16.
- a PKR inhibitor silences the expression of a PKR gene.
- the PKR inhibitor is an antibody that specifically binds to PKR. In one embodiment, binding of the antibody to PKR may interfere with the function of PKR, for example, by inhibiting binding activity or catalytic activity.
- the PKR inhibitor is a protein inhibitor. In one embodiment, the PKR inhibitor is a PRI short peptide.
- the PKR inhibitor is a chemical inhibitor.
- the PKR inhibitor is an inhibitor of RNA-induced PKR autophosphorylation.
- the PKR inhibitor is an ATP binding site directed inhibitor of PKR.
- the PKR inhibitor is 6,8-dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one .
- the PKR inhibitor is 2-aminopurine.
- the PKR inhibitor is C16.
- the PKR inhibitor is an RNA inhibitor. In one embodiment, the PKR inhibitor is circular RNA. In one embodiment, the PKR inhibitor is a circular RNA with a specific double-stranded stem-loop structure. In one embodiment, the PKR inhibitor is a circular RNA with a 16-26 bp double-stranded stem-loop structure.
- the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, Any one or more of circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- the circular RNA having a 16bp-26bp double-stranded stem-loop structure is circPOLR2A.
- the circPOLR2A is human circPOLR2A.
- the PKR inhibitor is a viral inhibitor.
- the viral inhibitor of PKR is vaccinia virus E3.
- the viral inhibitor of PKR is provided to the cell in the form of a nucleic acid encoding the inhibitor, wherein the nucleic acid is preferably RNA.
- viral inhibition of PKR The agent silences the expression of the PKR gene.
- Circular RNA Circular RNA
- Circular RNA is a class of single-stranded RNA with a continuous structure that has enhanced stability and lacks terminal motifs necessary for interaction with various cellular proteins.
- circRNA is a 3-5' covalently closed RNA loop, and circRNA does not display a cap or poly(A) tail.
- circRNAs lack free ends necessary for exonuclease-mediated degradation, making them resistant to multiple RNA turnover mechanisms and conferring them an extended lifespan compared with their linear mRNA counterparts. For this reason, cyclization can stabilize mRNA, which typically has a short half-life, and therefore improve the overall potency of the mRNA in a variety of applications.
- circRNA when transfected into cells, can have reduced immunogenicity relative to other forms of RNA, such as shRNA or double-stranded RNA.
- circRNAs are generated by the splicing process, and circularization occurs using conventional splice sites primarily at annotated exon boundaries. For circularization, the splice site is used in reverse: the downstream splice donor "backsplices" to the upstream splice acceptor.
- PKR protein kinase R
- PKR protein kinase R
- PRI short peptides or small molecule compounds 2-Aminopurine (2-AP), imidazo-oxindole derivatives (C16), etc. are examples of these existing small molecule compound inhibitors.
- 2-AP 2-Aminopurine
- C16 imidazo-oxindole derivatives
- these existing small molecule compound inhibitors have limitations or side effects that cannot be ignored: for example, the PRI short peptide can induce apoptosis to a certain extent, and 2-AP exists to target intracellular Non-specific inhibition of other kinases, and C16 inhibits normal cell proliferation to a certain extent after entering cells.
- Circular RNA synthesized by T4 RNA ligase including circRNAs that can be used as nucleic acid aptamers and translatable circRNAs, do not induce natural immune responses in cells.
- Circular RNA synthesized based on T4 RNA ligase not only has low immunogenicity, but also retains a short double-stranded structure of 16-26 bp similar to that in vivo. It can inhibit the activation of PKR in vitro and in cells, and is comparable to the reported PKR Small molecule inhibitors have about a thousand times better inhibitory effects.
- the present invention provides a circular RNA, which has a specific double-stranded stem-loop structure.
- specific double-stranded stem-loop structure means that the stem region of the double-stranded stem-loop structure has a specific length.
- a circular RNA with a double-stranded stem-loop structure of 16bp-26bp means that the stem region of the double-stranded stem-loop structure is 16bp.
- -26bp circular RNA In one embodiment, the length of the stem region of the specific double-stranded stem-loop structure is 16 bp to 26 bp.
- the length of the stem region of the specific double-stranded stem-loop structure is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 bp.
- the double-stranded RNAs forming the stem region of the double-stranded stem-loop structure are completely complementary to each other.
- the double-stranded RNAs forming the stem region of the double-stranded stem-loop structure may be partially complementary to each other as long as they can hybridize to each other to form the base-paired stem region. At this time, the double-stranded RNA in the stem region forming the double-stranded stem-loop structure has both complementary base pairs and mismatched base pairs.
- mismatched base pairs can form a bulge (protrusion) or internal loop (internal loop).
- the mismatched base pairs are less than or equal to 4, it is considered to still be part of the double-stranded stem-loop structure formed by RNA.
- the stem region of the particular double-stranded stem-loop structure includes up to 4 mismatched base pairs, up to 3 mismatched base pairs, up to 2 mismatched base pairs, or up to 1 Mismatched base pairs, or not Contains mismatched base pairs.
- the amount of complementarity between the double-stranded RNAs forming the stem of the double-stranded stem-loop structure generally shares at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, 99%, up to and including 100% complementarity.
- the circular RNA has 1-10 specific double-stranded stem-loop structures, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In one embodiment, the circular RNA has less than 5 specific double-stranded stem-loop structures. In one embodiment, the circular RNA has less than 4 specific double-stranded stem-loop structures. In one embodiment, the circular RNA has less than 3 specific double-stranded stem-loop structures. In one embodiment, the circular RNA has less than 2 specific double-stranded stem-loop structures. In one embodiment, the circular RNA has a specific double-stranded stem-loop structure. In one embodiment, the circular RNA has 2 specific double-stranded stem-loop structures.
- the circular RNA has 3 specific double-stranded stem-loop structures. In one embodiment, the circular RNA has four specific double-stranded stem-loop structures. In one embodiment, the circular RNA has 5 specific double-stranded stem-loop structures.
- the double-stranded stem-loop structures contained in the circular RNA are all specific double-stranded stem-loop structures.
- the double-stranded stem-loop structure contained in the circular RNA includes a specific double-stranded stem-loop structure and a non-specific double-stranded stem-loop structure.
- the double-stranded stem-loop structure contained in the circular RNA includes a specific double-stranded stem-loop structure.
- the double-stranded stem-loop structure contained in the circular RNA includes two specific double-stranded stem-loop structures.
- the double-stranded stem-loop structure contained in the circular RNA includes three specific double-stranded stem-loop structures.
- the circular RNA contains non-specific double-stranded stem-loop structures that are shorter than the specific double-stranded stem-loop structure, for example, for a circular RNA with a double-stranded stem-loop structure of 16bp-26bp, if it contains Non-specific double-stranded stem-loop structures, these non-specific double-stranded stem-loop structures are all shorter than 16bp.
- the circular RNA having a specific double-stranded stem-loop structure is a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, Any one or more of circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- the circular RNA with a 16bp-26bp double-stranded stem-loop structure is circPOLR2A. In one embodiment, the circular RNA with a 16bp-26bp double-stranded stem-loop structure is human circPOLR2A. In one embodiment, the gene encoding a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp includes the sequence of SEQ ID NO: 1. In one embodiment, the gene encoding the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp consists of the sequence of SEQ ID NO: 1.
- the gene encoding the circular RNA with a double-stranded stem-loop structure of 16bp-26bp includes 60%, 65%, 70%, 75%, 80%, 85%, Sequences that are 90%, 95%, 96%, 97%, 98%, 99% identical, or have 60%, 65%, 70%, 75%, 80%, 85%, 90% identity with SEQ ID NO: 1 %, 95%, 96%, 97%, 98%, 99% identical sequence composition.
- Circarid1b (Data Baseid: HSA_CIRCPEDIA_54093), which is positioned on the genomic group: 6 chromosome CHR6: 157,357,968-157,406,039. The corresponding linear radios 8)
- the circular sequence has 286 bases, including Arid1b The 2nd and 3rd exons of the gene.
- circCAMSAP1 data baseID: HSA_CIRCpedia_63397
- its location on the genome is: chr9:13,8773,478-138,774,924 on chromosome 9
- the corresponding linear gene is CAMSAP1 (chr9:138,700,333-138,799,005)
- the circular sequence has 425 bases base, including the 2nd and 3rd exons of the CAMSAP1 gene.
- circCCNB1 data baseID: HSA_CIRCpedia_52305
- its location on the genome is: chr5:68,470,703-68,471,364 on chromosome 5
- the corresponding linear gene is CCNB1 (chr5:68,462,837-68,474,070)
- the circular sequence has 378 bases, including CCNB1 The 6th and 7th exons of the gene.
- circCNN2 data baseID: HSA_CIRCpedia_24560
- its location on the genome is: chr19:1,032,390-1,032,695 on chromosome 19
- the corresponding linear gene is CNN2 (chr19:1,026,274-1,039,067)
- the circular sequence has 205 bases, including CNN2 The 3rd and 4th exons of the gene.
- circDHX34 data baseID: HSA_CIRCpedia_26297
- its location on the genome is: chr19:47,865,732-47,865,950 on chromosome 19
- the corresponding linear gene is DHX34 (chr19:47,852,538-47,885,961)
- the circular sequence has 218 bases, including DHX34 The 6th exon of the gene.
- circEPHB4 data baseID: HSA_CIRCpedia_56001
- its location on the genome is: chr7:100,410,368-100,410,830 on chromosome 7
- the corresponding linear gene is EPHB4 (chr7:100,400,187-100,423,148)
- the circular sequence has 362 bases, including EPHB4 The 10th and 11th exons of the gene.
- Circezh2 (Data Baseid: HSA_CIRCPEDIA_57174), which is positioned on the genomic group: chromosome CHR7: 148,543,561-148,544,397, the corresponding linear currency because of EZH2 (CHR7: 148,464-148,581,4444 1), the circular sequence has 253 bases, including EZH2 The 2nd and 3rd exons of the gene.
- circFCHO2 (data baseID: HSA_CIRCpedia_52515), its location on the genome is: chr5:72,370,568-72,373,320 on chromosome 5, the corresponding linear gene is FCHO2 (chr5:72,251,808-72,386,348), the circular sequence has 268 bases, including FCHO2 Exons 19 and 20 of the gene.
- circFGFR1 (data baseID: HSA_CIRCpedia_60993), its location on the genome is: chr8:38,314,873-38,315,052 on chromosome 8, the corresponding linear gene is FGFR1 (chr8:38,268,656-38,325,363), the circular sequence has 179 bases, including FGFR1 The 2nd exon of the gene.
- circFKBP8 (data baseID: HSA_CIRCpedia_25189), its location on the genome is: chr19:18,650,180-18,650,530 on chromosome 19, the corresponding linear gene is FKBP8 (chr19:18,642,561-18,654,387), the circular sequence has 259 bases, including FKBP8 The 3rd and 4th exons of the gene.
- circKIAA0368 (data baseID: HSA_CIRCpedia_62244), its location on the genome is: chr9:114,148,656-114,154,104 on chromosome 9, the corresponding linear gene is KIAA0368 (chr9:114,122,972-114,246,637), and the circular sequence has 435 bases , including KIAA0368 The 28th, 29th, 30th and 31st exons of the gene.
- circMBOAT2 data baseID: HSA_CIRCpedia_42589
- its location on the genome is: chr2:9,083,315-9,098,771 on chromosome 2
- the corresponding linear gene is MBOAT2 (chr2:8,992,820-9,143,942)
- the circular sequence has 224 bases, including MBOAT2 The 2nd and 3rd exons of the gene.
- circPIP5K1C data baseID: HSA_CIRCpedia_25726
- its location on the genome is: chr19:3,660,963-3,661,999 on chromosome 19
- the corresponding linear gene is PIP5K1C (chr19:3,630,179-3,700,477)
- the circular sequence has 249 bases, including PIP5K1 C
- circPOLR2A data baseID: HSA_CIRCpedia_22419
- its location on the genome is: chr17:7,402,357-7,402,810 on chromosome 17
- the corresponding linear gene is POLR2A (chr17:7,387,685-7,417,933)
- the circular sequence has 336 bases, including POLR2A The 9th and 10th exons of the gene.
- circPPP1CB data baseID: HSA_CIRCpedia_40659
- its location on the genome is: chr2:29,006,772-29,011,675 on chromosome 2
- the corresponding linear gene is PPP1CB (chr2:28,974,612-29,025,806)
- the circular sequence has 224 bases, including PPP1CB The 5th and 6th exons of the gene.
- circPROSC data baseID: HSA_CIRCpedia_60919
- its location on the genome is: chr8:37,623,043-37,623,873 on chromosome 8
- the corresponding linear gene is PROSC (chr8:37,620,101-37,637,286)
- the circular sequence has 220 bases, including PROSC The 2nd, 3rd and 4th exons of the gene.
- circPTK2 data baseID: HSA_CIRCpedia_60281
- its location on the genome is: chr8:141,889,569-141,900,868 on chromosome 8
- the corresponding linear gene is PTK2 (chr8:141,667,999-142,011,332)
- the circular sequence has 394 bases, including PTK2 The 3rd and 4th exons of the gene.
- circPVT1 data baseID: HSA_CIRCpedia_60029
- its location on the genome is: chr8:128,902,834-128,903,244 on chromosome 8
- the corresponding linear gene is PVT1 (chr8:128,806,779-129,113,499)
- the circular sequence has 410 bases, including PVT1 The 2nd exon of the gene.
- circRELL1 data baseID: HSA_CIRCpedia_48457
- its location on the genome is: chr4:37,633,006-37,640,126 on chromosome 4
- the corresponding linear gene is RELL1 (chr4:37,592,422-37,687,998)
- the circular sequence has 434 bases, including RELL1 The 4th, 5th and 6th exons of the gene.
- circSDHAF2 data baseID: HSA_CIRCpedia_4841
- its location on the genome is: chr11:61,205,096-61,205,585 on chromosome 11
- the corresponding linear gene is SDHAF2 (chr11:61,205,096-61,205,585)
- the circular sequence has 334 bases, including SDHAF2 The 2nd and 3rd exons of the gene.
- circSLC22A23 (data baseID: HSA_CIRCpedia_54791), its location on the genome is: chr6:3,410,421-3,416,089 on chromosome 6, the corresponding linear gene is SLC22A23 (chr6:3,269,196-3,457,256), the circular sequence has 259 bases, including SLC22A2 3 The 2nd and 3rd exons of the gene.
- circSNHG4 (data baseID: HSA_CIRCpedia_50464), its location on the genome is: chr5:138,614,015-138,614,818 on chromosome 5, the corresponding linear gene is SNHG4 (chr5:138,609,441-138,618,873), the circular sequence has 161 bases, including SNHG4 The 3rd and 4th exons of the gene.
- circTBCD data baseID: HSA_CIRCpedia_22969
- the corresponding linear gene is TBCD (chr17:80,709,940-80,881,609)
- the circular sequence has 389 bases, including TBCD The 17th, 18th, 19th, 20th, 21st and 22nd exons of the gene.
- circTMEM181 (data baseID: HSA_CIRCpedia_54188), its location on the genome is: chr6:159,004,985-159,010,814 on chromosome 6, the corresponding linear gene is TMEM181 (chr6:158,957,468-159,049,522), the circular sequence has 324 bases, including TMEM 181 The 3rd, 4th and 5th exons of the gene.
- circUIMC1 data baseID: HSA_CIRCpedia_51249
- its location on the genome is: chr5:176,370,335-176,385,155 on chromosome 5
- the corresponding linear gene is UIMC1 (chr5:176,332,006-176,433,409)
- the cyclization sequence has 397 bases, including UIMC1 The 7th, 8th, 9th and 10th exons of the gene.
- circVAPB data baseID: HSA_CIRCpedia_34824
- HSA_CIRCpedia_34824 its location on the genome is: chr20:57,014,000-57,016,139 on chromosome 20
- the corresponding linear gene is VAPB (chr20:56,964,175-57,026,156)
- the circular sequence has 258 bases, including VAPB The 4th and 5th exons of the gene.
- the circRNA with a specific double-stranded stem-loop structure is exogenous. In some embodiments, circRNAs with specific double-stranded stem-loop structures are endogenous. In some embodiments, the circRNA with a specific double-stranded stem-loop structure is human.
- Methods to generate circRNA can include in vitro transcription (IVT) of precursor linear RNA templates with specially designed primers.
- IVT in vitro transcription
- Three general strategies for RNA cyclization have been reported to date: cyanogen bromide or similar condensing agents Chemical methods, enzymatic methods using RNA or DNA ligases (such as T4 ligase) and ribozyme methods using self-splicing introns.
- the precursor RNA is synthesized by transcription and then heated in the presence of magnesium ions and GTP to promote cyclization. The RNA thus produced can efficiently transfect different types of cells.
- linear precursor RNA is produced by in vitro transcription using a polymerase chain reaction (PCR) generated template.
- DNA of interest from any source can be converted directly into a template for in vitro RNA synthesis by PCR using appropriate primers, buffers, RNA polymerase, and modified or unmodified nucleotides.
- the source of DNA may be, for example, genomic DNA, plasmid DNA, phage DNA, cDNA, digested DNA, synthetic DNA sequences or any other suitable DNA source.
- assays include, for example, "molecular biology” assays well known to those skilled in the art, such as Southern and northern blotting, RT-PCR and PCR; "biochemical” assays, such as detection of the presence or absence of specific peptides, e.g. by immunology Agents falling within the scope of the present disclosure are identified by means (ELISA and Western blot) or by assays described herein.
- the circular RNA with a double-stranded stem-loop structure of 16bp-26bp of the present invention can be prepared in vitro by the following method, which method includes: 1) providing the precursor of the circular RNA with a double-stranded stem-loop structure of 16bp-26bp.
- RNA precursor by transcribing from a nucleic acid vector encoding a circular RNA with a double-stranded stem-loop structure of 16bp-26bp; 2) Incubate the circular RNA precursor at a temperature where RNA circularization occurs in the presence of T4 ligase 3) optionally, treating the mixture obtained in step 2) with RNase R; and 4) harvesting the circular RNA obtained in step 2) or 3).
- the present invention provides a medicine or pharmaceutical composition, which contains the PKR inhibitor described herein or a circular RNA with a double-stranded stem-loop structure of 16bp-26bp, and a pharmaceutically acceptable carrier.
- the present invention provides a medicament or pharmaceutical composition comprising a delivery device (eg, nanoparticle) or coding containing a PKR inhibitor as described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp. Delivery vectors for PKR inhibitors or circular RNAs having a double-stranded stem-loop structure of 16 bp to 26 bp as described herein.
- the present invention provides a medicament or pharmaceutical composition, which medicament or pharmaceutical composition comprises (a) a delivery device (such as a nanoparticle) containing a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp ) or a delivery vector encoding a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp; and (b) a pharmaceutically acceptable carrier.
- a delivery device such as a nanoparticle
- a delivery device such as a nanoparticle
- a delivery device such as a nanoparticle
- a delivery device such as a nanoparticle
- a delivery vector encoding a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp to 26 bp
- a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier.
- the medicament or pharmaceutical composition is used to treat psoriasis or psoriasis-related symptoms in a subject. In one embodiment, the medicament or pharmaceutical composition is used to alleviate or reduce psoriasis-related symptoms in a subject suffering from psoriasis. In one embodiment, the medicament or pharmaceutical composition is used to prevent or delay the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis. In one embodiment, the medicament or pharmaceutical composition is used to prevent psoriasis in a subject.
- the psoriasis is telogen, remission or catagen psoriasis. In one embodiment, the psoriasis is progressive, active or inflammatory psoriasis. In one embodiment, the psoriasis is non-relapsing psoriasis or relapsing psoriasis, preferably relapsing psoriasis. In one embodiment, the cowhide Ringworm is acute psoriasis or chronic psoriasis, with chronic psoriasis being preferred.
- the psoriasis is mild, moderate, or severe psoriasis, preferably moderate/severe psoriasis. In one embodiment, the psoriasis is S100A8 positive, S100A9 positive, and S100A8 and S100A9 positive psoriasis.
- the psoriasis is selected from plaque psoriasis, guttate psoriasis, guttate psoriasis, inversion psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or Erythrodermic psoriasis.
- the psoriasis-related symptoms include skin lesions such as rash, itching, redness, swelling, vesicle formation (tiny blisters), fissures, oozing, crusting or scaling, and the like.
- the psoriasis-related symptoms include or involve overexpression of inflammatory cytokines (eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , etc.).
- the psoriasis-related symptoms include lymphoid organomegaly.
- the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- abnormal activation of RNase L or "abnormal activation of RNase L” as used in this application refers to the normal activation or activation of RNase L caused by recognition of natural immune stimulators and the downstream antiviral response of RNase L, etc., in autoimmune diseases such as psoriasis. Unnecessary activation or activation of RNase L in this chronic skin disease may cause and worsen the associated disease phenotype.
- the medicament or pharmaceutical composition is used to treat Alzheimer's disease or Alzheimer's disease-related symptoms in a subject. In one embodiment, the medicament or pharmaceutical composition is used to relieve or reduce Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease. In one embodiment, the medicament or pharmaceutical composition is used to prevent or delay the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease. In one embodiment, the medicament or pharmaceutical composition is used to prevent Alzheimer's disease in a subject.
- the Alzheimer's disease-related symptoms include pathological manifestations of Alzheimer's disease.
- the pathological hallmark of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or the production, assembly, aggregation or deposition of amyloid proteins, including A ⁇ peptides.
- the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory abilities (including spatial memory abilities), confusion, impaired judgment, personality changes, orientation Impairment or loss of language skills.
- the Alzheimer's disease-related symptoms include or involve overexpression of inflammatory cytokines (eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , IFN ⁇ , IL-1 ⁇ , etc.).
- inflammatory cytokines eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , IFN ⁇ , IL-1 ⁇ , etc.
- Alzheimer's disease refers to the atrophy or reduction of the gyri (ridges on the cerebral cortex) in the frontal and temporal lobes of the brain due to the killing of nerve cells in the cerebral cortex.
- Degenerative brain diseases specifically as defined by the NINCDS-ARDA criteria (National Institute of Neurological and Communicative Disorders and Stroke, and Alzheimer's Disease and Related Disorders Association).
- amyloid refers to a diverse but specific set of protein deposits (intracellular and/or extracellular) seen in many different diseases. Despite their differences, all amyloid deposits share common morphological features, being stained with a specific dye (such as Congo red) and having a characteristic red appearance in polarized light after staining. Green birefringence. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
- a ⁇ As used herein, the terms “A ⁇ ”, “A ⁇ peptide”, “A ⁇ protein”, “ ⁇ -amyloid peptide” and “amyloid ⁇ peptide” are synonyms and refer to proteins derived from amyloid ⁇ One or more peptide compositions of about 38-43 amino acids of the precursor protein ( ⁇ -APP).
- the subject is a human.
- PKR is aberrantly activated in the subject's immune cells.
- PKR is hyperphosphorylated in the subject's immune cells.
- inflammatory cytokines such as IFN ⁇ , IL6, IL17A, IL23, RIG-I, and TNF ⁇ are overexpressed in the subject's immune cells.
- the immune cells are selected from T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia. In one embodiment, the immune cells are B lymphocytes.
- the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, Any one or more of circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- the circular RNA having a 16bp-26bp double-stranded stem-loop structure is circPOLR2A.
- the circPOLR2A is human circPOLR2A.
- pharmaceutically acceptable carriers may include, but are not limited to, buffers, excipients, stabilizers or preservatives.
- pharmaceutically acceptable carriers are physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., such as salts, buffers, sugars, antioxidants, Aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifiers or combinations thereof.
- the amount of a pharmaceutically acceptable carrier in a drug or pharmaceutical composition can be determined experimentally based on the activity of the carrier and desired properties of the formulation, such as stability and/or minimal oxidation.
- a carrier is "acceptable" in the sense of being compatible with the drug or other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
- the medicament or pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
- the composition is formulated for intraarticular (in a joint), parenteral, intravenous, intramuscular, intradermal, intrabuccal, sublingual, nasal, intraperitoneal, subcutaneous,
- Application forms include oral, topical, intrathecal, inhalation, transrectal, patch, pump, transdermal, transrectal, muscle, body surface, mucosa, intracranial, etc.
- the medicament or pharmaceutical composition is formulated for intravenous or parenteral administration, such as embodiments involving psoriasis.
- the medicament or pharmaceutical composition is formulated for intracranial or intrathecal administration, such as embodiments involving Alzheimer's disease.
- the delivery device is selected from any one or more of the following: macromolecular complexes, liposomes, nanocapsules, nanoparticles, exosomes, exosome-lipid conjugates, microspheres, Beads, oil-in-water emulsions, lipid-nanoparticle conjugates, micelles, mixed micelles, and peptide-based polymeric complexes.
- suitable liposomes, nanoparticles, or lipid-nanoparticle conjugates comprise one or more noncationic lipids, one or more cholesterol-based lipids, and/or a or a variety of PEG-modified lipids.
- suitable lipids Lipids included in plastids, nanoparticles, or lipid-nanoparticle conjugates include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, cholic acid, and the like.
- the delivery device includes at least one targeting moiety.
- the targeting moiety is a binding ligand, a murine antibody, a human or humanized antibody, or a fragment thereof.
- a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp can be combined with a delivery device.
- binding may mean incorporated into a delivery device, encapsulated within the aqueous interior of a delivery device, dispersed within the delivery device of a delivery device, attached to a delivery device via a linker molecule, embedded in a delivery device
- complexed with a delivery device dispersed in a solution containing a delivery device, mixed with a delivery device, combined with a delivery device, contained in a delivery device as a suspension, contained in or complexed with micelles, attached to a colloidal dispersion near the system or otherwise integrated with the delivery device.
- compositions of delivery devices exist in any particular configuration without being limited to solution.
- they may exist in bilayer structures, micelles, or "folded" structures. They can also simply disperse in the solution, possibly forming aggregates that are not uniform in size or shape.
- the delivery vectors include non-viral, viral, plasmid and non-plasmid vectors.
- examples of viral delivery vectors include, but are not limited to, adenoviral vectors, adeno-associated virus (also known as adeno-associated virus, AAV) vectors, poxvirus vectors, herpes simplex virus I vectors, retroviral vectors , lentiviral vectors, etc.
- the delivery vector is an AAV vector.
- the coding sequence of the PKR inhibitor or circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is operably linked to an expression element on a delivery vector.
- the present invention provides a method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- the present invention provides a method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the present invention provides a method for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16bp-26bp. Circular RNA.
- the present invention provides a method of alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, comprising administering to the subject a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the present invention provides a method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor described herein or a double stranded protein having a 16bp-26bp Circular RNA with stem-loop structure.
- the present invention provides a method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis, comprising administering to the subject a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the present invention provides a method for preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- the present invention provides a method for preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of a drug disclosed herein. drugs, pharmaceutical compositions or preparations.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a medicament, pharmaceutical composition or formulation disclosed herein for use in treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a 16bp-26bp double-stranded stem-loop structure or a medicament, pharmaceutical composition or formulation disclosed herein for use in alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis. symptom.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a 16bp-26bp double-stranded stem-loop structure or a medicament, pharmaceutical composition or formulation disclosed herein for preventing or delaying psoriasis-related The onset or progression of symptoms.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a medicament, pharmaceutical composition or formulation disclosed herein for use in preventing psoriasis in a subject.
- the present invention provides the use of the PKR inhibitor described herein or the circular RNA having a 16bp-26bp double-stranded stem-loop structure in the preparation of a medicament, pharmaceutical composition or pharmaceutical combination for treating psoriasis or psoriasis-related symptoms in a subject.
- the present invention provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp as described herein in the preparation of a medicament, pharmaceutical composition or pharmaceutical combination for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis. the use of.
- the present invention provides the PKR inhibitor or circular RNA having a double-stranded stem-loop structure of 16bp-26bp described herein for preparing drugs and pharmaceutical compositions for preventing or delaying the occurrence or progression of psoriasis-related symptoms in subjects suffering from psoriasis. or use in pharmaceutical combinations.
- the present invention provides the use of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp in the preparation of a medicament, pharmaceutical composition or pharmaceutical combination for preventing psoriasis in a subject.
- the present invention provides a method for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor described herein or a double-stranded protein having a 16bp-26bp Circular RNA with stem-loop structure.
- the present invention provides a method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the present invention provides a method for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor described herein or having 16 bp -26bp double-stranded stem-loop structure circular RNA.
- the present invention provides a method of alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein .
- the present invention provides a method of preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibition described herein agent or circular RNA with a 16bp-26bp double-stranded stem-loop structure.
- the present invention provides a method for preventing or delaying the occurrence or progression of symptoms related to Alzheimer's disease in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a drug disclosed herein, a drug Composition or preparation.
- the present invention provides a method for preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- the present invention provides a method for preventing Alzheimer's disease in a subject, the method comprising administering to the subject a preventive effective amount of the present invention.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a medicament, pharmaceutical composition or preparation disclosed herein for use in treating Alzheimer's disease or Alzheimer's disease in a subject Symptoms related to Alzheimer's disease.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a 16bp-26bp double-stranded stem-loop structure or a medicament, pharmaceutical composition or preparation disclosed herein for use in relieving Alzheimer's disease in a subject. or reduce symptoms associated with Alzheimer’s disease.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a 16bp-26bp double-stranded stem-loop structure or a medicament, pharmaceutical composition or preparation disclosed herein for preventing Alzheimer's disease in a subject. or delay the onset or progression of Alzheimer’s-related symptoms.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a medicament, pharmaceutical composition or formulation disclosed herein for use in preventing Alzheimer's disease in a subject.
- the present invention provides the use of the PKR inhibitor described herein or the circular RNA with a 16bp-26bp double-stranded stem-loop structure in the preparation of drugs, pharmaceutical compositions, or drugs for treating Alzheimer's disease or Alzheimer's disease-related symptoms in subjects. Use in drug combinations.
- the present invention provides a PKR inhibitor or a circular RNA having a 16bp-26bp double-stranded stem-loop structure described herein for preparing a medicament for alleviating or alleviating symptoms related to Alzheimer's disease in subjects suffering from Alzheimer's disease. , pharmaceutical compositions or pharmaceutical combinations.
- the present invention provides that the PKR inhibitor described herein or the circular RNA having a double-stranded stem-loop structure of 16bp-26bp is prepared for preventing or delaying the occurrence of Alzheimer's disease-related symptoms in subjects suffering from Alzheimer's disease. or use in pharmaceuticals, pharmaceutical compositions or pharmaceutical combinations.
- the present invention provides the use of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp in the preparation of a medicament, pharmaceutical composition or pharmaceutical combination for preventing Alzheimer's disease in a subject.
- subject is intended to include living organisms in which an immune response can be elicited, and may include, but is not limited to, mammals, such as humans or non-human mammals, such as domesticated, agricultural or wild animals, and birds. and aquatic animals.
- a "patient” is a subject who suffers from or is at risk of developing a disease, disorder or condition or who is otherwise in need of the agents, drugs, pharmaceutical compositions and methods provided herein.
- administering refers to a method that can be used to enable delivery of a composition to the desired site of biological action. These methods include, but are not limited to, intra-articular (in a joint), parenteral, intravenous, intramuscular, intradermal, intrabuccal, sublingual, nasal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, trans. Rectal, patch, pump, transcutaneous, transrectal, muscle, body surface, mucous membrane, intracranial, etc.
- treatment refers to any indication of success in treating or ameliorating a disease or condition. Treatment may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency with which a patient experiences symptoms of a disease, defect, disorder, undesirable condition, or the like.
- prevention refers to preventing a disease or condition in a patient, such as the development of psoriasis. For example, if an individual at risk of developing psoriasis is treated with the methods of the present disclosure and subsequently does not develop psoriasis, the disease has been prevented in that individual, at least for a period of time. For example, if a person at risk of developing Alzheimer's disease If an individual is treated with the methods of the present disclosure and does not subsequently develop Alzheimer's disease, the disease has been prevented in the individual, at least for a period of time.
- a “therapeutically effective amount” is an amount of a composition or active component thereof that is sufficient to provide a beneficial effect or otherwise reduce non-beneficial events to an individual to whom the composition is administered.
- the effects include clinical results, such as inhibition, containment, or reduction of symptoms of a treated condition in an individual compared to a control.
- a “therapeutically effective amount” refers to an amount that produces one or more desired or desired (eg, beneficial) effects upon administration, one or more times over a given period of time.
- the precise amount administered to provide an "effective amount" of a component to an individual will depend on the mode of administration, the type and severity of the disease or condition, and on individual characteristics such as general health, age, gender, weight, and drug tolerance .
- the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages are known for approved therapeutics and can be determined by one skilled in the art using known techniques based on the individual condition, the type of condition being treated, etc. (see, e.g., Lieberman, Pharmaceutical Dosage Forms (pp. 1-3) Volume, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).
- S100A8 or “S100A9” refers to fecal calprotectin (FCP), which refers to S100 calcium-binding protein A8 (NCBI reference sequence NP_002955.2) and S100 calcium-binding protein A9 (NCBI reference sequence NP_002956.1), respectively, and their Fragments or variations.
- FCP is a complex of mammalian proteins S100A8 and S100A9 produced by neutrophils, monocytes, and epithelial cells under inflammatory conditions.
- Calprotectin can inhibit the growth of Staphylococcus aureus in abscesses by chelating the nutrients Mn 2+ and Zn 2+ .
- fecal calprotectin levels at concentrations above 50 ⁇ g/g are considered a "positive" result.
- the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, Any one or more of circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- the circular RNA having a 16bp-26bp double-stranded stem-loop structure is circPOLR2A.
- the circPOLR2A is human circPOLR2A.
- the psoriasis is telogen, remission or catagen psoriasis. In one embodiment, the psoriasis is progressive, active or inflammatory psoriasis. In one embodiment, the psoriasis is non-relapsing psoriasis or relapsing psoriasis, preferably relapsing psoriasis. In one embodiment, the psoriasis is acute psoriasis or chronic psoriasis, preferably chronic psoriasis.
- the psoriasis is mild, moderate, or severe psoriasis, preferably moderate/severe psoriasis. In one embodiment, the psoriasis is S100A8 positive, S100A9 positive, and S100A8 and S100A9 positive psoriasis.
- the psoriasis is selected from plaque psoriasis, guttate psoriasis, guttate psoriasis, inversion psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or red Dermatological psoriasis.
- the psoriasis-related symptoms include skin lesions such as rash, itching, redness, swelling, vesicle formation (tiny blisters), fissures, oozing, crusting or scaling, and the like.
- the psoriasis-related symptoms include or involve overexpression of inflammatory cytokines (eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , etc.).
- the psoriasis-related symptoms include lymphoid organomegaly.
- the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- the Alzheimer's disease-related symptoms include pathological manifestations of Alzheimer's disease.
- the pathological hallmark of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or the production, assembly, aggregation or deposition of amyloid proteins, including A ⁇ peptides.
- the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory abilities (including spatial memory abilities), confusion, impaired judgment, personality changes, orientation Impairment or loss of language skills.
- the Alzheimer's disease-related symptoms include or involve overexpression of inflammatory cytokines (eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , IFN ⁇ , IL-1 ⁇ , etc.).
- inflammatory cytokines eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , IFN ⁇ , IL-1 ⁇ , etc.
- the subject is a human.
- PKR is aberrantly activated in the subject's immune cells.
- PKR is hyperphosphorylated in the subject's immune cells.
- inflammatory cytokines such as IFN ⁇ , IL6, IL17A, IL23, RIG-I, and TNF ⁇ are overexpressed in the subject's immune cells.
- the immune cells are selected from T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia. In one embodiment, the immune cells are B lymphocytes.
- the methods of the invention result in the administration of a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug, drug disclosed herein compared to a subject who is not administered RNA or a subject who is administered the corresponding linear RNA.
- Abnormal activation levels of PKR, particularly in B lymphocytes and/or monocytes, are reduced in a subject of the composition or formulation.
- the methods of the invention result in the administration of a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug, drug disclosed herein compared to a subject who is not administered RNA or a subject who is administered the corresponding linear RNA.
- the expression level of an inflammatory cytokine (especially an inflammatory cytokine in B lymphocytes and/or monocytes) selected from one or more of the following is reduced in a subject of the composition or preparation: IFN ⁇ , IL6, IL17A, IL23, RIG-I and TNF ⁇ .
- the present invention provides a method for reducing the abnormal activation level of PKR in a subject, the method comprising administering to the subject an effective amount of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- the present invention provides a method of reducing abnormal activation levels of PKR in a subject, the method comprising administering to the subject an effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the aberrant PKR activation level is an aberrant PKR activation level in B lymphocytes and/or monocytes.
- the present invention provides a method for reducing the expression level of inflammatory cytokines in a subject, the method comprising administering to the subject an effective amount of a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- the present invention provides a method for reducing the expression level of inflammatory cytokines in a subject, the method comprising administering to the subject with a therapeutically effective amount of a drug, pharmaceutical composition or formulation disclosed herein.
- the inflammatory cytokine is an inflammatory cytokine in B lymphocytes and/or monocytes.
- the inflammatory cytokine is selected from IFN ⁇ , IL6, IL17A, IL23, RIG-I and TNF ⁇ .
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or preparation disclosed herein for reducing abnormal PKR activation levels in a subject.
- the abnormal activation level of PKR is an abnormal activation level of PKR in B lymphocytes and/or monocytes.
- the present invention provides a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a medicament, pharmaceutical composition or preparation disclosed herein for reducing the expression level of inflammatory cytokines in a subject.
- the inflammatory cytokine is an inflammatory cytokine in B lymphocytes and/or monocytes.
- the inflammatory cytokine is selected from IFN ⁇ , IL6, IL17A, IL23, RIG-I and TNF ⁇ .
- the present invention provides the use of the PKR inhibitor described herein or the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp in the preparation of a drug, pharmaceutical composition or pharmaceutical combination for reducing the abnormal activation level of PKR in a subject.
- the aberrant PKR activation is an aberrant PKR activation level in B lymphocytes and/or monocytes.
- the present invention provides the use of the PKR inhibitor described herein or the circular RNA having a 16bp-26bp double-stranded stem-loop structure in the preparation of a drug, pharmaceutical composition or pharmaceutical combination for reducing the expression level of inflammatory cytokines in a subject .
- the inflammatory cytokine is an inflammatory cytokine in B lymphocytes and/or monocytes.
- the inflammatory cytokine is selected from IFN ⁇ , IL6, IL17A, IL23, RIG-I and TNF ⁇ .
- the PKR inhibitors described herein or the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or the pharmaceutical or pharmaceutical composition of the present invention can be administered in various forms depending on the chosen route of administration. patient administration.
- the specific mode of administration and administration regimen will be selected by the attending clinician taking into account the details of the case (eg, individual, disease, disease conditions involved, specific treatment).
- the method includes converting a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp, a drug or pharmaceutical composition of the invention into a compound selected from intra-articular (in the joint ), parenteral, intravenous, intramuscular, intradermal, intrabuccal, sublingual, nasal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transrectal, patch, pump, transdermal, transrectal , muscles, body surface, mucosa, intracranial, etc.
- parenteral administration can be by continuous infusion over a selected period of time.
- the PKR inhibitors described herein or the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp e.g., circPOLR2A
- the drugs of the invention are formulated to be selected from intra-articular (in the joint (medium), parenteral, intravenous, intramuscular, intradermal, intrabuccal, sublingual, nasal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transrectal, patch, pump, transdermal, trans It can be administered in the rectum, muscles, body surface, mucosa, intracranium, etc.
- the PKR inhibitors described herein or the circular RNA with a 16bp-26bp double-stranded stem-loop structure are formulated as tablets, intrabuccal In the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, powders, or solutions.
- the drugs and pharmaceutical compositions of the present invention are formulated in the form of parenterally acceptable solutions, such as sterile aqueous solutions or dispersions and sterile Powder form, or in addition to the PKR inhibitor described herein or the circular RNA with a double-stranded stem-loop structure of 16bp-26bp, it may also contain an isotonic carrier, such as sodium chloride injection, Ringer's injection (Ringer's injection) , dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection or other carriers known in the art.
- an isotonic carrier such as sodium chloride injection, Ringer's injection (Ringer's injection) , dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection or other carriers known in the art.
- the PKR inhibitors described herein or the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp can generally be combined with, for example, hydroxypropyl fiber.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohols, and oils. These preparations may contain preservatives to prevent the growth of microorganisms under ordinary conditions of storage and use.
- the methods may include administering a compound described herein once daily, multiple times daily, or less than once daily (eg, weekly, monthly, etc.) over a period of days to months or even years.
- the method includes daily administration, every other day administration, twice weekly administration, once weekly administration, once every two weeks, once monthly administration, once every other month, once every 3 months.
- the medicament or pharmaceutical composition is formulated for once daily administration, once every other day, twice weekly, once weekly, once every two weeks, once every other day. It can be applied once a month, once every other month, once every 3 months, or once every 6 months.
- the appropriate dose will depend, for example, on the particular PKR inhibitor or circular RNA with a 16bp-26bp double-stranded stem-loop structure used, the subject, the mode of administration and the nature and severity of the condition being treated, as well as the nature of the prior treatment the patient has experienced. Certainly. Ultimately, the attending physician will decide the amount of PKR inhibitor or circular RNA with a 16bp-26bp double-stranded stem-loop structure for each individual. In some embodiments, the attending physician can administer a low dose of a PKR inhibitor or a circular RNA with a 16bp-26bp double-stranded stem-loop structure and observe the individual's response.
- an initial dose of the PKR inhibitor or circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered to the individual, and the dose is then adjusted downward until relapse symptoms occur.
- Higher doses of PKR inhibitors or circular RNAs with a 16bp-26bp double-stranded stem-loop structure can be administered until the individual achieves optimal therapeutic effect, and at this time, the dose generally will not be increased further.
- the medicament, pharmaceutical composition or formulation is formulated to contain from about 0.006 mg to about 600 mg, from about 0.06 mg to about 600 mg, from about 0.3 mg to about 600 mg, from about 0.6 mg to about 600 mg, per dosage unit.
- the medicament, pharmaceutical composition or formulation is administered in a single dose of 0.0001 mg/kg to about 10 mg/kg, About 0.001 mg/kg to about 10 mg/kg, about 0.005 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 1 mg/kg to about 10mg/kg, about 2mg/kg to about 10mg/kg, about 5mg/kg to about 10mg/kg, about 0.0001mg/kg to about 5mg/kg, about 0.001mg/kg to about 5mg/kg, about 0.005mg/ kg to about 5mg/kg, about 0.01mg/kg to about 5mg/kg, about 0.1mg/kg to about 10mg/kg, about 1mg/kg to about 5mg/kg, about 2mg/kg to about 5mg/kg, about 0.0001 mg/kg to about 1 mg/kg, about 0.001 mg/kg, about 0.00
- methods include administering as the sole active ingredient a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein.
- Methods include administering alone a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein.
- a PKR inhibitor or a circular RNA having a 16 bp to 26 bp double-stranded stem-loop structure described herein is the only active component for treating or preventing psoriasis in a subject.
- a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp described herein is the only active component for treating or preventing Alzheimer's disease in a subject.
- a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is the only active component of the medicament or pharmaceutical composition.
- the medicament or pharmaceutical composition is formulated for single administration.
- the subject is administered alone a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition, or drug disclosed herein. preparation.
- the drug or pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.
- the medicament or pharmaceutical composition may comprise a delivery device (eg, a nanoparticle) containing a PKR inhibitor as described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or encoding a PKR as described herein Inhibitors or delivery vectors of circular RNA with a double-stranded stem-loop structure of 16bp-26bp (such as AAV vectors).
- the delivery device may be a nanoparticle.
- the drug or pharmaceutical composition comprises nanoparticles comprising circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- the delivery vector may be an AAV vector.
- the medicament or pharmaceutical composition comprises an AAV vector encoding a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- methods include administering a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein in combination with an additional component or therapy.
- the medicament, pharmaceutical composition or pharmaceutical combination includes additional components.
- the subject is administered an additional component or therapy.
- the terms "co-administered,””administered in combination with” will be meant to encompass the administration of two or more therapeutic agents or therapies to a single individual, and is intended to encompass the administration thereof by the same or different routes of administration or in the same or A treatment regimen in which a therapeutic agent or therapy is administered at different times. These terms encompass the administration of two or more therapeutic agents to an individual such that the therapeutic agents and/or metabolites thereof are simultaneously present in the individual.
- the additional component or therapy is a component that increases the efficacy of the drug, pharmaceutical composition, or pharmaceutical combination.
- the additional components or therapies are improved A component of one or more side effects associated with a drug, pharmaceutical composition, or combination of drugs.
- a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein and additional components are administered in a single composition.
- a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein and additional components are administered in separate compositions.
- a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein and additional components are incorporated into the composition.
- a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein may be used with additional components or therapies. The components or treatments are administered simultaneously or sequentially.
- PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a drug, pharmaceutical composition or formulation disclosed herein with additional components or therapies. order.
- the additional components or therapies are other components or therapies that treat psoriasis or psoriasis-related symptoms. In some cases, the additional components or therapies are other components or therapies that treat Alzheimer's disease or Alzheimer's disease-related symptoms. In some embodiments, additional components or therapies include topical drug therapies (over-the-counter nonsteroidal compounds and steroidal compounds), light therapy, and systemic therapies (eg, with biologics or chemicals).
- kits for treating or preventing psoriasis are provided herein.
- kits for alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis are provided herein.
- kits for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis may include a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug containing a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or Pharmaceutical compositions.
- kits may contain a circular RNA for administering a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp or a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Tools such as syringes or prefilled pens
- instructions for use of circRNA drugs or pharmaceutical compositions are included in a circular RNA for administering a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp.
- kits may contain additional therapeutic agents for the treatment or prevention of psoriasis, for example for use with loaded PKR inhibitors described herein or circular RNAs having a 16bp-26bp double-stranded stem-loop structure or containing Additional therapeutic agents delivered in combination with drugs or pharmaceutical compositions of PKR inhibitors or circular RNAs with a double-stranded stem-loop structure of 16 bp to 26 bp (as described above).
- kits comprising: a) a PKR inhibitor as described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a PKR inhibitor as described herein or a double-stranded stem-loop having a 16bp-26bp double-stranded stem-loop structure; A drug or pharmaceutical composition of a structured circular RNA; and b) instructions.
- the kit is used to treat psoriasis or psoriasis-related symptoms.
- the kit is used to prevent psoriasis.
- the kit is used to relieve or reduce psoriasis-related symptoms in a subject suffering from psoriasis. In one embodiment, the kit is used to prevent or delay the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis. Also provided herein is a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp or a method comprising a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp. Use of a medicament or pharmaceutical composition in the preparation of a kit for treating or preventing psoriasis.
- This article also provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug or medicine comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- a composition in the preparation of a kit for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis.
- This article also provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug or medicine comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- a composition in the manufacture of a kit for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- kits for treating or preventing Alzheimer's disease Provided herein are kits for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- kits for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease may include a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug containing a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or Pharmaceutical compositions.
- kits may contain a circular RNA for administering a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp or a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Tools such as syringes or prefilled pens
- instructions for use of circRNA drugs or pharmaceutical compositions are included in a circular RNA for administering a PKR inhibitor described herein or having a double-stranded stem-loop structure of 16 bp to 26 bp.
- kits may contain additional therapeutic agents for the treatment or prevention of Alzheimer's disease, for example for use with loaded PKR inhibitors described herein or circular RNAs having a double-stranded stem-loop structure of 16bp-26bp or Additional therapeutic agents are delivered in combination with drugs or pharmaceutical compositions comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp (as described above).
- kits comprising: a) a PKR inhibitor as described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a PKR inhibitor as described herein or a double-stranded stem-loop having a 16bp-26bp double-stranded stem-loop structure; A drug or pharmaceutical composition of a structured circular RNA; and b) instructions.
- the kit is used to treat Alzheimer's disease or Alzheimer's disease-related symptoms.
- the kit is used to prevent Alzheimer's disease.
- the kit is used to alleviate or reduce symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- the kit is used to prevent or delay the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- This article also provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug or medicine comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- This article also provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug or medicine comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- a composition in the preparation of a kit for alleviating or alleviating symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- This article also provides a PKR inhibitor or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp or a drug or medicine comprising a PKR inhibitor described herein or a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- a composition in the manufacture of a kit for preventing or delaying the onset or progression of symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- the circular RNA having a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A 23. circSNHG4, circTBCD, circTMEM181, circUIMC1, any one or more of circVAPB.
- the circular RNA having a 16bp-26bp double-stranded stem-loop structure is circPOLR2A.
- the circPOLR2A is human circPOLR2A.
- the psoriasis is telogen, remission or catagen psoriasis. In one embodiment, the psoriasis is progressive, active or inflammatory psoriasis. In one embodiment, the psoriasis is non-relapsing psoriasis or relapsing psoriasis, preferably relapsing psoriasis. In one embodiment, the psoriasis is acute psoriasis or chronic psoriasis, preferably chronic psoriasis.
- the psoriasis is mild, moderate, or severe psoriasis, preferably moderate/severe psoriasis. In one embodiment, the psoriasis is S100A8 positive, S100A9 positive, and S100A8 and S100A9 positive psoriasis. In some embodiments, the psoriasis is selected from plaque psoriasis, guttate psoriasis, guttate psoriasis, inversion psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or Erythrodermic psoriasis.
- the psoriasis-related symptoms include skin lesions such as rash, itching, redness, swelling, vesicle formation (tiny blisters), fissures, oozing, crusting or scaling, and the like.
- the psoriasis-related symptoms include or involve overexpression of inflammatory cytokines (eg, IFN ⁇ , IL6, IL17A, IL23, RIG-I, TNF ⁇ , etc.).
- the psoriasis-related symptoms include lymphoid organomegaly.
- the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- the Alzheimer's disease-related symptoms include pathological manifestations of Alzheimer's disease.
- the pathological hallmark of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or the production, assembly, aggregation or deposition of amyloid proteins, including A ⁇ peptides.
- the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory abilities (including spatial memory abilities), confusion, impaired judgment, personality changes, orientation Impairment or loss of language skills.
- the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Example 1 Construction of a mouse model stably overexpressing circular RNA in whole body tissues
- RNA circPOLR2A a stable overexpression mouse model was constructed.
- the circPOLR2A sequence was obtained from the circexplorer database (http://yanglab.github.io/CIRCexplorer/).
- the specific DNA sequence corresponding to circPOLR2A is: ATGGTTCCTCGCATGATTGTCACCCCCCAGAGCAATCGGCCTGTCATGGGTATTGTGCAGGACACACTCACAGCAGTGCGCAAATTCACCAGAGAGACGTCTTCCTGGAGCGGGTGGAACGGCACATGTGTGATGGGGACATTGTTATCTTCA ACCGGCAGCCAACTCTGCACAAAATGTCCATGATGGGGCATCGGGTCCGCATTCCCATGGTCTACCTT TCCGCTTGAATCTTAGTGTGACAACTCCGTACAATGCAGACTTTGACGGGGATGAGATGAACTTGCACCTGCCACAGTCTCTGGAGACGCGAGCAGAGATCCAGGAGCTGGCC (SEQ ID NO: 1), as shown in the results in Figure 1, through sequence alignment through the NCBI database (https://pubmed.ncbi.nlm.nih.gov), the circPOLR2A sequence is conserved between humans and mice, but Due to the lack of long interspersed nuclear elements (LINE
- RNA circPOLR2A In order to test whether the human endogenously expressed circular RNA circPOLR2A can be stably produced and expressed in mice, the sequence of overexpressed circPOLR2A was knocked in at the ROSA26 site through CRISPR/CAS9, and homologous recombination was performed through FuGENE HD Transfection Reagent (Promega). The Donor plasmid and sgRNA were transfected into mouse stem cell R1 cells. After Trizol extraction of RNA and combined with RT-PCR, two single clones #3 and #29 that were positive for single gene insertion were selected and identified. As shown in Figure 2, absolute quantitative analysis of circPOLR2A copy number in each cell was performed on single clone #29 by qPCR. In three repeated experiments, each R1 cell in each clone #29 could stably express approximately 300, 550 , 430 circPOLR2A.
- mice were purchased from Biocytogen Biotech.
- the mice were purchased from Biocytogen Biotech.
- one group of mice was generated by the EF1 ⁇ promoter.
- the expression is driven by two overexpression sequences in series, respectively overexpressing circPOLR2A and the corresponding linearPOLR2A; another group of mice is driven by the CAG promoter, including a sequence that overexpresses circPOLR2A or linearPOLR2A.
- CAG promoter-driven overexpression of circPOLR2A mice had significant changes in heart tissue, spleen tissue, The expression level is higher in lung tissue and liver tissue, and the exonuclease RNaseR digestion experiment demonstrated the successful construction of a stable overexpression circPOLR2A mouse model driven by the CAG promoter.
- Example 2 Microactivation of RNase L and downregulation of circular RNA expression in imiquimod-induced psoriasis mouse model. Abnormal activation of PKR
- Imiquimod (IMQ)-induced mouse model simulates psoriasis disease phenotype
- a mouse model of psoriasis was induced by administration of imiquimod (Fits et al., J Immunol, 2009, PMID: 19380832).
- imiquimod purchased from 3M Pharmaceuticals
- 5 groups of mice were applied with imiquimod (purchased from 3M Pharmaceuticals) on their backs for continuous induction for 1 day, 2 days, 3 days, 5 days and 8 days respectively.
- vaseline vaseline
- the doses of imiquimod and vaseline were both 62.5 mg/animal.
- mice at the corresponding time points were taken, the spleens of the mice were dissected and separated after sacrifice, and the pictures were taken, as shown in Figure 7 and the results in Table 1 (Table 1 counts the pixels occupied by the spleen in the photos in Figure 7).
- Table 1 counts the pixels occupied by the spleen in the photos in Figure 7.
- Imiquimod (IMQ)-induced RNase L is transiently activated in the spleen of mice, and the expression of endogenous circular RNA in mice is down-regulated.
- mice Take 5 groups of mice and apply imiquimod (purchased from 3M Pharmaceuticals) on their backs for continuous induction for 1 day, 2 days, 3 days, 5 days and 8 days.
- the dosage is 62.5mg/each animal.
- the mice at the corresponding time points were taken, and the spleens of the mice were dissected and separated after sacrifice.
- the spleens were ground in a 70 ⁇ m cell strainer, and 3 times the cell volume of red blood cell lysis solution was added to remove red blood cells, and lymphocytes were collected.
- Trizol was added to extract total RNA, and RT-qPCR was performed to detect the expression changes of psoriasis-related cytokines mIFN ⁇ , mIL17A, mIL23, mIL6, and mPKR.
- Table 2-7 the expression level shown in Table 2-7 is based on one mouse on D0 day as 1, calculating the fold change of the corresponding target gene expression
- mIFN ⁇ , mIL17A, mIL23 The expression level increased with the increase of application time, but the expression levels of mIL6 and mPKR were the highest on D1, and gradually decreased with the increase of application time.
- RNase L activation was further determined by combining RctB ligation and RT-qPCR to detect changes in tRNA-His-21. It was found that RNase L was transiently activated, with the highest degree of activation at D1. As the induction time of RNase L increased, RNase L The degree of L activation gradually decreases.
- RNA-Seq high-throughput sequencing
- RT-qPCR was used to detect the expression changes of mCnot2, mFam120A, and mNco2 at the pre-mRNA, mRNA, and circRNA levels.
- the expression level shown in Table 8-10 is based on one mouse on D0 day as 1, and the fold of the corresponding target gene expression change is calculated
- the detection results were consistent.
- the expression levels of the three target genes in pre-mRNA and mRNA did not change significantly as the application time increased, but the expression level of circular RNA continued to decrease from D1.
- PKR is abnormally activated in the spleen of mouse model induced by imiquimod (IMQ)
- mice Three groups of wild-type mice were taken on their backs without treatment, treated with imiquimod (administered dose: 62.5 mg/each animal) for 8 consecutive days, or smeared with Vaseline (administered dose: 62.5 mg/each animal) for continuous treatment.
- imiquimod administered dose: 62.5 mg/each animal
- Vaseline administered dose: 62.5 mg/each animal
- the mouse spleen tissue was dissected and separated after sacrifice. The spleen was ground in a 70 ⁇ m cell strainer, and 3 times the cell volume of red blood cell lysis solution was added to remove red blood cells, and lymphocytes were collected.
- PKR in the spleen cells of the two groups of mice did not change significantly, but the expression of PKR in the spleen cells of the mice in the imiquimod group was The phosphorylation level of PKR was increased, and PKR was not activated in the control group of mice treated with petroleum jelly. This shows that the abnormal activation of PKR in mice induced by imiquimod is not related to the treatment action of applying the drug for 8 days, but is related to the psoriasis disease phenotype induced by imiquimod.
- mice On D0, the backs of the mice were shaved, and 5 groups of mice were applied with imiquimod (purchased from 3M Pharmaceuticals) on their backs for continuous induction for 1 day, 2 days and 5 days. The dosage was 62.5 mg/animal. After the mice were killed, the mouse spleens were dissected and removed. The spleens were ground in a 70 ⁇ m cell strainer, and 3 times the cell volume of red blood cell lysis solution was added to remove the red blood cells and lymphocytes were collected.
- imiquimod purchased from 3M Pharmaceuticals
- CD3 + cells were analyzed by flow cytometry, and CD4 + or CD8 + cells were further analyzed to determine the cytotoxicity of CD4 + helper T cells and CD8 + Changes in the proportion of different immune cell subtypes in spleen cells in wild-type mice as the time of drug application increases.
- Figure 11 and the results in Tables 11-14 the number of CD4 + helper T cells and CD8 + killer T cells gradually decreased as the treatment time increased, indicating that T cells play an important role in this psoriasis model mouse. The proportion gradually decreases with drug induction.
- CD45 + cells were analyzed by flow cytometry, and CD11b + or CD11c + cells were further analyzed to determine CD11b + monocytes.
- Figure 11 and Table 11-14 the proportion of CD11b + monocytes and CD11c + dendritic cells gradually increased as the treatment time increased, indicating that the proportion of monocytes and dendritic cells increased with the application time. With the increase of drug treatment time, the proportion of psoriasis model mice gradually increased.
- circular RNA can be used as a new target for molecular diagnosis or intervention treatment of autoimmune diseases such as psoriasis.
- mice were shaved, and the corresponding transgenic mice stably overexpressing circPOLR2A or linearPOLR2A were selected and applied on the backs for continuous induction for 1 day, 2 days, 3 days, 5 days and 8 days respectively.
- the mice at the corresponding treatment time points were taken, and the spleens of the mice were dissected and weighed after sacrifice.
- the weight of the spleens of mice overexpressing circPOLR2A and linearPOLR2A was the same, and changed with the time of continuous drug application.
- mice gradually became larger, but at D5 and D8, the spleen weight of mice overexpressing circPOLR2A did not increase significantly compared with mice overexpressing linearPOLR2A, indicating that overexpression of circPOLR2A helps to a certain extent. Alleviating the splenomegaly phenotype of psoriasis model mice.
- mice were shaved, and the corresponding mice overexpressing circPOLR2A or linearPOLR2A were applied on the backs for continuous treatment for 1 day, 2 days, 3 days, 5 days and 8 days respectively.
- the spleen of the mouse corresponding to the treatment time point, grind the spleen in a 70 ⁇ m cell strainer, add 3 times the cell volume of red blood cell lysis solution to remove the red blood cells, and collect the lymphocytes.
- Trizol was added to extract total RNA, and the expression changes of psoriasis-related cytokines mIFN ⁇ , mIL6, and gene mPKR were detected by RT-qPCR.
- the expression level shown in Table 16-18 is calculated based on the fold change of the corresponding target gene expression based on one mouse on D0 day).
- the expression level of mIFN ⁇ was relatively high on D1 and D2
- the expression level of mIFN ⁇ did not change significantly and remained at a low expression level
- the expression level of mIL6 was the highest on D1.
- the expression level of mIL6 did not change significantly and was maintained at a low expression level.
- mice were shaved, and the corresponding overexpressing circPOLR2A or linearPOLR2A mice were applied on the backs for 2 consecutive days.
- the mice were killed and the spleens of the mice were dissected and separated, and the spleens were placed on a 70 ⁇ m cell strainer. Grind the solution and add 3 times the cell volume of red blood cell lysis solution to remove red blood cells and collect lymphocytes.
- Add DPBS to rinse the cells once, use magnetic beads to sort B cells, T cells, and monocytes.
- Trizol to extract the total RNA of each immune cell subpopulation, and detect psoriasis-related marker genes mS100A8 and mS100A9 through RT-qPCR. , and the expression changes of inflammatory factors mIL6 and mTNF ⁇ .
- S100A8/9 is a calcium-binding protein that is expressed and released by keratinocytes under stress, inducing the migration of neutrophils and forming an inflammatory response (Walter et al., Nat Commun, 2013, PMID: 23463003).
- the expression changes of psoriasis-related marker genes mS100A8 and mS100A9 and the inflammatory factor mIL6 were different in the mouse model overexpressing circPOLR2A compared with the mouse model overexpressing linearPOLR2A.
- PKR expression was detected in spleen cells of wild-type mice, overexpressing circPOLR2A and overexpressing linear POLR2A mouse models. According to the results shown in Figure 15, the expression of PKR in B cells and monocytes is higher than that in T cells. , it is speculated that the expression level of PKR may affect the involvement of circRNA in the regulation of the innate immune response and inflammatory response of different immune cell subpopulations.
- Example 4 The introduction of in vitro synthesized circular RNA with a specific double-stranded structure can alleviate the psoriasis disease phenotype induced by imiquimod.
- the DNA sequence corresponding to circPOLR2A (in vitro transcription) synthesized by T4 RNA ligase (purchased from NEB Company) is: ATGGTTCCTCGCATGATTGTCACCCCCCAGAGCAATCGGCCTGTCATGGGTATTGTGCAGGACACACTCACAGCAGTGCGCAAATTCACCAGAGAGACGTCTTCCTGGAGCGGGTGGAACGGCACATGTGTGATGGGG ACATTGTTATCTTCAACCGGCAGCCAACTCTGCACAAAATGTCCATGATGGGGCATCGGGTCCGCATTCTCCCATGGTCTACCTTTCGCTTGAATCTTAGTGTGACAACTCCGTACAATGCAGACTTTGACGGGGATGAGATGAACTTGCACCTGCCACAGTCTCTGGAGACGCGAGCAGAGATCCAGGAGCTGGCC(SEQ ID NO: 1)) has a double-stranded RNA structural region of 16-26 bp (blue marked region).
- This circular RNA with a special double-stranded RNA structure can inhibit the phosphorylation activation of PKR induced by 79bp dsRNA in in vitro isotope experiments, and therefore can be used as an inhibitor of PKR.
- circPOLR2A with a special double-stranded RNA structure was introduced into the imiquimod-induced autoimmune disease psoriasis mouse model through tail vein injection, and it was found that the inflammatory response related to the disease model mice was alleviated to a certain extent.
- mice After 6 hours, apply imiquimod (administered dose: 62.5 mg/animal) to induce psoriasis disease symptoms. After continuous treatment for 2 days, the mice were sacrificed. The mouse spleens were dissected and separated, weighed, and placed in 70 ⁇ m cells. Grind in a filter, add 3 times the cell volume of red blood cell lysis solution to remove the red blood cells, collect the lymphocytes, and add Trizol reagent to extract the total RNA of the cells. RT-qPCR was performed to detect the mRNA expression of cytokines mIFN ⁇ , mTNF ⁇ and mIL6 respectively. The results of this series of examples show that the introduction of circular RNA with a special double-stranded structure prepared in vitro can alleviate the psoriasis disease phenotype induced by imiquimod to a certain extent.
- mice In order to improve the efficacy of circular RNA in treating imiquimod-induced psoriasis in mice, we treated psoriasis model mice by injecting nano-encapsulated in vitro synthesized circular RNA into the tail vein. In vitro-synthesized circular RNA wrapped in nanoparticles was injected intravenously into the tail. After 24 hours, the mice were sacrificed. The mouse liver, spleen, lungs and kidneys were dissected and separated. The spleen was ground in a 70 ⁇ m cell strainer and added 3 times.
- Red blood cell lysis solution of cell volume was used to remove red blood cells, collect lymphocytes, add Trizol reagent to extract the total RNA of the cells, grind the liver, lung and kidney tissues and add Trizol reagent to extract the total RNA of the cells, and analyze the circular RNA delivery target by Northern Blotting Targeted organs, as shown in Figure 19A, we found that circRNA was mainly delivered to the spleen.
- Figure 19B circular RNA synthesized in vitro is more stable in mice than linear RNA. Circular RNA and linear RNA synthesized in vitro wrapped in nanoparticles were injected into the tail intravenously, and the mice were killed at 6 hours, 24 hours, and 48 hours respectively.
- mice and spleens were dissected and separated, and the spleens were ground in a 70 ⁇ m cell strainer, and Add 3 times the cell volume of red blood cell lysis buffer to remove the red blood cells, collect the lymphocytes, add Trizol reagent to extract the total RNA of the cells, and further analyze it through Northern Blotting.
- Linear RNA is basically completely degraded in 24 hours, and circular RNA is basically completely degraded in 48 hours. Complete degradation, overall, in vitro synthesized circular RNA is more stable in mice than linear RNA. Further analysis was conducted to determine whether the circular RNA delivered to mice can still maintain a double-stranded structure.
- Imiquimod was applied for induction for two consecutive days, and on the 1.5th day, the same volume of physiological saline (PBS) was injected into the tail vein to encapsulate 0.5 ⁇ g, 5 ⁇ g and 15 ⁇ g of circPOLR2A. After 24 hours, the mice were sacrificed after application and dissected. Isolate the mouse spleen, weigh it, grind the spleen in a 70 ⁇ m cell strainer, add 3 times the cell volume of red blood cell lysis solution to remove the red blood cells, collect the lymphocytes, and add RIPA reagent to extract the total protein of the cells. Changes in the phosphorylation level of PKR were further analyzed.
- PBS physiological saline
- PKR was significantly inhibited in mice injected with 5 ⁇ g and 15 ⁇ g of circPOLR2A, indicating that the in vitro synthesized circular RNA with a double-stranded structure caused early onset of disease in the imiquimod-induced psoriasis mouse model. It plays an important regulatory role and can have a therapeutic effect.
- PKR knockout can alleviate imiquimod-induced psoriasis-related phenotypes
- PKR Since the expression level of PKR shows a trend of first increasing and then decreasing during the pathogenesis of psoriasis, we want to further explore the role of PKR in the mouse model induced by imiquimod. As shown in Figure 20A, PKR The expression level of background protein increased significantly on the first day of imiquimod induction, and the expression level was the highest on the second day. Later, as the induction time became longer, the expression of PKR protein also decreased; PKR phosphorylation The protein expression level was highest on the second day after imiquimod application induction. Later, as the application induction time became longer, the expression of PKR phosphorylated protein also decreased; the PKR downstream protein eIF2 ⁇ was expressed on the second day after imiquimod application induction.
- PKR knockout C57/BL6 mouse strain was constructed. As shown in Figure 21A, PKR mice were knocked out by deleting a large fragment of the third exon using CRISPR/CAS9 technology to cause a frameshift mutation.
- PKR KO mice were knocked out by deleting a large fragment of the third exon using CRISPR/CAS9 technology to cause a frameshift mutation.
- RNA-seq analysis of the expression of the third exon and western blotting experiments We found that in imiquimod-induced PKR KO mice, the expression of circular RNA decreased on the first day, as shown in Figure 21B.
- Circular RNA acts as an inhibitor of PKR.
- PKR Circular RNA acts as an inhibitor of PKR.
- IFN ⁇ IFN ⁇ -related marker genes
- the expression levels of mIfi44, mIsg15, mMX2 and the inflammatory factor mIL6 were low, and there were significant differences.
- the expression levels of mIfih1h and mStat1 did not change significantly, as shown in Figure 23.
- Example 6 Brain-localized injection of AAV2/9 overexpressing circPOLR2A can alleviate Alzheimer's disease-related phenotypes
- AAV is currently the safest and most feasible gene overexpression tool and has been successfully used in treatment.
- the therapeutic effect of circPOLR2A overexpression on AD disease was studied in 5 ⁇ FAD mice using AAV as an overexpression vector.
- a plasmid system for AAV overexpression of circPOLR2A and its control linear POLR2A was constructed ( Figure 24A).
- the two ends of the two exons of POLR2A are two complete reverse complementary sequences and two eGFP sequences. The pairing of reverse complementary sequences will promote the back splicing of exons, thereby successfully expressing circPOLR2A.
- the two segments of eGFP will also be spliced to form a complete eGFP mRNA, which will be further translated to express the eGFP fluorescent protein.
- the linear POLR2A plasmid has removed the complete reverse complementary sequence at the 3' end and cannot effectively promote circularization.
- Linear POLR2A is generated by classical splicing. AAV virus was injected stereotaxically into the hippocampus and midbrain of 5xFAD mice, and green fluorescent protein production was detected in the hippocampus three weeks later (Figure 24B, scale bar is 100 ⁇ m). This indicates that the AAV overexpression system of circPOLR2A was successfully established.
- AAV2/9-L and AAV2/9-C were injected into the hippocampus of 8-month-old 5 ⁇ FAD mice, and samples were collected and tested 4 weeks later.
- the injection area that is, the mouse hippocampus tissue
- GFP expression in AAV-C injected mice indicating circPOLR2A production.
- the absolute expression level of circPOLR2A was detected using qPCR, and the results are shown in Table 1. It can be seen that the expression level of circPOLR2A in the mouse samples injected into the intracerebroventricular cavity is relatively high, but there are also relatively greater individual differences.
- Northern Blot detected successful expression of circPOLR2A in hippocampal tissue, and a very small amount of circPOLR2A produced through spontaneous back-splicing was also seen in the linear control group ( Figure 25).
- mice tail vein injection was chosen to achieve overexpression of circPOLR2A in the whole brain of mice.
- AAV-PHP.eB-circPOLR2A was injected into the tail vein of 5 ⁇ FAD mice, and circPOLR2A was successfully overexpressed in the hippocampus and cortex of the mice 4 weeks later (Figure 28, scale bar is 650 ⁇ m).
- the absolute quantification is as follows in Table 2. Extraction of RNA and protein from corresponding tissue homogenates revealed that the expression of related immune genes in the hippocampus and cortex of overexpressed mice was lower than that of control 5 ⁇ FAD mice expressing GFP, and the phosphorylation levels of A ⁇ and PKR were also reduced (Figure 29). Staining of frozen sections of hippocampal tissue showed that the A ⁇ protein plaque load was reduced in circPOLR2A overexpression mice, and there was a statistically significant difference (Figure 30, scale bar is 100 ⁇ m).
- this example uses two different AAV methods to overexpress circPOLR2A, which alleviates Alzheimer's disease-related phenotypes to a certain extent and improves the spatial memory ability of mice.
- circPOLR2A the complementation of circular RNA with a special double-stranded structure (taking circPOLR2A as an example) can alleviate the related phenotypes of Alzheimer's disease to a certain extent, and serve as a PKR inhibitor for the circular RNA aptamer with a special structure.
- Agents may be involved in the treatment of Alzheimer's disease.
- Embodiment 1 Use of circPOLR2A in the preparation of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 2 Use of circPOLR2A in the preparation of a medicament for alleviating or reducing symptoms associated with psoriasis in a subject suffering from psoriasis.
- Embodiment 3 Use of circPOLR2A in the preparation of a medicament for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 4 The use of any of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 5 The use of any of the preceding, wherein the psoriasis is progressive, active or inflammatory phase psoriasis.
- Embodiment 6 The use of any of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 7 The use of any of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 8 The use of any of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 9 The use of any of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive bovine Ringworm.
- Embodiment 10 The use of any of the preceding, wherein the psoriasis-related symptoms comprise skin lesions.
- Embodiment 11 The use of any of the preceding, wherein the psoriasis-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 12 The use of any of the preceding, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 13 The use of any of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 14 The use of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 15 The use of any of the preceding, wherein PKR is abnormally activated in immune cells of the subject.
- Embodiment 16 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 17 The use of embodiment 16, wherein said immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells.
- Embodiment 18 The use of any of the preceding, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 19 The use of any of the preceding, wherein the medicament comprises nanoparticles comprising circPOLR2A.
- Embodiment 20 The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal or oral administration.
- Embodiment 21 The use of any of the preceding, wherein the medicament is formulated to comprise from about 0.03 mg to about 300 mg of circPOLR2A per dosage unit.
- Embodiment 22 The use of any one of the preceding, wherein the single administration amount of the drug is about 0.005 mg/kg to about 5 mg/kg of circPOLR2A.
- Embodiment 23 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 24 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 25 Use of circPOLR2A in the preparation of a medicament for preventing psoriasis.
- Embodiment 26 Use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 27 Use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 28 Use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 29 The use of any of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 30 The use of any of the preceding, wherein the psoriasis is progressive, active or inflammatory phase psoriasis.
- Embodiment 31 The use of any of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 32 The use of any of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 33 The use of any of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 34 The use of any of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 35 The use of any of the preceding, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 36 The use of any of the preceding, wherein the psoriasis-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 37 The use of any of the preceding, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 38 The use of any of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 39 The use of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 40 The use of any of the preceding, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 41 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 42 The use of embodiment 41, wherein said immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells.
- Embodiment 43 The use of any of the preceding, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, Any one or more of circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFG
- Embodiment 44 The use of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16bp-26bp is circPOLR2A.
- Embodiment 45 The use of embodiment 44, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 46 The use of any one of the preceding, wherein the medicament comprises nanoparticles comprising circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 47 The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal or oral administration.
- Embodiment 48 The use of any one of the preceding, wherein the medicament is formulated to comprise from about 0.03 mg to about 300 mg of circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp per dosage unit.
- Embodiment 49 The use of any of the preceding, wherein the single administration amount of the drug is about 0.005 mg/kg to Approximately 5 mg/kg of circular RNA with a 16bp-26bp double-stranded stem-loop structure.
- Embodiment 50 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 51 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 52 Use of circular RNA with a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for preventing psoriasis.
- Embodiment 53 Use of a PKR inhibitor in the manufacture of a medicament for treating psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 54 Use of a PKR inhibitor in the manufacture of a medicament for alleviating or reducing symptoms associated with psoriasis in a subject suffering from psoriasis.
- Embodiment 55 Use of a PKR inhibitor in the manufacture of a medicament for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 56 The use of any of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 57 The use of any of the preceding, wherein the psoriasis is progressive, active or inflammatory phase psoriasis.
- Embodiment 58 The use of any one of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 59 The use of any of the preceding, wherein said psoriasis is chronic psoriasis.
- Embodiment 60 The use of any of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 61 The use of any of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 62 The use of any of the preceding, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 63 The use of any of the preceding, wherein the psoriasis-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 64 The use of any of the preceding, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 65 The use of any of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 66 The use of any of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 67 The use of any of the preceding, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 68 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 69 The use of embodiment 68, wherein said immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells.
- Embodiment 70 The use of any one of the preceding, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- Embodiment 71 The use of embodiment 70, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2 , any one or more of circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFG
- Embodiment 72 The use of embodiment 73, wherein the circular RNA having a double-stranded stem-loop structure of 16bp-26bp is circPOLR2A.
- Embodiment 73 The use of embodiment 74, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 74 The use of any of the preceding, wherein the medicament comprises nanoparticles comprising a PKR inhibitor.
- Embodiment 75 The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal or oral administration.
- Embodiment 76 The use of any of the preceding, wherein the medicament is formulated to contain from about 0.03 mg to about 300 mg of a PKR inhibitor per dosage unit.
- Embodiment 77 The use of any one of the preceding, wherein the single administration amount of the drug is from about 0.005 mg/kg to about 5 mg/kg of a PKR inhibitor.
- Embodiment 78 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 79 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 80 Use of a PKR inhibitor in the preparation of a medicament for preventing psoriasis.
- Embodiment 81 circPOLR2A for treating psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 82 circPOLR2A for use in alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 83 circPOLR2A for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 84 circPOLR2A for the use of any one of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 85 The circPOLR2A of any of the preceding for the use, wherein the psoriasis is progressive, active or inflammatory phase psoriasis.
- Embodiment 86 The circPOLR2A of any one of the preceding for the use, wherein the psoriasis is relapsing psoriasis.
- Embodiment 87 The circPOLR2A of any of the preceding for the use, wherein the psoriasis is chronic Psoriasis.
- Embodiment 88 The circPOLR2A of any one of the preceding for the use, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 89 The circPOLR2A of any of the preceding for the use, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 90 The circPOLR2A of any of the preceding for the use, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 91 The circPOLR2A of any of the preceding for the use, wherein the psoriasis-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 92 The circPOLR2A of any of the preceding for the use, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 93 circPOLR2A for the use of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 94 The circPOLR2A for the use of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 95 The circPOLR2A of any of the preceding for the use, wherein PKR in the immune cells of the subject is aberrantly activated.
- Embodiment 96 The circPOLR2A of any of the preceding for the use, wherein the PKR in the immune cells of the subject is hyperphosphorylated.
- Embodiment 97 The circPOLR2A for the use of embodiment 96, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells.
- Embodiment 98 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 99 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is comprised in a nanoparticle.
- Embodiment 100 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered intravenously, subcutaneously, intramuscularly, topically, topically, inhaled, mucosally, or orally.
- Embodiment 101 The circPOLR2A for the use of any one of the preceding, wherein the dosage unit of the circPOLR2A is from about 0.03 mg to about 300 mg.
- Embodiment 102 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 103 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered once daily, once every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 104 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered once a month, once every other month, once every 3 months, or once every 6 months.
- Embodiment 105 circPOLR2A for preventing psoriasis.
- Embodiment 106 A circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA, which is used to treat psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 107 A circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA for use in alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 108 A circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 109 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 110 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis is progressive, active or inflammatory stage psoriasis.
- Embodiment 111 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis is relapsing psoriasis.
- Embodiment 112 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis is chronic psoriasis.
- Embodiment 113 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 114 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 115 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 116 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the psoriasis-related symptoms include or involve overexpression of inflammatory cytokines.
- Embodiment 117 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the psoriasis-related symptoms include lymphoid organ enlargement.
- Embodiment 118 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the psoriasis-related symptoms are related to or mediated by abnormal activation of PKR.
- Embodiment 119 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of any one of the preceding, wherein the psoriasis-related symptoms are related to or mediated by abnormal activation of RNase L.
- Embodiment 120 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein PKR in the immune cells of the subject is abnormally activated.
- Embodiment 121 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein PKR in the immune cells of the subject is hyperphosphorylated.
- Embodiment 122 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of embodiment 121, wherein the immune cell is selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells .
- Embodiment 123 A circular shape with a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding RNA, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC , any one or more of circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2,
- Embodiment 124 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp-26 bp is circPOLR2A.
- Embodiment 125 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of embodiment 124, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 126 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp-26 bp is contained in a nanoparticle.
- Embodiment 127 The circular RNA with a double-stranded stem-loop structure of 16-26bp for the use according to any one of the preceding items, wherein the circular RNA with a double-stranded stem-loop structure of 16-26bp is passed intravenously, subcutaneously, muscle, Topical, topical, inhalation, mucosal or oral administration.
- Embodiment 128 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the dosage unit of the circular RNA having a double-stranded stem-loop structure of 16-26 bp is about 0.03 mg. to about 300mg.
- Embodiment 129 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA having a 16-26 bp double-stranded stem-loop structure is administered at about 0.005 mg/kg to Approximately 5 mg/kg is administered.
- Embodiment 130 The circular RNA with a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is administered once a day and once every other day. administration, twice weekly, once weekly, or once every two weeks.
- Embodiment 131 The circular RNA with a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is administered once a month and once every other month. Apply, once every 3 months, or once every 6 months.
- Embodiment 132 Circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA, which is used to prevent psoriasis.
- Embodiment 133 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in treating psoriasis or psoriasis-related symptoms in a subject.
- Embodiment 134 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in alleviating or reducing psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 135. A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis.
- Embodiment 136 The PKR inhibitor for use according to any one of the preceding items or a medicament containing a PKR inhibitor
- Embodiment 137 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis is progressive, active or inflammatory phase psoriasis.
- Embodiment 138 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 139 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 140 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 141 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 142 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 143 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 144 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis-related symptoms include lymphadenopathy.
- Embodiment 145 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 146 The PKR inhibitor for the use of any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the psoriasis-related symptoms are related to or mediated by abnormal activation of RNase L.
- Embodiment 147 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein PKR in the immune cells of the subject is abnormally activated.
- Embodiment 148 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein PKR in the immune cells of the subject is hyperphosphorylated.
- Embodiment 149 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 148, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes and dendritic cells .
- Embodiment 150 The PKR inhibitor for the use according to any one of the preceding items or the pharmaceutical composition comprising the PKR inhibitor, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 151 The PKR inhibitor for the use of Embodiment 150 or the pharmaceutical composition comprising a PKR inhibitor, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM18 1. Any one of circUIMC1, circVAPB or Multiple.
- Embodiment 152 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 150, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 153 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 152, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 154 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the PKR inhibitor is contained in a nanoparticle.
- Embodiment 155 The PKR inhibitor for use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is administered intravenously, subcutaneously, intramuscularly, topically, on the body, inhaled, mucosally or Administer orally.
- Embodiment 156 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the dosage unit of the PKR inhibitor is from about 0.03 mg to about 300 mg.
- Embodiment 157 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the PKR inhibitor is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 158 The PKR inhibitor for use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is administered once daily, once every other day, twice a week, every Apply once a week, or once every two weeks.
- Embodiment 159 The PKR inhibitor for the use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is administered once a month, once every other month, or once every 3 months, Or apply every 6 months.
- Embodiment 160 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in preventing psoriasis.
- Embodiment 161 A method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 162 A method of alleviating or alleviating psoriasis-related symptoms in a subject having psoriasis, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 163 A method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject having psoriasis, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 164 The method of any one of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 165 The method of any one of the preceding, wherein the psoriasis is progressive, active, or inflammatory phase psoriasis.
- Embodiment 166 The method of any one of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 167 The method of any one of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 168 The method of any one of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 169 The method of any one of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 170 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise skin lesions.
- Embodiment 171 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise or involve inflammatory cytokine overexpression.
- Embodiment 172 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 173 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by aberrant activation of PKR.
- Embodiment 174 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 175. The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 176 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 177 The method of Embodiment 176, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, and dendritic cells.
- Embodiment 178 The method of any one of the preceding, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 179 The method of any one of the preceding, wherein said circPOLR2A is comprised in a nanoparticle.
- Embodiment 180 The method of any one of the preceding, wherein said circPOLR2A is administered intravenously, subcutaneously, intramuscularly, topically, topically, inhaled, mucosally, or orally.
- Embodiment 181 The method of any one of the preceding, wherein the dosage unit of circPOLR2A is from about 0.03 mg to about 300 mg.
- Embodiment 182 The method of any one of the preceding, wherein said circPOLR2A is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 183 The method of any one of the preceding, wherein the circPOLR2A is administered once daily, every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 184 The method of any one of the preceding, wherein the circPOLR2A is administered monthly, every other month, every 3 months, or every 6 months.
- Embodiment 185 A method of preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of circPOLR2A.
- Embodiment 186 A method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a double-stranded stem-loop structure of 16-26 bp.
- Embodiment 187 A method of alleviating or alleviating psoriasis-related symptoms in a subject suffering from psoriasis, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a 16-26 bp double-stranded stem-loop structure.
- Embodiment 188 A method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject suffering from psoriasis, comprising administering to the subject a therapeutically effective amount of a circular RNA having a 16-26 bp double-stranded stem-loop structure.
- Embodiment 189 The method of any one of the preceding, wherein the psoriasis is telogen, remission or catagen. Ringworm.
- Embodiment 190 The method of any one of the preceding, wherein the psoriasis is progressive, active, or inflammatory phase psoriasis.
- Embodiment 191 The method of any one of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 192 The method of any one of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 193 The method of any one of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 194 The method of any one of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 195 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise skin lesions.
- Embodiment 196 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise or involve inflammatory cytokine overexpression.
- Embodiment 197 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise lymphadenopathy.
- Embodiment 198 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by aberrant activation of PKR.
- Embodiment 199 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 200 The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 201 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 202 The method of Embodiment 201, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, and dendritic cells.
- Embodiment 203 The method of any one of the preceding, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, Any one or more of circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2,
- Embodiment 204 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 205 The method of embodiment 204, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 206 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is contained in a nanoparticle.
- Embodiment 207 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered intravenously, subcutaneously, intramuscularly, topically, topically, inhaled, mucosally, or orally.
- Embodiment 208 The method of any one of the preceding, wherein the dosage unit of the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is from about 0.03 mg to about 300 mg.
- Embodiment 209 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 210 The method of any one of the preceding, wherein the circular RNA having a 16bp-26bp double-stranded stem-loop structure is administered once daily, once every other day, twice weekly, once weekly, or every two weeks One application.
- Embodiment 211 The method of any one of the preceding items, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered once a month, once every other month, once every 3 months, or once every 6 months.
- Embodiment 212 A method of preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of a circular RNA having a 16-26 bp double-stranded stem-loop structure.
- Embodiment 21 A method of treating psoriasis or psoriasis-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 214 A method of alleviating or reducing symptoms associated with psoriasis in a subject having psoriasis, comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 215. A method of preventing or delaying the onset or progression of psoriasis-related symptoms in a subject having psoriasis, comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 216 The method of any one of the preceding, wherein the psoriasis is quiescent, remission or catagen psoriasis.
- Embodiment 217 The method of any one of the preceding, wherein the psoriasis is progressive, active, or inflammatory phase psoriasis.
- Embodiment 218 The method of any one of the preceding, wherein the psoriasis is relapsing psoriasis.
- Embodiment 219. The method of any one of the preceding, wherein the psoriasis is chronic psoriasis.
- Embodiment 220 The method of any one of the preceding, wherein the psoriasis is moderate/severe psoriasis.
- Embodiment 2221 The method of any one of the preceding, wherein the psoriasis is S100A8 and/or S100A9 positive psoriasis.
- Embodiment 222 The method of any one of the preceding, wherein the psoriasis-related symptoms include skin lesions.
- Embodiment 223. The method of any one of the preceding, wherein the psoriasis-related symptoms comprise or involve inflammatory cytokine overexpression.
- Embodiment 224 The method of any one of the preceding, wherein the psoriasis-related symptoms comprise lymphoid organomegaly.
- Embodiment 225 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by aberrant activation of PKR.
- Embodiment 226 The method of any one of the preceding, wherein the psoriasis-related symptoms are associated with or mediated by abnormal activation of RNase L.
- Embodiment 227 The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 228 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 229. The method of Embodiment 228, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, and dendritic cells.
- Embodiment 230 The method of any one of the preceding, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 231 The method of embodiment 230, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2 , any one or more of circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circ
- Embodiment 232 The method of embodiment 233, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 233 The method of embodiment 234, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 234 The method of any one of the preceding, wherein the PKR inhibitor is comprised in a nanoparticle.
- Embodiment 235 The method of any one of the preceding, wherein the PKR inhibitor is administered intravenously, subcutaneously, intramuscularly, topically, topically, by inhalation, mucosally, or orally.
- Embodiment 236 The method of any one of the preceding, wherein the dosage unit of the PKR inhibitor is from about 0.03 mg to about 300 mg.
- Embodiment 237 The method of any one of the preceding, wherein the PKR inhibitor is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 238 The method of use of any of the preceding, wherein the PKR inhibitor is administered once daily, every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 239. The method of any one of the preceding, wherein the PKR inhibitor is administered monthly, every other month, every 3 months, or every 6 months.
- Embodiment 240 A method of preventing psoriasis in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor.
- Embodiment 24 Use of circPOLR2A in the preparation of a medicament for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 242 Use of circPOLR2A in the preparation of a medicament for alleviating or reducing symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- Embodiment 243 Use of circPOLR2A in the preparation of a medicament for preventing or delaying the onset or progression of symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- Embodiment 244 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 245. The use of embodiment 244, wherein the pathological signature of Alzheimer's disease is selected from the group consisting of Tau Protein phosphorylation, or production, assembly, aggregation or deposition of A ⁇ peptide.
- Embodiment 246 The use of any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 247 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 248 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 249. The use of any of the preceding, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 250 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 251 The use of embodiment 250, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia.
- Embodiment 252 The use of any of the preceding, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 253 The use of any of the preceding, wherein the medicament comprises nanoparticles comprising circPOLR2A.
- Embodiment 254 The use of any of the preceding, wherein the medicament comprises a delivery vector encoding circPOLR2A.
- Embodiment 255 The use of embodiment 254, wherein the delivery vector is an AAV vector.
- Embodiment 256 The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal, intracranial, intrathecal, or oral administration.
- Embodiment 257 The use of any of the preceding, wherein the medicament is formulated to contain from about 0.03 mg to about 300 mg of circPOLR2A per dosage unit.
- Embodiment 258 The use of any one of the preceding, wherein a single administration of the drug is from about 0.005 mg/kg to about 5 mg/kg of circPOLR2A.
- Embodiment 259 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 260 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 26 Use of circPOLR2A in the preparation of a medicament for preventing Alzheimer's disease.
- Embodiment 262 Use of circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 263 Use of a circular RNA having a 16-26 bp double-stranded stem-loop structure in the preparation of a medicament for alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- Embodiment 264 Preparation of circular RNA with a 16-26 bp double-stranded stem-loop structure for use in patients with Alzheimer's disease Use in drugs that prevent or delay the onset or progression of symptoms associated with Alzheimer's disease in subjects with Alzheimer's disease.
- Embodiment 265. The use of any of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 266 The use of embodiment 265, wherein the pathological hallmark of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or production, assembly, aggregation or deposition of A[beta] peptide.
- Embodiment 267 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 268 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 269. The use of any of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 270 The use of any of the preceding, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 271 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 272 The use of embodiment 271, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia.
- Embodiment 273 The use of any of the preceding, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, Any one or more of circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circ
- Embodiment 274 The use of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16bp-26bp is circPOLR2A.
- Embodiment 275 The use of embodiment 274, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 276 The use of any one of the preceding, wherein the medicament comprises a nanoparticle comprising a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 277 The use of embodiment 276, wherein the medicament comprises a delivery vector encoding a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 278 The use of embodiment 277, wherein the delivery vector is an AAV vector.
- Embodiment 279. The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal, intracranial, intrathecal, or oral administration.
- Embodiment 280 The use of any of the preceding, wherein the medicament is formulated to comprise from about 0.03 mg to about 300 mg of circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp per dosage unit.
- Embodiment 281. The use of any of the preceding, wherein the single administration amount of the drug is from about 0.005 mg/kg to Approximately 5 mg/kg of circular RNA with a 16bp-26bp double-stranded stem-loop structure.
- Embodiment 282 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 283 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 28 Use of circular RNA with a 16-26 bp double-stranded stem-loop structure in the preparation of drugs for preventing Alzheimer's disease.
- Embodiment 285. Use of a PKR inhibitor in the manufacture of a medicament for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 286 Use of a PKR inhibitor in the manufacture of a medicament for alleviating or reducing symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- Embodiment 287 The use of a PKR inhibitor in the manufacture of a medicament for preventing or delaying the onset or progression of symptoms associated with Alzheimer's disease in a subject suffering from Alzheimer's disease.
- Embodiment 288 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 289. The use of embodiment 288, wherein the pathological sign of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or production, assembly, aggregation or deposition of A[beta] peptide.
- Embodiment 290 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 291 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 292 The use of any of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 293 The use of any of the preceding, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 294 The use of any of the preceding, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 295. The use of embodiment 294, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia.
- Embodiment 296 The use of any one of the preceding, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16bp-26bp.
- Embodiment 297 The use of embodiment 296, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2 , circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, Any one or more of circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFG
- Embodiment 298 The use of embodiment 296, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 299. The use of embodiment 298, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 300 The use of any of the preceding, wherein the medicament comprises nanoparticles comprising a PKR inhibitor.
- Embodiment 301 The use of any of the preceding, wherein the medicament comprises a delivery vector encoding a PKR inhibitor.
- Embodiment 302. The use of embodiment 301, wherein the delivery vector is an AAV vector.
- Embodiment 303 The use of any of the preceding, wherein the medicament is formulated for intravenous, subcutaneous, intramuscular, topical, topical, inhalation, mucosal, intracranial, intrathecal, or oral administration.
- Embodiment 304 The use of any of the preceding, wherein the medicament is formulated to contain from about 0.03 mg to about 300 mg of a PKR inhibitor per dosage unit.
- Embodiment 305 The use of any one of the preceding, wherein the single administration amount of the drug is from about 0.005 mg/kg to about 5 mg/kg of a PKR inhibitor.
- Embodiment 306 The use of any of the preceding, wherein the medicament is formulated for daily administration, every other day administration, twice weekly administration, weekly administration, or biweekly administration.
- Embodiment 307 The use of any of the preceding, wherein the medicament is formulated for administration once a month, every other month, every 3 months, or every 6 months.
- Embodiment 308 Use of a PKR inhibitor in the manufacture of a medicament for preventing Alzheimer's disease.
- Embodiment 309 circPOLR2A for treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 310 circPOLR2A for use in alleviating or reducing Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- Embodiment 311 circPOLR2A for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- Embodiment 312 The circPOLR2A of any of the preceding for the use, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 314. circPOLR2A for the use according to any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, and impaired judgment. impairment, personality changes, disorientation, or loss of language skills.
- Embodiment 315 The circPOLR2A of any of the preceding for the use, wherein the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 316 The circPOLR2A of any of the preceding for the use, wherein the Alzheimer's disease Relevant symptoms are related to or mediated by abnormal activation of PKR.
- Embodiment 317 The circPOLR2A of any of the preceding for the use, wherein PKR is aberrantly activated in immune cells of the subject.
- Embodiment 318 The circPOLR2A of any of the preceding for the use, wherein the PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 319 The circPOLR2A for the use of embodiment 318, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia.
- Embodiment 320 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 3221 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is comprised in a nanoparticle.
- Embodiment 322 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is encoded in a delivery vector.
- Embodiment 323 The use of embodiment 322, wherein the delivery vector is an AAV vector.
- Embodiment 324 The circPOLR2A for the use of any of the preceding, wherein the circPOLR2A is administered intravenously, subcutaneously, intramuscularly, topically, topically, by inhalation, mucosally, intracranially, intrathecally, or orally.
- Embodiment 325 The circPOLR2A for the use of any one of the preceding, wherein the dosage unit of the circPOLR2A is from about 0.03 mg to about 300 mg.
- Embodiment 326 The circPOLR2A of any of the preceding for the use, wherein the circPOLR2A is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 327 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered once daily, every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 328 The circPOLR2A for the use of any one of the preceding, wherein the circPOLR2A is administered once a month, once every other month, once every 3 months, or once every 6 months.
- Embodiment 329 circPOLR2A for preventing Alzheimer's disease.
- Embodiment 330 A circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA, which is used to treat Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 331 Circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA for use in alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease. symptom.
- Embodiment 332 Circular RNA having a 16-26 bp double-stranded stem-loop structure or a pharmaceutical composition comprising the circular RNA for preventing or delaying Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease The onset or progression of symptoms.
- Embodiment 333 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the Alzheimer's disease-related symptoms include pathological manifestations of Alzheimer's disease.
- Embodiment 334 A circular shape having a 16-26 bp double-stranded stem-loop structure for the use of Embodiment 333 RNA, wherein the pathological manifestation of Alzheimer's disease is selected from phosphorylation of Tau protein, or production, assembly, aggregation or deposition of A ⁇ peptide.
- Embodiment 335 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, Loss of learning and memory, confusion, impaired judgment, personality changes, disorientation, or loss of language skills.
- Embodiment 336 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the Alzheimer's disease-related symptoms include or involve overexpression of inflammatory cytokines.
- Embodiment 337 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein the Alzheimer's disease-related symptoms are related to or mediated by abnormal activation of PKR. .
- Embodiment 338 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein PKR in the immune cells of the subject is abnormally activated.
- Embodiment 339 The circular RNA having a 16-26 bp double-stranded stem-loop structure for use according to any one of the preceding items, wherein PKR in the immune cells of the subject is hyperphosphorylated.
- Embodiment 340 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of embodiment 339, wherein the immune cell is selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, and dendritic cells and microglia.
- Embodiment 341 The circular RNA with a 16-26 bp double-stranded stem-loop structure for use in any of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, and circCCNB1 , circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM1 81. Any one of circUIMC1 and circVAPB or more.
- Embodiment 342 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA having a 16-26 bp double-stranded stem-loop structure is circPOLR2A.
- Embodiment 343 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use of embodiment 342, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 344 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp-26 bp is contained in a nanoparticle.
- Embodiment 345 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp-26 bp is encoded in a delivery vector.
- Embodiment 346 The use of embodiment 345, wherein the delivery vector is an AAV vector.
- Embodiment 347 The circular RNA with a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is passed intravenously, subcutaneously, muscle, Topical, topical, inhalation, mucosal, intracranial, intrathecal, or oral administration.
- Embodiment 348 The circular RNA having a double-stranded stem-loop structure of 16-26 bp for the use according to any one of the preceding items, wherein the dosage unit of the circular RNA having a double-stranded stem-loop structure of 16-26 bp is about 0.03 mg. to date 300mg.
- Embodiment 349 The circular RNA having a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA having a 16-26 bp double-stranded stem-loop structure is administered at about 0.005 mg/kg to Approximately 5 mg/kg is administered.
- Embodiment 350 The circular RNA with a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is administered once a day and once every other day. administration, twice weekly, once weekly, or once every two weeks.
- Embodiment 351 The circular RNA with a 16-26 bp double-stranded stem-loop structure for the use according to any one of the preceding items, wherein the circular RNA with a 16-26 bp double-stranded stem-loop structure is administered once a month and once every other month. Apply, once every 3 months, or once every 6 months.
- Embodiment 352 Circular RNA having a double-stranded stem-loop structure of 16-26 bp or a pharmaceutical composition comprising the circular RNA for preventing Alzheimer's disease.
- Embodiment 353 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject.
- Embodiment 354 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in alleviating or reducing Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- Embodiment 355. A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease.
- Embodiment 356 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 357 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 356, wherein the pathological manifestation of Alzheimer's disease is selected from the group consisting of phosphorylation of Tau protein, or phosphorylation of A ⁇ peptide. To produce, assemble, gather or deposit.
- Embodiment 358 The PKR inhibitor for the use of any one of the preceding, or a pharmaceutical composition comprising a PKR inhibitor, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, Loss of learning and memory, confusion, impaired judgment, personality changes, disorientation, or loss of language skills.
- Embodiment 359 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the Alzheimer's disease-related symptoms include or involve overexpression of inflammatory cytokines.
- Embodiment 360 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by abnormal activation of PKR .
- Embodiment 361 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein PKR in immune cells of the subject is abnormally activated.
- Embodiment 362 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein PKR in the immune cells of the subject is hyperphosphorylated.
- Embodiment 363 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 362, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells and microglia.
- Embodiment 364 The PKR inhibitor for use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 365 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 364, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM18 1. Any one of circUIMC1, circVAPB or Multiple.
- Embodiment 366 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 364, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 367 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of embodiment 366, wherein the circPOLR2A is human circPOLR2A.
- Embodiment 368 The PKR inhibitor of any of the preceding for said use, wherein said PKR inhibitor is comprised in a nanoparticle.
- Embodiment 369 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the PKR inhibitor is encoded in a delivery vector.
- Embodiment 370 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of Embodiment 369, wherein the delivery vehicle is an AAV vector.
- Embodiment 371 The PKR inhibitor for use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is administered intravenously, subcutaneously, intramuscularly, topically, on the body, inhaled, mucosally, Intracranial, intrathecal, or oral administration.
- Embodiment 372 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the dosage unit of the PKR inhibitor is from about 0.03 mg to about 300 mg.
- Embodiment 373 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the PKR inhibitor is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 374 The PKR inhibitor or pharmaceutical composition comprising a PKR inhibitor for the use of any one of the preceding, wherein the PKR inhibitor is administered once daily, once every other day, twice weekly, every Apply once a week, or once every two weeks.
- Embodiment 375 The PKR inhibitor for use according to any one of the preceding items or a pharmaceutical composition comprising a PKR inhibitor, wherein the PKR inhibitor is administered once a month, once every other month, or once every 3 months, Or apply every 6 months.
- Embodiment 376 A PKR inhibitor or a pharmaceutical composition comprising a PKR inhibitor for use in preventing Alzheimer's disease.
- Embodiment 377 A method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 378 A method of alleviating or reducing symptoms associated with Alzheimer's disease in a subject having Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 379 A method of preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject having Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of circPOLR2A.
- Embodiment 380 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 381. The method of Embodiment 380, wherein the pathological sign of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or production, assembly, aggregation or deposition of A[beta] peptide.
- Embodiment 382 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 383 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise or involve inflammatory cytokine overexpression.
- Embodiment 384 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by aberrant activation of PKR.
- Embodiment 385 The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 386 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 387 The method of Embodiment 386, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells, and microglia.
- Embodiment 388 The method of any one of the preceding, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 389 The method of any one of the preceding, wherein said circPOLR2A is comprised in a nanoparticle.
- Embodiment 390 The method of any one of the preceding, wherein said circPOLR2A is encoded in a delivery vector.
- Embodiment 391. The method of embodiment 390, wherein the delivery vector is an AAV vector.
- Embodiment 392 The method of any one of the preceding, wherein the circPOLR2A is administered intravenously, subcutaneously, intramuscularly, topically, topically, inhalation, mucosally, intracranially, intrathecally, or orally.
- Embodiment 393 The method of any one of the preceding, wherein the dosage unit of circPOLR2A is from about 0.03 mg to about 300 mg.
- Embodiment 394 The method of any one of the preceding, wherein said circPOLR2A is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 395 The method of any one of the preceding, wherein the circPOLR2A is administered once daily, every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 396 The method of any of the preceding, wherein the circPOLR2A is administered once a month, once every other month Apply, once every 3 months, or once every 6 months.
- Embodiment 397 A method of preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of circPOLR2A.
- Embodiment 398 A method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a circular RNA having a 16-26 bp double-stranded stem-loop structure.
- Embodiment 399 A method of alleviating or alleviating Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a double-stranded stem-loop structure having a 16-26 bp of circular RNA.
- Embodiment 400 A method of preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject suffering from Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a 16-26 bp doublet. Circular RNA with stem-loop structure.
- Embodiment 401 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 402. The method of Embodiment 401, wherein the pathological sign of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or production, assembly, aggregation or deposition of A[beta] peptide.
- Embodiment 403. The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory abilities, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 404 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms include or involve inflammatory cytokine overexpression.
- Embodiment 405 The method of any of the preceding, wherein the Alzheimer's disease-related symptoms are associated with or mediated by abnormal activation of PKR.
- Embodiment 406 The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 407 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 408 The method of Embodiment 407, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells, and microglia.
- Embodiment 409 The method of any one of the preceding, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, Any one or more of circMBOAT2, circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2,
- Embodiment 410 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 411 The method of embodiment 410, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 412 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is contained in a nanoparticle.
- Embodiment 413 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is encoded in a delivery vector.
- Embodiment 414 The method of Embodiment 413, wherein the delivery vector is an AAV vector.
- Embodiment 415 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered intravenously, subcutaneously, intramuscularly, topically, topically, by inhalation, mucosally, intracranially, intrathecally, or orally. .
- Embodiment 416 The method of any one of the preceding, wherein the dosage unit of the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is from about 0.03 mg to about 300 mg.
- Embodiment 417 The method of any one of the preceding, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 418 The method of any one of the preceding, wherein the circular RNA having a 16bp-26bp double-stranded stem-loop structure is administered once a day, every other day, twice a week, once a week, or every two weeks One application.
- Embodiment 419 The method of any one of the preceding, wherein the circular RNA having a 16bp-26bp double-stranded stem-loop structure is administered once a month, once every other month, once every 3 months, or once every 6 months.
- Embodiment 420 A method of preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of a circular RNA having a double-stranded stem-loop structure of 16-26 bp.
- Embodiment 421 A method of treating Alzheimer's disease or Alzheimer's disease-related symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 422 A method of alleviating or reducing symptoms associated with Alzheimer's disease in a subject having Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 423 A method of preventing or delaying the onset or progression of Alzheimer's disease-related symptoms in a subject having Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of a PKR inhibitor.
- Embodiment 424 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise pathological manifestations of Alzheimer's disease.
- Embodiment 425 The method of Embodiment 424, wherein the pathological hallmark of Alzheimer's disease is selected from the group consisting of Tau protein phosphorylation, or production, assembly, aggregation or deposition of A[beta] peptide.
- Embodiment 426 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms are selected from the group consisting of cognitive decline, neurodegeneration, memory loss, loss of learning and memory ability, confusion, impaired judgment, personality changes, disorientation Impairment or loss of language skills.
- Embodiment 427 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms comprise or involve inflammatory cytokine overexpression.
- Embodiment 428 The method of any one of the preceding, wherein the Alzheimer's disease-related symptoms are associated with abnormal PKR activity. ionization or mediated by abnormal activation of PKR.
- Embodiment 429 The method of any one of the preceding, wherein PKR is aberrantly activated in the subject's immune cells.
- Embodiment 430 The method of any one of the preceding, wherein PKR in the subject's immune cells is hyperphosphorylated.
- Embodiment 431 The method of Embodiment 430, wherein the immune cells are selected from the group consisting of T lymphocytes, B lymphocytes, monocytes, dendritic cells, and microglia.
- Embodiment 432 The method of any one of the preceding, wherein the PKR inhibitor is a circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp.
- Embodiment 433 The method of embodiment 432, wherein the circular RNA with a 16bp-26bp double-stranded stem-loop structure is selected from the group consisting of circARID1B, circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circFGFR1, circFKBP8, circKIAA0368, circMBOAT2 , any one or more of circPIP5K1C, circPOLR2A, circPPP1CB, circPROSC, circPTK2, circPVT1, circRELL1, circSDHAF2, circSLC22A23, circSNHG4, circTBCD, circTMEM181, circUIMC1, and circVAPB.
- circARID1B circCAMSAP1, circCCNB1, circCNN2, circDHX34, circEPHB4, circEZH2, circFCHO2, circ
- Embodiment 434 The method of embodiment 433, wherein the circular RNA having a double-stranded stem-loop structure of 16 bp to 26 bp is circPOLR2A.
- Embodiment 435 The method of embodiment 434, wherein said circPOLR2A is human circPOLR2A.
- Embodiment 436 The method of any one of the preceding, wherein the PKR inhibitor is comprised in a nanoparticle.
- Embodiment 437 The method of any one of the preceding, wherein the PKR inhibitor is encoded in a delivery vector.
- Embodiment 438 The method of Embodiment 437, wherein the delivery vector is an AAV vector.
- Embodiment 439 The method of any one of the preceding, wherein the PKR inhibitor is administered intravenously, subcutaneously, intramuscularly, topically, topically, by inhalation, mucosally, intracranially, intrathecally, or orally.
- Embodiment 440 The method of any one of the preceding, wherein the dosage unit of the PKR inhibitor is from about 0.03 mg to about 300 mg.
- Embodiment 4421 The method of any one of the preceding, wherein the PKR inhibitor is administered at about 0.005 mg/kg to about 5 mg/kg.
- Embodiment 442 The method of use of any of the preceding, wherein the PKR inhibitor is administered once daily, every other day, twice weekly, once weekly, or once every two weeks.
- Embodiment 443 The method of any one of the preceding, wherein the PKR inhibitor is administered monthly, every other month, every 3 months, or every 6 months.
- Embodiment 444 A method of preventing Alzheimer's disease in a subject, the method comprising administering to the subject a prophylactically effective amount of a PKR inhibitor.
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Abstract
提供一种治疗对象中的牛皮癣或阿尔兹海默症的方法，包括向所述对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA。
Description
本发明涉及生物医药领域，具体而言，涉及治疗对象中的牛皮癣或阿尔兹海默症的方法，其包括向所述对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA。
发明背景
牛皮癣是一种慢性皮肤病，发病后大部分都会持续10-20年的时间，即使经过治疗会暂时好转，也必须终生冒着可能复发的风险生活。牛皮癣以边界分明的银白色鳞屑覆盖的红斑性皮肤病变为特征，主要在受到刺激较多部位的胳膊肘、膝盖、臀部、头皮等处发生。另外，牛皮癣通常会伴随多种并发症。其中，包括牛皮癣患者产生的特异性关节炎即牛皮癣关节炎。这种牛皮癣目前还没有能够直接预防发病的方法，预防其恶化就是最佳的方法。
阿尔兹海默症(AD)作为一类神经退行性疾病已被研究数十年。过去的研究多数集中在Aβ斑的沉积及神经纤维缠结上，但是并未发现有效的阿尔兹海默症治疗手段。近年来，越来越多的研究开始关注阿尔兹海默症中的神经免疫系统的异常激活。有大量研究发现在阿尔兹海默症患者及小鼠模型中PKR的表达水平及磷酸化水平有明显升高。PKR作为一类双链RNA结合蛋白，在众多天然免疫信号通路中发挥作用。同时，研究发现PKR可以作为Tau磷酸化激酶，直接影响Tau磷酸化水平，PKR敲除可以提高阿尔兹海默症(AD)模型小鼠的学习与记忆能力。
因此，有必要针对牛皮癣以及阿尔兹海默症疾病提供有效的治疗及预防方法。
发明内容
本发明人首次发现，PKR在牛皮癣患者中存在异常活化，以及具有特定双链结构的环形RNA的表达水平可以作为一种全新靶点用于自身免疫疾病如牛皮癣(psoriasis)的干预治疗中。尤其是，具有16bp-26bp双链茎环结构的环形RNA能够通过抑制PKR二聚化，缓解PKR的异常活化，降低与牛皮癣相关的炎性细胞因子(尤其是B淋巴细胞和单核细胞中的炎性细胞因子)的表达水平，如IFNβ、IL6、IL17A、IL23、RIG-I及TNFα，进而治疗或预防牛皮癣。
在第一方面，本发明提供circPOLR2A在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。本发明还提供circPOLR2A在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。本发明还提供circPOLR2A在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。本发明还提供circPOLR2A在制备用于预防牛皮癣的药物中的用途。
在第二方面，本发明提供具有16-26bp双链茎环结构的环形RNA在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于预防牛皮癣的药物中的用途。
在第三方面，本发明提供PKR抑制剂在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。本发明还提供PKR抑制剂在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。本发明还提供PKR抑制剂在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。本发明还提供PKR抑制剂在制备用于预防牛皮癣的药物中的用途。
在第四方面，本发明提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在对象中治疗牛皮癣或牛皮癣相关症状。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在对象中预防牛皮癣。
在第五方面，本发明提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在对象中治疗牛皮癣或牛皮癣相关症状。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在对象中预防牛皮癣。
在第六方面，本发明提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在对象中治疗牛皮癣或牛皮癣相关症状。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在对象中预防牛皮癣。
在第七方面，本发明提供一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本发明还提供一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本发明还提供一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本
发明还提供一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的circPOLR2A或包含circPOLR2A的药物组合物。
在第八方面，本发明提供一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。
在第九方面，本发明提供一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。
本发明人还证明，具有16bp-26bp双链茎环结构的环形RNA能够通过抑制PKR二聚化，缓解PKR的异常活化，从而在一定程度上缓解阿尔兹海默症的疾病表型，说明环形RNA有望成为一种全新的针对阿尔兹海默症的早期干预与治疗手段。
在第十方面，本发明提供circPOLR2A在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。本发明还提供circPOLR2A在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。本发明还提供circPOLR2A在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。本发明还提供circPOLR2A在制备用于预防阿尔兹海默症的药物中的用途。
在第十一方面，本发明提供具有16-26bp双链茎环结构的环形RNA在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。本发明还提供具有16-26bp双链茎环结构的环形RNA在制备用于预防阿尔兹海默症的药物中的用途。
在第十二方面，本发明提供PKR抑制剂在制备用于治疗对象的阿尔兹海默症或阿
尔兹海默症相关症状的药物中的用途。本发明还提供PKR抑制剂在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。本发明还提供PKR抑制剂在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。本发明还提供PKR抑制剂在制备用于预防阿尔兹海默症的药物中的用途。
在第十三方面，本发明提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。本发明还提供circPOLR2A或包含circPOLR2A的药物组合物，其用于在对象中预防阿尔兹海默症。
在第十四方面，本发明提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。本发明还提供具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在对象中预防阿尔兹海默症。
在第十五方面，本发明提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。本发明还提供PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在对象中预防阿尔兹海默症。
在第十六方面，本发明提供一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的circPOLR2A或包含circPOLR2A的药物组合物。本发明还提供一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的circPOLR2A或包含circPOLR2A的药物组合物。
在第十七方面，本发明提供一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。本发明还提供一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的具有16bp-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物。
在第十八方面，本发明提供一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。本发明还提供一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的PKR抑制剂或包含PKR抑制剂的药物组合物。
附图简述
图1：circPOLR2A序列在人鼠之间保守，促进环形RNA形成的顺式作用原件在人鼠之间不保守，因此小鼠中通常不表达circPOLR2A。
图2：通过CRISPR/CAS9在ROSA26位点敲入的过表达circPOLR2A的序列的检测。
图3：构建稳定表达circPOLR2A以及对应线性linearPOLR2A的转基因小鼠。
图4：转基因小鼠模型的不同组织中circPOLR2A/linearPOLR2A的表达量。
图5：转基因小鼠脾脏组织中circPOLR2A或者linearPOLR2A的表达量。
图6：转基因小鼠中circPOLR2A在各个组织中的表达。
图7：咪喹莫特诱导的小鼠模型模拟牛皮癣疾病表型。
图8：咪喹莫特诱导的小鼠模型脾脏细胞中细胞因子的瞬时表达。
图9：咪喹莫特诱导的小鼠模型脾脏细胞中环形RNA表达水平的变化。
图10：咪喹莫特处理后PKR蛋白表达量及PKR磷酸化水平的变化。
图11：咪喹莫特诱导的小鼠脾脏细胞中不同免疫细胞亚型变化。
图12：咪喹莫特处理的过表达环形RNA或线性RNA小鼠模型牛皮癣表型及细胞因子表达上的变化。
图13：咪喹莫特处理的过表达环形RNA小鼠模型在不同免疫亚型细胞中牛皮癣标志物及细胞因子表达上的变化。
图14：poly(I:C)处理的过表达环形RNA或线性RNA小鼠模型不同免疫亚型细胞中细胞因子表达水平的变化。
图15：过表达circPOLR2A和过表达linear POLR2A小鼠模型的脾脏细胞中的PKR表达量。
图16：circPOLR2A的体外合成以及PKR活性的抑制。
图17：体外合成的具有特定双链结构环形RNA的引入能够缓解咪喹莫特诱导牛皮癣疾病表型。
图18：circPOLR2A及同一类26个具有特定双链结构的环形RNA及不含有特定双链结构的环形RNA circSMARCA5二级结构示意图。
图19：通过LNP递送体外合成的circPOLR2抑制PKR磷酸化，缓解咪喹莫特诱导牛皮癣疾病表型。
图20：咪喹莫特处理后PKR本底蛋白表达量以及激活水平的变化，以及分析表达量升高的基因。
图21：咪喹莫特处理的PKR KO小鼠中环形RNA和线形RNA表达量的变化。
图22：咪喹莫特处理的PKR KO小鼠中IFN-alpha通路激活水平受到一定程度的抑制。
图23：咪喹莫特处理的过表达环形RNA小鼠模型在IFN-alpha通路表达上的变化。
图24：POLR2A线性和环形AAV过表达质粒的构建及小鼠海马脑定位注射AAV3周后可检测到GFP表达。
图25：northern印迹杂交检测到AAV注射小鼠成功表达circPOLR2A。
图26：AAV注射过表达circPOLR2A的5×FAD小鼠相对线性过表达小鼠表现出p-Tau及淀粉样蛋白表达降低，炎症反应减弱。
图27：AAV过表达circPOLR2A小鼠相对线性过表达小鼠在海马组织中p-Tau及淀粉样蛋白水平降低。
图28：AAV-PHPeB-circPOLR2A通过尾静脉注射成功感染小鼠全脑并表达GFP。
图29：尾静脉注射AAV过表达circPOLR2A降低神经炎症及Aβ和p-PKR表达水平。
图30：尾静脉注射AAV过表达circPOLR2A降低Aβ淀粉样蛋白在海马组织中的积聚。
图31：水迷宫实验检测circPOLR2A过表达小鼠空间学习与记忆能力相比5×FAD AAV-GFP小鼠有显著提升。
发明详述
除非另有指示或定义，否则所有所用术语均具有本领域中的通常含义，该含义将为
本领域技术人员所了解。此外，除非另有说明，否则未具体详述的所有方法、步骤、技术及操作均可以且已经以本身已知的方式进行，该方式将为本领域技术人员所了解。亦参考例如标准手册、上述一般现有技术及其中引用的其他参考文献。
“核酸序列”、“多核苷酸”、“核苷酸序列”或“核酸片段”可互换使用并且是单链或双链RNA或DNA聚合物，任选地可含有合成的、非天然的或改变的核苷酸碱基。核苷酸通过如下它们的单个字母名称来指代：“A”为腺苷或脱氧腺苷(分别对应RNA或DNA)，“C”表示胞苷或脱氧胞苷，“G”表示鸟苷或脱氧鸟苷，“U”表示尿苷，“T”表示脱氧胸苷，“R”表示嘌呤(A或G)，“Y”表示嘧啶(C或T)，“K”表示G或T，“H”表示A或C或T，“D”表示A、T或G，“I”表示肌苷，并且“N”表示任何核苷酸。尽管本文中的核苷酸序列可能以DNA序列表示(包含T)，但在提及RNA时，本领域技术人员可以容易地确定相应的RNA序列(即用U替换T)。
序列“相同性”具有本领域公认的含义，并且可以利用公开的技术计算两个核酸或多肽分子或区域之间序列相同性的百分比。可以沿着多核苷酸或多肽的全长或者沿着该分子的区域测量序列相同性。(参见，例如：Computational Molecular Biology,Lesk,A.M.,ed.,Oxford University Press,New York,1988；Biocomputing:Informatics and Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993；Computer Analysis of Sequence Data,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana Press,New Jersey,1994；Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987；and Sequence Analysis Primer,Gribskov,M.and Devereux,J.,eds.,M Stockton Press,New York,1991)。许多算法可用于确定序列相同性百分比。适合于确定序列相同性百分比的算法的一个实例是在基本局部比对搜索工具(以下为“BLAST”)中使用的算法，见例如Altschul等人，J.Mol.Biol.215:403-410,1990和Altschul等人，Nucleic Acids Res.,15:3389-3402,1997。进行BLAST分析的软件是通过国家生物技术信息中心(以下为“NCBI”)公开地可获得的。在使用从NCBI可获得的软件(如针对核酸序列的BLASTN)来确定序列相同性所使用的默认参数在McGinnis等人Nucleic Acids Res.,32:W20-W25,2004中有所描述。
如本文所用，“约”可意指正或负小于1％或1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、25％、30％或大于30％，这取决于本领域技术人员已知或可知的情况。
术语“可操作地连接”是指调节序列和异源核酸序列之间的功能性连接，导致后者的表达。例如，当第一核酸序列与第二核酸序列处于功能关系时，第一核酸序列与第二核酸序列可操作地连接。例如，如果启动子影响编码序列的转录或表达，则启动子与编码序列可操作地连接。可操作地连接的DNA序列可以是彼此相邻的，并且，例如，当需要连接两个编码区时，它们在同一读码框中。
双链(ds)RNA依赖性蛋白激酶(PKR)抑制剂
本文中使用的术语“PKR”是指称为以下的蛋白：“双链RNA依赖性蛋白激酶”、“双
链RNA依赖性eIF-2α激酶”、“DAI”(Jimenez-Garcia，等，J.Cell Sci.106：11-12，1993)、“dSI”、“p68(人类)或p65(鼠类)激酶”(Lee，等，J.Interferon Cytokine Res.16：1073-1078，1996)或dsRNA-PK，或具有上述蛋白的功能的蛋白。也可以参见：Clemens，等，J.Interferon Res.13：241，1993。PKR是干扰素诱导的RNA依赖性丝氨酸/苏氨酸蛋白激酶，它负责控制抗病毒防御途径，该酶的激活需要二聚化以及随后的自磷酸化(Galabru，J.&Hovanessian，A.，J.Biol.Chem.262：15538-15544，1987；Meurs，E.等，Cell，62：379-390，1990)。已经报道PKR在与激活刺激物(例如胰岛素、IGF、BCAA)相互作用后可形成同二聚体并自磷酸化。PKR能够催化目标底物的磷酸化，鉴定得最为充分的体内PKR底物为真核启动因子-2的α亚基(eIF-2α)。一旦磷酸化，eIF2将eIF2B(翻译的限速组分)隔离，它能够最终抑制细胞和病毒蛋白合成(Hershey，J.W.B.，Ann.Rev.Biochem.60：717-755，1991)。PKR的其他生物学功能是推定其作为信号传导者的作用。Kumar等证实，PKR可以磷酸化IκBα，导致核因子-κB(NF-κB)的释放和活化(Kumar，A.等，Proc.Natl.Acad.Sci.USA 91，6288-6292，1994)。PKR可与IκK复合物物理结合并刺激NF-κB诱导激酶(NIK)，同时使IκK磷酸化，导致其随后降解。一些研究表明，NF-κB被PKR通过不依赖于其eIF2激酶活性的机理激活，而其它研究表明，eIF2-α的磷酸化是激活NF-κB所必需的。PKR的活化包括在串联至双链RNA中的两个分子结合(即PKR的二聚化)，然后在发生于分子中的事件中彼此磷酸化(Wu等1997，J.Biol.Chem 272：1291-1296)。PKR参与了各种细胞过程，包括信号转导、分化和凋亡，尤其是与到作为体内控制机制的细胞凋亡的过程中，包括抗病毒活性、细胞生长调控和肿瘤生长(Donze等EMBO J.，14：3828-3834，1995；Lee等，Virology，199：491-496，1994；Jagus等Int.J.Biochem.Cell.Biol.1989，vol.9：1576-86)。
本领域已知，PKR也可以称作EIF2AK1；MGC126524；PRKR；OTTHUMP00000201320；P1/eIF2α蛋白激酶；双链RNA激活蛋白激酶；eIF2α蛋白激酶2；干扰素诱导的双链RNA-激活蛋白激酶；干扰素诱导型RNA-依赖性蛋白激酶；干扰素诱导型eIF2α激酶；p68激酶；RNA激活蛋白激酶；蛋白激酶、干扰素诱导型双链RNA依赖性或真核生物翻译起始因子2-α激酶2。作为典型示例，PKR蛋白质序列在中以NP_002750提供，将其引入本申请参考，而PKR mRNA序列在中以NM_002759提供。
术语“PKR表达”是指编码PKR的核酸序列的转录和翻译，其产物包括前体RNA、mRNA、多肽、转译后处理的多肽及其衍生物。用于PKR表达的分析包括例如自磷酸化分析(Der和Lau，Proc.Natl.Acad.Sci.USA，92：8841-8845，1995)、eIF2α磷酸化分析(Zamanian-Daryoush，M.等，Oncogenes，18：315-326，1999)、通过PKR免疫沉淀法进行的激酶分析和激酶体外分析(Zamanian-Daryoush，M.等，Mol.Cell.Biol，20：1278-1290，2000)。PKR表达和/或产物的典型分析包括蛋白分析(例如蛋白印迹法)和PKR mRNA分析(例如逆转录聚合酶链反应(RT-PCR)分析)、Northern印迹分析、斑点印迹分析或根据编码PKR的核酸序列采用适当标记的探针进行的原位杂交分析。
本申请所用的术语“PKR异常活化”或“PKR异常激活”是指相对于识别天然免疫刺激物引起的PKR正常活化或激活以及PKR下游抗病毒反应等，在疾病例如自身免疫疾病(例如牛皮癣这种慢性皮肤病)或阿尔兹海默症中，天然免疫因子PKR的不必要活化或激活以及可能引起及加重相关疾病表型的不必要活化或激活。
本申请所用的术语“PKR抑制剂”是指抑制至少部分PKR活性或抑制至少部分PKR表达的物质、试剂或组合物。在一些实施方案中，所述抑制剂至少部分干扰PKR激酶活性。可以通过本领域的任意方法检测激酶活性，包括，例如用于PKR表达的分析、针对PKR或其主要下游靶标的eIF2α的磷酸特异性抗体和体外测定测定法。
在一个实施方案中，所述PKR抑制剂针对PKR蛋白，并且优选对PKR具有特异性。在一个实施方案中，所述PKR抑制剂可以通过以下方式发挥作用：例如直接地降低PKR的活性(如阻止PKR自磷酸化、阻止PKR二聚化)、提供PKR假激活物、提供PKR假底物、抑制eIF2α磷酸化、使eIF2-α去磷酸化或间接地促进PKR或eIF2α磷酸酶的活性。
根据本发明，术语“降低PKR的活性”涉及导致以下的手段：与其中PKR的活性未降低/未人工降低的正常情况，特别是细胞中的正常情况相比，PKR的较低程度的二聚化、PKR的较低程度的自磷酸化和/或作为PKR的激酶底物(例如eIF2-α)的靶标的较低程度的磷酸化。优选地，所述术语包括导致PKR的较低程度的二聚化的所有手段。在一个实施方案中，在例如细胞中降低PKR的活性包括用PKR的表达和/或活性的抑制剂处理例如细胞。根据本发明，术语“抑制PKR表达和/或活性”包括对PKR表达和/或活性的完全、基本上完全或部分的抑制以及表达和/或活性的降低，例如PKR表达和/或活性为未被抑制的PKR表达和/或活性的0％、10％、20％、30％、40％、50％、60％、70％或80％。
根据本发明，可以采用PKR抑制剂治疗牛皮癣的疾病。根据本发明，可以采用PKR抑制剂治疗阿尔兹海默症的疾病。可以适用于本发明药物、药物组合物、试剂盒、用途和方法的PKR抑制剂包括那些描述于下列文献的抑制剂：Shimazawa等，Neurosci.Lett.，409：192-195，2006；Peel，J.Neuropathol.Exp.Neurol，63：97-105，2004；Bando等，Neurochem.Int.，46：11-18，2005；Peel等，Hum.Mol.Genet.，10：1531-1538，2001；和Chang等，J.Neurochem.83：1215-1225，2002。
在一个实施方案中，PKR抑制剂是诱饵dsRNA(decoy dsRNA)，例如腺病毒VAI RNA、艾普斯登-巴尔病毒(Epstein-Barr virus)EBER、HIV TAR。其中，诱饵RNA是其结构类似于酶的RNA底物的假底物RNA，目的是使酶与假底物结合而不是与真底物结合，从而阻断酶的活性。在一个实施方案中，PKR抑制剂是影响PKR降解的化合物或试剂，例如脊髓灰质炎病毒2Apro。在一个实施方案中，PKR抑制剂是抑制PKR激活的化合物或试剂，例如通过隐藏病毒dsRNA来抑制PKR激活的化合物(例如痘苗病毒E3/E3L、呼肠孤病毒σ3(reovirus sigma3)、流感病毒NS1、单纯疱疹病毒1型(herpes simplex virustype 1，HSV-1)US11)。在一个实施方案中，PKR抑制剂是阻断PKR二聚化
的化合物或试剂，例如流感病毒p58IPK、丙型肝炎病毒NS5A、本发明的具有特定结构的环形RNA(如circPOLR2A)。在一个实施方案中，PKR抑制剂是抑制eIF2-α磷酸化的化合物或试剂。在一个实施方案中，抑制eIF2-α磷酸化包括抑制PKR和/或提供模拟eIF2-α的假底物。在一个实施方案中，模拟eIF2-α的假底物是模拟eIF2-α的病毒假底物。在一个实施方案中，模拟eIF2-α的病毒假底物是痘苗病毒K3。在一个实施方案中，PKR抑制剂是假底物，例如痘苗病毒K3/K3L；腺病毒VAI RNA；HIV Tat；艾普斯登-巴尔病毒EBER1RNA。在一个实施方案中，将假底物以编码病毒假底物的核酸的形式提供给细胞，其中所述核酸优选地为RNA。在一个实施方案中，PKR抑制剂是去磷酸化的底物，例如单纯疱疹病毒ICP34.5。在一个实施方案中，PKR抑制剂是抑制PKR自磷酸化的化合物或试剂，如PKR的ATP结合位点定向抑制剂。在一个实施方案中，抑制PKR自磷酸化的化合物或试剂是咪唑并-羟吲哚化合物。在一个实施方案中，抑制PKR自磷酸化的化合物或试剂是6，8-二氢-8-(1H-咪唑-5-基亚甲基)-7H-吡咯并[2，3-g]苯并噻唑-7-酮、2-氨基嘌呤或C16。在一个实施方案中，PKR抑制剂使PKR基因的表达沉默。
在一个实施方案中，PKR抑制剂是与PKR特异性结合的抗体。在一个实施方案中，所述抗体与PKR的结合可例如通过抑制结合活性或催化活性来干扰PKR的功能。
在一个实施方案中，PKR抑制剂是蛋白抑制剂。在一个实施方案中，PKR抑制剂是PRI短肽。
在一个实施方案中，PKR抑制剂是化学抑制剂。优选地，PKR抑制剂是RNA诱导的PKR自磷酸化的抑制剂。优选地，PKR抑制剂是PKR的ATP结合位点定向抑制剂。在一个实施方案中，PKR抑制剂是6，8-二氢-8-(1H-咪唑-5-基亚甲基)-7H-吡咯并[2，3-g]苯并噻唑-7-酮。在一个实施方案中，PKR抑制剂是2-氨基嘌呤。在一个实施方案中，PKR抑制剂是C16。
在一个实施方案中，PKR抑制剂是RNA抑制剂。在一个实施方案中，PKR抑制剂是环形RNA。在一个实施方案中，PKR抑制剂是具有特定双链茎环结构的环形RNA。在一个实施方案中，PKR抑制剂是具有16-26bp双链茎环结构的环形RNA。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA为circPOLR2A。在一个实施方案中，所述circPOLR2A是人circPOLR2A。
在一个实施方案中，PKR抑制剂是病毒抑制剂。在一个实施方案中，PKR的病毒抑制剂是痘苗病毒E3。在一个实施方案中，PKR的病毒抑制剂以编码抑制剂的核酸的形式提供给细胞，其中所述核酸优选地为RNA。在一个实施方案中，PKR的病毒抑制
剂使PKR基因的表达沉默。
环形RNA(circRNA)
环形RNA(circRNA)是一类具有连续结构的单链RNA，其具有增强的稳定性并且缺乏与各种细胞蛋白相互作用所必需的末端基序。circRNA是3-5’共价闭合的RNA环，并且circRNA不显示帽或poly(A)尾。circRNA缺乏核酸外切酶介导的降解所必需的游离末端，使得它们对多种RNA转换机制具有抗性，并且与它们的线性mRNA对应物相比，赋予它们延长的寿命。出于这个原因，环化可以使通常具有短半衰期的mRNA稳定，因此可以提高mRNA在各种应用中的总体效力。此外，当转染到细胞中时，circRNA相对于其它形式的RNA(例如shRNA或双链RNA)可具有降低的免疫原性。circRNA由剪接过程产生，并且环化使用主要在注释的外显子边界处的常规剪接位点发生。对于环化，剪接位点反向使用：下游剪接供体“反向剪接”到上游剪接受体。
前期工作发现具有特定双链结构的环形RNA在RNA病毒感染下被快速降解，并和PKR(protein kinase R)的异常激活有关。PKR是核酸识别受体，目前已报道的抑制细胞内核酸受体PKR异常磷酸化激活的抑制剂包括PRI短肽或小分子化合物2-Aminopurine(2-AP)，咪唑并-羟吲哚衍生物(C16)等，但是需要指出的是，这些已有的小分子化合物抑制剂均存在不可忽视的局限性或副作用：例如PRI短肽会一定程度上诱导细胞凋亡，2-AP存在针对细胞内其它激酶的非特性抑制现象，而C16在进入细胞后存在一定程度抑制细胞正常增殖的现象等。
前期研究发现通过T4 RNA连接酶合成的环形RNA，包括可作为核酸适配体的环形RNA以及可翻译的环形RNA，均不会引起细胞内天然免疫反应。基于T4 RNA连接酶合成的环形RNA，不仅免疫原性低，且可以保留和体内相似的16-26bp短的双链结构，能够在体外及细胞内抑制PKR的激活，并且相对于已经报道的PKR小分子抑制剂具有约千倍以上更好的抑制效果。
本发明提供一种环形RNA，其具有特定双链茎环结构。术语“特定双链茎环结构”是指双链茎环结构的茎区具有特定的长度，例如具有16bp-26bp双链茎环结构的环形RNA是指具有双链茎环结构的茎区为16bp-26bp的环形RNA。在一个实施方案中，所述特定双链茎环结构的茎区的长度为16bp-26bp。在一个实施方案中，所述特定双链茎环结构的茎区的长度为16、17、18、19、20、21、22、23、24、25或26bp。在一个实施方案中，形成双链茎环结构的茎区的双链RNA彼此完全互补。在一个实施方案中，形成双链茎环结构的茎区的双链RNA可以彼此部分互补，只要它们能够彼此杂交形成碱基配对的茎区就可以。此时，形成双链茎环结构的茎区的双链RNA同时存在互补碱基对以及错配碱基对。其中，错配碱基对可以形成bulge(突起)或internal loop(内环)。其中，如果错配碱基对小于或等于4个，即认为其仍然属于RNA形成的双链茎环结构的一部分。在一些实施方案中，其中所述特定双链茎环结构的茎区包含至多4个错配碱基对，至多3个错配碱基对，至多2个错配碱基对，或者至多1个错配碱基对，或者不
包含错配碱基对。在一个实施方案中，形成双链茎环结构的茎的双链RNA之间的互补性的量通常共享至少50％、60％、70％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、至多且包括100％的互补性。
在本文中，“特定双链茎环结构”与“16bp-26bp双链茎环结构”可互换使用。
在一个实施方案中，所述环形RNA具有1-10个特定双链茎环结构，如1、2、3、4、5、6、7、8、9、10个。在一个实施方案中，所述环形RNA具有少于5个特定双链茎环结构。在一个实施方案中，所述环形RNA具有少于4个特定双链茎环结构。在一个实施方案中，所述环形RNA具有少于3个特定双链茎环结构。在一个实施方案中，所述环形RNA具有少于2个特定双链茎环结构。在一个实施方案中，所述环形RNA具有1个特定双链茎环结构。在一个实施方案中，所述环形RNA具有2个特定双链茎环结构。在一个实施方案中，所述环形RNA具有3个特定双链茎环结构。在一个实施方案中，所述环形RNA具有4个特定双链茎环结构。在一个实施方案中，所述环形RNA具有5个特定双链茎环结构。
在一个实施方案中，所述环形RNA所含有的双链茎环结构均为特定双链茎环结构。在一个实施方案中，所述环形RNA所含有的双链茎环结构包含特定双链茎环结构以及非特定双链茎环结构。在一个实施方案中，所述环形RNA所含有的双链茎环结构包含1个特定双链茎环结构。在一个实施方案中，所述环形RNA所含有的双链茎环结构包含2个特定双链茎环结构。在一个实施方案中，所述环形RNA所含有的双链茎环结构包含3个特定双链茎环结构。在一个实施方案中，所述环形RNA所含有的非特定双链茎环结构均短于特定双链茎环结构，例如对于具有16bp-26bp双链茎环结构的环形RNA而言，若其含有非特定双链茎环结构，其这些非特定双链茎环结构均短于16bp。
在一个实施方案中，所述具有特定双链茎环结构的环形RNA是具有16bp-26bp双链茎环结构的环形RNA。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA为circPOLR2A。在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA为人circPOLR2A。在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA的编码基因包含SEQ ID NO:1的序列。在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA的编码基因由SEQ ID NO:1的序列组成。在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA的编码基因包含与SEQ ID NO:1具有60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％相同性的序列，或由与SEQ ID NO:1具有60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％相同性的序列组成。
所述环形RNA具体信息如下(结构信息如图18所示)：
circARID1B(data baseID：HSA_CIRCpedia_54093)，其在基因组上的定位为：6号染色体chr6:157,357,968-157,406,039，相应的线性基因为ARID1B(chr6:157,256,600-157,473,538)，环化序列有286个碱基，包含ARID1B基因的第2个和第3个外显子。
circCAMSAP1(data baseID：HSA_CIRCpedia_63397)，其在基因组上的定位为：9号染色体chr9:13,8773,478-138,774,924，相应的线性基因为CAMSAP1(chr9:138,700,333-138,799,005)，环化序列有425个碱基，包含CAMSAP1基因的第2个和第3个外显子。
circCCNB1(data baseID：HSA_CIRCpedia_52305)，其在基因组上的定位为：5号染色体chr5:68,470,703-68,471,364，相应的线性基因为CCNB1(chr5:68,462,837-68,474,070)，环化序列有378个碱基，包含CCNB1基因的第6个和第7个外显子。
circCNN2(data baseID：HSA_CIRCpedia_24560)，其在基因组上的定位为：19号染色体chr19:1,032,390-1,032,695，相应的线性基因为CNN2(chr19:1,026,274-1,039,067)，环化序列有205个碱基，包含CNN2基因的第3个和第4个外显子。
circDHX34(data baseID：HSA_CIRCpedia_26297)，其在基因组上的定位为：19号染色体chr19:47,865,732-47,865,950，相应的线性基因为DHX34(chr19:47,852,538-47,885,961)，环化序列有218个碱基，包含DHX34基因的第6个外显子。
circEPHB4(data baseID：HSA_CIRCpedia_56001)，其在基因组上的定位为：7号染色体chr7:100,410,368-100,410,830，相应的线性基因为EPHB4(chr7:100,400,187-100,423,148)，环化序列有362个碱基，包含EPHB4基因的第10个和第11个外显子。
circEZH2(data baseID：HSA_CIRCpedia_57174)，其在基因组上的定位为：7号染色体chr7:148,543,561-148,544,397，相应的线性基因为EZH2(chr7:148,504,464-148,581,441)，环化序列有253个碱基，包含EZH2基因的第2个和第3个外显子。
circFCHO2(data baseID：HSA_CIRCpedia_52515)，其在基因组上的定位为：5号染色体chr5:72,370,568-72,373,320，相应的线性基因为FCHO2(chr5:72,251,808-72,386,348)，环化序列有268个碱基，包含FCHO2基因的第19个和第20个外显子。
circFGFR1(data baseID：HSA_CIRCpedia_60993)，其在基因组上的定位为：8号染色体chr8:38,314,873-38,315,052，相应的线性基因为FGFR1(chr8:38,268,656-38,325,363)，环化序列有179个碱基，包含FGFR1基因的第2个外显子。
circFKBP8(data baseID：HSA_CIRCpedia_25189)，其在基因组上的定位为：19号染色体chr19:18,650,180-18,650,530，相应的线性基因为FKBP8(chr19:18,642,561-18,654,387)，环化序列有259个碱基，包含FKBP8基因的第3个和第4个外显子。
circKIAA0368(data baseID：HSA_CIRCpedia_62244)，其在基因组上的定位为：9号染色体chr9:114,148,656-114,154,104，相应的线性基因为KIAA0368(chr9:114,122,972-114,246,637)，环化序列有435个碱基，包含KIAA0368基因的第28个,第29个,第30个和第31个外显子。
circMBOAT2(data baseID：HSA_CIRCpedia_42589)，其在基因组上的定位为：2号染色体chr2:9,083,315-9,098,771，相应的线性基因为MBOAT2(chr2:8,992,820-9,143,942)，环化序列有224个碱基，包含MBOAT2基因的第2个和第3个外显子。
circPIP5K1C(data baseID：HSA_CIRCpedia_25726)，其在基因组上的定位为：19号染色体chr19:3,660,963-3,661,999，相应的线性基因为PIP5K1C(chr19:3,630,179-3,700,477)，环化序列有249个碱基，包含PIP5K1C基因的第4个和第5个外显子。
circPOLR2A(data baseID：HSA_CIRCpedia_22419)，其在基因组上的定位为：17号染色体chr17:7,402,357-7,402,810，相应的线性基因为POLR2A(chr17:7,387,685-7,417,933)，环化序列有336个碱基，包含POLR2A基因的第9个和第10个外显子。
circPPP1CB(data baseID：HSA_CIRCpedia_40659)，其在基因组上的定位为：2号染色体chr2:29,006,772-29,011,675，相应的线性基因为PPP1CB(chr2:28,974,612-29,025,806)，环化序列有224个碱基，包含PPP1CB基因的第5个和第6个外显子。
circPROSC(data baseID：HSA_CIRCpedia_60919)，其在基因组上的定位为：8号染色体chr8:37,623,043-37,623,873，相应的线性基因为PROSC(chr8:37,620,101-37,637,286)，环化序列有220个碱基，包含PROSC基因的第2个,第3个和第4个外显子。
circPTK2(data baseID：HSA_CIRCpedia_60281)，其在基因组上的定位为：8号染色体chr8:141,889,569-141,900,868，相应的线性基因为PTK2(chr8:141,667,999-142,011,332)，环化序列有394个碱基，包含PTK2基因的第3个和第4个外显子。
circPVT1(data baseID：HSA_CIRCpedia_60029)，其在基因组上的定位为：8号染色体chr8:128,902,834-128,903,244，相应的线性基因为PVT1(chr8:128,806,779-129,113,499)，环化序列有410个碱基，包含PVT1基因的第2个外显子。
circRELL1(data baseID：HSA_CIRCpedia_48457)，其在基因组上的定位为：4号染色体chr4:37,633,006-37,640,126，相应的线性基因为RELL1(chr4:37,592,422-37,687,998)，环化序列有434个碱基，包含RELL1基因的第4个,第5个和第6个外显子。
circSDHAF2(data baseID：HSA_CIRCpedia_4841)，其在基因组上的定位为：11号染色体chr11:61,205,096-61,205,585，相应的线性基因为SDHAF2(chr11:61,205,096-61,205,585)，环化序列有334个碱基，包含SDHAF2基因的第2个和第3个外显子。
circSLC22A23(data baseID：HSA_CIRCpedia_54791)，其在基因组上的定位为：6号染色体chr6:3,410,421-3,416,089，相应的线性基因为SLC22A23(chr6:3,269,196-3,457,256)，环化序列有259个碱基，包含SLC22A23基因的第2个和第3个外显子。
circSNHG4(data baseID：HSA_CIRCpedia_50464)，其在基因组上的定位为：5号染色体chr5:138,614,015-138,614,818，相应的线性基因为SNHG4(chr5:138,609,441-138,618,873)，环化序列有161个碱基，包含SNHG4基因的第3个和第4个外显子。
circTBCD(data baseID：HSA_CIRCpedia_22969)，其在基因组上的定位为：17号染色体chr17:80,858,526-80,869,665，相应的线性基因为TBCD(chr17:80,709,940-80,881,609)，环化序列有389个碱基，包含TBCD基因的第17个,第18个,第19个,第20个,第21个和第22个外显子。
circTMEM181(data baseID：HSA_CIRCpedia_54188)，其在基因组上的定位为：6号染色体chr6:159,004,985-159,010,814，相应的线性基因为TMEM181(chr6:158,957,468-159,049,522)，环化序列有324个碱基，包含TMEM181基因的第3个,第4个和第5个外显子。
circUIMC1(data baseID：HSA_CIRCpedia_51249)，其在基因组上的定位为：5号染色体chr5:176,370,335-176,385,155，相应的线性基因为UIMC1(chr5:176,332,006-176,433,409)，环化序列有397个碱基，包含UIMC1基因的第7个,第8个,第9个和第10个外显子。
circVAPB(data baseID：HSA_CIRCpedia_34824)，其在基因组上的定位为：20号染色体chr20:57,014,000-57,016,139，相应的线性基因为VAPB(chr20:56,964,175-57,026,156)，环化序列有258个碱基，包含VAPB基因的第4个和第5个外显子。
在一些实施方案中，所述具有特定双链茎环结构的circRNA是外源的。在一些实施方案中，具有特定双链茎环结构的circRNA是内源的。在一些实施方案中，所述具有特定双链茎环结构的circRNA是人的。
产生circRNA的方法可以包括用特别设计的引物体外转录(IVT)前体线性RNA模板。迄今为止已经报道了用于RNA环化的三种一般策略：使用溴化氰或类似缩合剂的
化学方法，使用RNA或DNA连接酶(如T4连接酶)的酶促方法和使用自剪接内含子的核酶方法。在优选的实施方案中，通过转录合成前体RNA，然后在镁离子和GTP存在下加热以促进环化。如此产生的RNA可有效转染不同种类的细胞。
在一些方面，使用聚合酶链式反应(PCR)产生的模板通过体外转录产生线性前体RNA。使用合适的引物、缓冲液、RNA聚合酶和修饰或未修饰的核苷酸，可以通过PCR将来自任何来源的目的DNA直接转化为模板用于体外RNA合成。DNA的来源可以是例如基因组DNA、质粒DNA、噬菌体DNA、cDNA、消化的DNA、合成的DNA序列或任何其它合适的DNA来源。
为了确认宿主细胞中存在circRNA，可以进行多种测定。此类测定包括例如本领域技术人员熟知的“分子生物学”测定，诸如Southern和northern印迹、RT-PCR和PCR；“生物化学”测定，诸如检测特定肽的存在或不存在，例如通过免疫学手段(ELISA和蛋白质印迹)或通过本文所述的测定来鉴定落入本公开范围内的剂。
在一个实施方案中，本发明的具有16bp-26bp双链茎环结构的环形RNA可以通过以下方法体外制备，所述方法包括：1)提供具有16bp-26bp双链茎环结构的环形RNA的前体或从编码具有16bp-26bp双链茎环结构的环形RNA的核酸载体转录获得环形RNA前体；2)在存在T4连接酶的情况下，在RNA环化发生的温度下温育环形RNA前体；3)任选地，以RNase R处理步骤2)获得的混合物；和4)收获步骤2)或3)所获得的环形RNA。
药物或药物组合物
本发明提供一种药物或药物组合物，其包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA，和药学上可接受的载体。本发明提供一种药物或药物组合物，所述药物或药物组合物包含含有本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送装置(例如纳米颗粒)或编码本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送载体。本发明提供一种药物或药物组合物，所述药物或药物组合物包含(a)含有本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送装置(例如纳米颗粒)或编码本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送载体；和(b)药学上可接受的载体。
在一个实施方案中，所述药物或药物组合物用于在对象中治疗牛皮癣或牛皮癣相关症状。在一个实施方案中，所述药物或药物组合物用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。在一个实施方案中，所述药物或药物组合物用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。在一个实施方案中，所述药物或药物组合物用于在对象中预防牛皮癣。
在一个实施方案中，所述牛皮癣是静止期、缓解期或退行期牛皮癣。在一个实施方案中，所述牛皮癣是进展期、活动期或炎症期牛皮癣。在一个实施方案中，所述牛皮癣是非复发型牛皮癣或复发型牛皮癣，优选复发型牛皮癣。在一个实施方案中，所述牛皮
癣是急性牛皮癣或慢性牛皮癣，优选慢性牛皮癣。在一个实施方案中，所述牛皮癣是轻度、中度、或重度牛皮癣，优选中/重度牛皮癣。在一个实施方案中，所述牛皮癣是S100A8阳性、S100A9阳性、以及S100A8和S100A9阳性牛皮癣。
在一些实施方案中，所述牛皮癣选自斑块状牛皮癣、滴状牛皮癣、点状牛皮癣、反转型牛皮癣、脓疱性牛皮癣、掌跖脓疱病(Palmo-Plantar Pustulosis)、寻常型牛皮癣或红皮病性牛皮癣。
在一个实施方案中，所述牛皮癣相关症状包括皮肤损害，例如皮疹、瘙痒、发红、肿胀、囊泡形成(微小水泡)、龟裂、渗液、结硬皮或鳞屑等。在一个实施方案中，所述牛皮癣相关症状包括或涉及炎性细胞因子(例如IFNβ、IL6、IL17A、IL23、RIG-I、TNFα等)过表达。在一个实施方案中，所述牛皮癣相关症状包括淋巴器官肿大。在一个实施方案中，所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。在一个实施方案中，牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
本申请所用的术语“RNase L异常活化”或“RNase L异常激活”是指相对于识别天然免疫刺激物引起的RNase L正常活化或激活以及RNase L下游抗病毒反应等，在自身免疫疾病例如牛皮癣这种慢性皮肤病中，RNase L的不必要活化或激活以及可能引起及加重相关疾病表型的不必要活化或激活。
在一个实施方案中，所述药物或药物组合物用于在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状。在一个实施方案中，所述药物或药物组合物用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。在一个实施方案中，所述药物或药物组合物用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。在一个实施方案中，所述药物或药物组合物用于在对象中预防阿尔兹海默症。
在一个实施方案中，所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。在一个实施方案中，所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或淀粉样蛋白(包括Aβ肽)的产生、组装、聚集或沉积。在一个实施方案中，所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力(包括空间记忆能力)丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。在一个实施方案中，所述阿尔兹海默症相关症状包括或涉及炎性细胞因子(例如IFNβ、IL6、IL17A、IL23、RIG-I、TNFα、IFNα、IL-1β等)过表达。
如本文中使用的，术语“阿尔兹海默症”是指将大脑皮层中的神经细胞杀死而使大脑的额叶和颞叶中的脑回(大脑皮层上的脊)萎缩或减小的退行性大脑疾病，特别是如由NINCDS-ARDA标准(国家神经和沟通障碍和中风研究所(National Institute of Neurological and Communicative Disorders and Stroke)，和阿尔兹海默症及相关疾病协会)所定义的。
如本文中所述，术语“淀粉状蛋白”是指一组不同的但在许多不同疾病中所见到的特异性蛋白沉积(胞内和/或胞外)。虽然其存在不同，但是所有淀粉状蛋白沉积都具有共同的形态特征，被特定染料(例如刚果红)染色并且具有染色后在偏振光中出现特征性红
绿双折射。它们也享有共同的超微结构特征和共同的X射线衍射和红外光谱。
如本文中所述，术语“Aβ”、“Aβ肽”、“Aβ蛋白”、“β-淀粉样蛋白肽”和“淀粉样蛋白β肽”是同义语，是指衍生自β淀粉样蛋白前体蛋白(β-APP)的约38-43个氨基酸的一种或多种肽组合物。
在一个实施方案中，所述对象是人。在一个实施方案中，所述对象的免疫细胞中的PKR被异常活化。在一个实施方案中，所述对象的免疫细胞中的PKR被过度磷酸化。在一个实施方案中，所述对象的免疫细胞中炎性细胞因子(如IFNβ、IL6、IL17A、IL23、RIG-I及TNFα)过表达。在一个实施方案中，所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。在一个实施方案中，所述免疫细胞为B淋巴细胞。
在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA为circPOLR2A。在一个实施方案中，所述circPOLR2A是人circPOLR2A。
在一个实施方案中，药学上可接受的载体可以包括但不限于缓冲剂、赋形剂、稳定剂或防腐剂。药学上可接受的载体的实例是生理上相容的溶剂、分散介质、包衣、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等，如盐、缓冲液、糖类、抗氧化剂、水性或非水性载体、防腐剂、润湿剂、表面活性剂或乳化剂或其组合。可以基于载体的活性和制剂的所需特性，如稳定性和/或最小氧化，通过实验确定药物或药物组合物中的药学上可接受的载体的量。载体在与药物或药物组合物的其它成分相容且对其接受者无害的意义上是“可接受的”。
本发明的药物或药物组合物被调配成可与其预定施用途径相容。在一实施方式中，根据常规程序将组合物被配制为以关节内(在关节中)、肠胃外、静脉内、肌肉内、皮内、颊内、舌下、经鼻、腹膜内、皮下、口服、局部、鞘内、吸入、经直肠、贴片、泵、经皮、经直肠、肌肉、体表、黏膜、颅内等方式施用的形式。在优选实施方式中，药物或药物组合物被配制为用于静脉内或胃肠外施用的形式，例如涉及牛皮癣的实施方案时。在优选实施方式中，药物或药物组合物被配制为用于颅内或鞘内施用的形式，例如涉及阿尔兹海默症的实施方案时。
在一个实施方案中，所述递送装置选自以下任一项或多项：大分子复合物、脂质体、纳米胶囊、纳米颗粒、外来体、外来体-脂质缀合物、微球、珠、水包油乳液、脂质-纳米颗粒缀合物、胶束、混合胶束和基于肽的聚合复合物。在一些实施方案中，合适的脂质体、纳米颗粒、或脂质-纳米颗粒缀合物包含一种或多种非阳离子脂质、一种或多种基于胆固醇的脂质和/或一种或多种PEG修饰的脂质。在另一个实施方案中，合适的脂
质体、纳米颗粒、或脂质-纳米颗粒缀合物包含的脂质包括(不限于)单甘油酯、甘油二酯、硫脂、溶血卵磷脂、磷脂、皂甙、胆酸等。
在一个实施方案中，所述递送装置包含至少一种靶向部分。在另一个实施方案中，靶向部分是结合配体、鼠抗体、人或人源化抗体或其片段。
在一些实施方案中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA可以与递送装置结合。在一些实施方案中，所述结合可以指并入递送装置中、被包封在递送装置的水性内部、散布在递送装置的递送装置内、通过连接分子连接到递送装置上、包埋在递送装置中、与递送装置复合、分散在含有递送装置的溶液中、与递送装置混合、与递送装置组合、作为悬浮液包含在递送装置中、包含在胶束中或与胶束复合、附着在胶体分散系统附近、或以其它方式与递送装置结合。递送装置的相关组合物以不限于溶液中的任何特定结构存在。例如，它们可能以双层结构、胶束或“折叠”结构存在。它们也可以简单地散布在溶液中，可能形成尺寸或形状不均匀的聚集体。
在一个实施方案中，所述递送载体包括非病毒、病毒、质粒和非质粒载体。在一个实施方案中，所述病毒递送载体的实例包括但不限于腺病毒载体、腺伴随病毒(也称为腺相关病毒，AAV)载体、痘病毒载体、单纯疱疹病毒I载体、逆转录病毒载体、慢病毒载体等。在一个实施方案中，所述递送载体是AAV载体。在一个实施方案中，所述PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的编码序列与递送载体上的表达元件可操作地连接。
治疗及预防方法及用途
本发明提供一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的本文公开的药
物、药物组合物或制剂。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中治疗牛皮癣或牛皮癣相关症状。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中预防牛皮癣。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在对象中预防牛皮癣的药物、药物组合物或药物组合中的用途。
本发明提供一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的本文公开的药物、药物组合物或制剂。
本发明提供一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的本
文公开的药物、药物组合物或制剂。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中预防阿尔兹海默症。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物、药物组合物或药物组合中的用途。本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在对象中预防阿尔兹海默症的药物、药物组合物或药物组合中的用途。
如本文所用，“对象”旨在包括其中可引发免疫反应的活生物体，可包括但不限于哺乳动物，诸如人或非人哺乳动物，例如驯养的、农业的或野生的动物、以及鸟类和水生动物。如本文所用，“患者”是患有或处于发展疾病、障碍或病症的风险或另外需要本文提供的试剂、药物、药物组合物和方法的对象。
如本文所用，“施用”是指可用于使得能够将组合物递送到所需生物作用部位的方法。这些方法包含但不限于关节内(在关节中)、肠胃外、静脉内、肌肉内、皮内、颊内、舌下、经鼻、腹膜内、皮下、口服、局部、鞘内、吸入、经直肠、贴片、泵、经皮、经直肠、肌肉、体表、黏膜、颅内等。本文所描述的药剂和方法可采用的施用技术可见于例如以下中：Goodman和Gilman,《治疗学的药理学基础(The Pharmacological Basis of Therapeutics)》，现用版；Pergamon和Remington,《药物科学(Pharmaceutical Sciences)》(现用版)，宾夕法尼亚州伊斯顿(Easton,Pa)的Mack Publishing Co.。
如本文所用，“治疗”是指在治疗或改善疾病或病症中成功的任何指征。治疗可包括例如降低、延迟或减轻疾病或病症的一种或多种症状的严重程度，或其可包括降低患者经历疾病、缺陷、障碍或不良病症等的症状的频率。
如本文所用，“预防”是指预防患者的疾病或病症，例如牛皮癣形成。例如，如果处于发展牛皮癣的风险中的个体用本公开的方法治疗并且随后不发展牛皮癣，则该疾病已经在该个体中至少在一段时间内被预防。例如，如果处于发展阿尔兹海默症的风险中的
个体用本公开的方法治疗并且随后不发展阿尔兹海默症，则该疾病已经在该个体中至少在一段时间内被预防。
如本文所用，“治疗有效量”是组合物或其活性组分的量，该量足以对施用该组合物的个体提供有益效果或以其它方式减少非有益事件。所述效果包含临床结果，例如相比于对照抑制、遏制或减少个体的所治疗病状的症状。本文中的“治疗有效量”是指对施用产生一种或多种所需或期望的(例如有益的)效果的量，这种施用在给定的时间段内发生一次或多次。向个体提供“有效量”的组分的精确施用量将取决于施用模式、疾病或病状的类型和严重强度，以及取决于个体特征，如一般健康状况、年龄、性别、体重和药物耐受性。所属领域的技术人员将能够根据这些和其它因素确定恰当剂量。当与其它治疗剂组合施用时，例如当与其他治疗牛皮癣或阿尔兹海默症的治疗剂组合施用时，任何额外治疗剂的“有效量”将取决于所使用的药物类型。合适的剂量对于批准的治疗剂是已知的，且可由所属领域的技术人员根据个体的病状、所治疗的病状类型等使用已知技术确定(参见，例如Lieberman，Pharmaceutical Dosage Forms(第1-3卷，1992)；Lloyd，TheArt，Science and Technology of Pharmaceutical Compounding(1999)；以及Pickar，Dosage Calculations(1999))。
术语“S100A8”或“S100A9”是指粪便钙卫蛋白(FCP)，其分别指S100钙结合蛋白A8(NCBI参考序列NP_002955.2)和S100钙结合蛋白A9(NCBI参考序列NP_002956.1)及其片段或变体。FCP是在炎性条件下由嗜中性粒细胞、单核细胞和上皮细胞产生的哺乳动物蛋白S100A8和S100A9的复合体。钙卫蛋白可以通过螯合营养物Mn2+和Zn2+抑制金黄色葡萄球菌在脓肿中的生长。在一些实施方案中，将浓度超过50μg/g的粪便钙卫蛋白水平视为“阳性”结果。
在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA为circPOLR2A。在一个实施方案中，所述circPOLR2A是人circPOLR2A。
在一个实施方案中，所述牛皮癣是静止期、缓解期或退行期牛皮癣。在一个实施方案中，所述牛皮癣是进展期、活动期或炎症期牛皮癣。在一个实施方案中，所述牛皮癣是非复发型牛皮癣或复发型牛皮癣，优选复发型牛皮癣。在一个实施方案中，所述牛皮癣是急性牛皮癣或慢性牛皮癣，优选慢性牛皮癣。在一个实施方案中，所述牛皮癣是轻度、中度、或重度牛皮癣，优选中/重度牛皮癣。在一个实施方案中，所述牛皮癣是S100A8阳性、S100A9阳性、以及S100A8和S100A9阳性牛皮癣。
在一些实施方案中，所述牛皮癣选自斑块状牛皮癣、滴状牛皮癣、点状牛皮癣、反转型牛皮癣、脓疱性牛皮癣、掌跖脓疱病(Palmo-Plantar Pustulosis)、寻常型牛皮癣或红
皮病性牛皮癣。
在一个实施方案中，所述牛皮癣相关症状包括皮肤损害，例如皮疹、瘙痒、发红、肿胀、囊泡形成(微小水泡)、龟裂、渗液、结硬皮或鳞屑等。在一个实施方案中，所述牛皮癣相关症状包括或涉及炎性细胞因子(例如IFNβ、IL6、IL17A、IL23、RIG-I、TNFα等)过表达。在一个实施方案中，所述牛皮癣相关症状包括淋巴器官肿大。在一个实施方案中，所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。在一个实施方案中，牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
在一个实施方案中，所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。在一个实施方案中，所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或淀粉样蛋白(包括Aβ肽)的产生、组装、聚集或沉积。在一个实施方案中，所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力(包括空间记忆能力)丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。在一个实施方案中，所述阿尔兹海默症相关症状包括或涉及炎性细胞因子(例如IFNβ、IL6、IL17A、IL23、RIG-I、TNFα、IFNα、IL-1β等)过表达。
在一个实施方案中，所述对象是人。在一个实施方案中，所述对象的免疫细胞中的PKR被异常活化。在一个实施方案中，所述对象的免疫细胞中的PKR被过度磷酸化。在一个实施方案中，所述对象的免疫细胞中炎性细胞因子(如IFNβ、IL6、IL17A、IL23、RIG-I及TNFα)过表达。在一个实施方案中，所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。在一个实施方案中，所述免疫细胞为B淋巴细胞。
在一些情况下，本发明的方法使得与未施用RNA的对象或施用相应线性RNA的对象相比，施用PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂的对象中PKR的异常活化水平(尤其是B淋巴细胞和/或单核细胞中的PKR的异常活化水平)降低。在一些情况下，本发明的方法使得与未施用RNA的对象或施用相应线性RNA的对象相比，施用PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂的对象中选自以下一项或多项的炎性细胞因子(尤其是B淋巴细胞和/或单核细胞中的炎性细胞因子)的表达水平降低：IFNβ、IL6、IL17A、IL23、RIG-I及TNFα。
本发明提供一种在对象中降低PKR异常活化水平的方法，所述方法包括向对象施用有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中降低PKR异常活化水平的方法，所述方法包括向对象施用有效量的本文公开的药物、药物组合物或制剂。在一个实施方案中，PKR异常活化水平是B淋巴细胞和/或单核细胞中的PKR异常活化水平。
本发明提供一种在对象中降低炎性细胞因子的表达水平的方法，所述方法包括向对象施用有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。本发明提供一种在对象中降低炎性细胞因子的表达水平的方法，所述方法包括向对象施
用治疗有效量的本文公开的药物、药物组合物或制剂。在一个实施方案中，所述炎性细胞因子是B淋巴细胞和/或单核细胞中的炎性细胞因子。在一个实施方案中，所述炎性细胞因子选自IFNβ、IL6、IL17A、IL23、RIG-I和TNFα。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中降低PKR异常活化水平。在一个实施方案中，所述PKR异常活化水平是B淋巴细胞和/或单核细胞中的PKR异常活化水平。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂，其用于在对象中降低炎性细胞因子的表达水平。在一个实施方案中，所述炎性细胞因子是B淋巴细胞和/或单核细胞中的炎性细胞因子。在一个实施方案中，所述炎性细胞因子选自IFNβ、IL6、IL17A、IL23、RIG-I和TNFα。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在对象中降低PKR异常活化水平的药物、药物组合物或药物组合中的用途。在一个实施方案中，所PKR异常活化是B淋巴细胞和/或单核细胞中的PKR异常活化水平。
本发明提供本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA在制备用于在对象中降低炎性细胞因子的表达水平的药物、药物组合物或药物组合中的用途。在一个实施方案中，所述炎性细胞因子是B淋巴细胞和/或单核细胞中的炎性细胞因子。在一个实施方案中，所述炎性细胞因子选自IFNβ、IL6、IL17A、IL23、RIG-I和TNFα。
如所属领域的技术人员将理解，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本发明的药物或药物组合物可取决于所选择施用途径以多种形式向患者施用。施用和施用方案的特定模式将通过主治临床医生考虑病例细节(例如个体、疾病、所涉及的疾病病况，特定治疗)进行选择。在一些实施方案中，所述方法包括将本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA、本发明的药物或药物组合物为以选自关节内(在关节中)、肠胃外、静脉内、肌肉内、皮内、颊内、舌下、经鼻、腹膜内、皮下、口服、局部、鞘内、吸入、经直肠、贴片、泵、经皮、经直肠、肌肉、体表、黏膜、颅内等的方式施用。在一些实施方案中，肠胃外施用可以在所选择时间段内通过连续输注进行。在一些实施方案中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA(例如circPOLR2A)、本发明的药物、药物组合物被配制为以选自关节内(在关节中)、肠胃外、静脉内、肌肉内、皮内、颊内、舌下、经鼻、腹膜内、皮下、口服、局部、鞘内、吸入、经直肠、贴片、泵、经皮、经直肠、肌肉、体表、黏膜、颅内等方式施用的形式。例如，对于口服施用来说，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA(例如circPOLR2A)、本发明的药物、药物组合物被配制为呈片剂、颊内片剂、糖锭、胶囊、酏剂、悬浮液、糖浆、薄片(wafer)、粉剂、或溶液的形式。对于静脉内、皮肤或皮下注射施用来说，本文所述的PKR抑制
剂或具有16bp-26bp双链茎环结构的环形RNA(例如circPOLR2A)、本发明的药物、药物组合物被配制为非经肠可接受的溶液的形式，例如无菌水溶液或分散液和无菌粉剂形式，又或者除本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA外也可含有等张载体，诸如氯化钠注射液、林格氏注射液(Ringer's injection)、右旋糖注射液、右旋糖及氯化钠注射液、乳酸化林格氏注射液或本领域已知的其他载体。对于肠胃外施用来说，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA(例如circPOLR2A)、本发明的药物、药物组合物一般可在适合与如羟基丙基纤维素的表面活性剂混合的水中制备。还可以在甘油、液体聚乙二醇、DMSO和其混合物(具有或不具有醇)和油中制备分散液。在一般的存储和使用条件下，这些制剂可以含有防腐剂以防止微生物生长。
在一些实施方案中，所述方法可包括在几天到数月或甚至数年时间段内每天一次或每天多次或小于每天一次(如每周一次或每月一次等)施用本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA、本发明的药物或药物组合物。在一个实施方案中，所述方法包括每日一次施用、隔日一次施用、每周两次施用、每周一次施用、每两周一次、每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次向对象施用(治疗/预防)有效量的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA、本发明的药物或药物组合物。在一个实施方案中，在本文所述的用途中，所述药物或药物组合物被配制为每日一次施用、隔日一次施用、每周两次施用、每周一次施用、每两周一次、每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用的形式。
合适的剂量将视例如所用特定的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA、对象、施用模式及所治疗病状的性质及严重度以及患者已经历的在先治疗的性质而定。最终，主治医师将决定个别个体的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的量。在一些实施方式中，主治医师可施用低剂量的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA且观察个体的应答。在其他实施方式中，施用至个体的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的初始剂量较高，接着向下调整剂量直至出现复发症状为止。可施用较大剂量的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA，直至个体获得最佳治疗作用为止，且在此时，剂量一般不会进一步提高。在一些实施方式中，所述药物、药物组合物或制剂被配制为每剂量单元包含约0.006mg至约600mg、约0.06mg至约600mg、约0.3mg至约600mg、约0.6mg至约600mg、约6mg至约600mg、约60mg至约600mg、约120mg至约600mg、约300mg至约600mg、约0.006mg至约300mg、约0.06mg至约300mg、约0.06mg至约300mg、约0.6mg至约300mg、约6mg至约60mg、约60mg至约300mg、约120mg至约300mg、约0.006mg至约60mg、约0.06mg至约60mg、约0.3mg至约60mg、约0.6mg至约60mg或约6mg至约60mg的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。在一些实施方式中，所述药物、药物组合物或制剂的单次施用量为0.0001mg/kg至约10mg/kg、
约0.001mg/kg至约10mg/kg、约0.005mg/kg至约10mg/kg、约0.01mg/kg至约10mg/kg、约0.1mg/kg至约10mg/kg、约1mg/kg至约10mg/kg、约2mg/kg至约10mg/kg、约5mg/kg至约10mg/kg、约0.0001mg/kg至约5mg/kg、约0.001mg/kg至约5mg/kg、约0.005mg/kg至约5mg/kg、约0.01mg/kg至约5mg/kg、约0.1mg/kg至约10mg/kg、约1mg/kg至约5mg/kg、约2mg/kg至约5mg/kg、约0.0001mg/kg至约1mg/kg、约0.001mg/kg至约1mg/kg、约0.005mg/kg至约1mg/kg、约0.01mg/kg至约1mg/kg或约0.1mg/kg至约1mg/kg的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA。
在一些情况下，方法包括将本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂作为唯一活性组分施用。方法包括将本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂单独施用。在一个实施方案中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA是在对象中治疗或预防牛皮癣的唯一活性组分。在一个实施方案中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA是在对象中治疗或预防阿尔兹海默症的唯一活性组分。在一个实施方案中，在本文所述的用途中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA是所述药物或药物组合物的唯一活性组分。在一个实施方案中，在本文所述的用途中，所述药物或药物组合物被配制为单独施用的形式。在一个实施方案中，在本文所述的用途中，所述对象被单独施用本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂。
如上文所述，所述药物或药物组合物可进一步包含药学上可接受的载体。如上文所述，所述药物或药物组合物可包含含有本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送装置(例如纳米颗粒)或编码本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的递送载体(例如AAV载体)。在一个实施方案中，所述递送装置可以是纳米颗粒。在一个实施方案中，所述药物或药物组合物包含包含具有16bp-26bp双链茎环结构的环形RNA的纳米颗粒。在一个实施方案中，所述递送载体可以是AAV载体。在一个实施方案中，所述药物或药物组合物包含编码具有16bp-26bp双链茎环结构的环形RNA的AAV载体。
在一些情况下，方法包括将本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂与额外的组分或疗法组合施用。在一个实施方案中，在本文所述的用途中，所述药物、药物组合物或药物组合包括额外的组分。在一个实施方案中，在本文所述的用途中，所述对象被施用额外的组分或疗法。
如本文所用，术语“共同施用”、“与……组合施用”将意指涵盖向单一个体施用两种或更多种治疗剂或疗法，且意图包含其中通过相同或不同施用途径或在相同或不同时间施用治疗剂或疗法的治疗方案。这些术语涵盖向个体施用两种或更多种治疗剂，使得治疗剂和/或其代谢物同时存在于个体中。在一些情况下，所述额外的组分或疗法是增加药物、药物组合物或药物组合功效的组分。在一些情况下，所述额外的组分或疗法是改善
与药物、药物组合物或药物组合相关的一种或多种副作用的组分。在一些实施例中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂和额外的组分在单一组合物中施用。在一些实施例中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂和额外的组分在分开的组合物中施用。在一些实施例中，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂和额外的组分掺合于组合物中。当与一或多种额外的组分或疗法共施用时，本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂可与额外的组分或疗法同时或依次施用。若依次施用，则主治医师将决定施用本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或本文公开的药物、药物组合物或制剂与额外的组分或疗法的适当顺序。
在一些情况下，所述额外的组分或疗法是其他治疗牛皮癣或牛皮癣相关症状的组分或疗法。在一些情况下，所述额外的组分或疗法是其他治疗阿尔兹海默症或阿尔兹海默症相关症状的组分或疗法。在一些实施方案中，额外的组分或疗法包括局部药物疗法(非处方非甾体化合物及甾体化合物)、光疗法及全身性疗法(例如用生物制剂或化学物质)。
治疗或预防牛皮癣或阿尔兹海默症的试剂盒
本文提供用于治疗或预防牛皮癣的试剂盒。本文提供用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的试剂盒。本文提供用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的试剂盒。这些试剂盒可包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物。另外，这些试剂盒可包含用于施用本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物的工具(例如注射器或预填充笔)及使用说明书。这些试剂盒可含有用于治疗或预防牛皮癣的额外的治疗剂，例如用于与所装入的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物组合递送的额外的治疗剂(如上所述)。
因此，本文公开试剂盒，其包含：a)本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物；及b)说明书。在一个实施方案中，所述试剂盒用于治疗牛皮癣或牛皮癣相关症状。在一个实施方案中，所述试剂盒用于预防牛皮癣。在一个实施方案中，所述试剂盒用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。在一个实施方案中，所述试剂盒用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的
药物或药物组合物在制备用于治疗或预防牛皮癣的试剂盒中的用途。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的试剂盒中的用途。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的试剂盒中的用途。
本文提供用于治疗或预防阿尔兹海默症的试剂盒。本文提供用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的试剂盒。本文提供用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的试剂盒。这些试剂盒可包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物。另外，这些试剂盒可包含用于施用本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物的工具(例如注射器或预填充笔)及使用说明书。这些试剂盒可含有用于治疗或预防阿尔兹海默症的额外的治疗剂，例如用于与所装入的本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物组合递送的额外的治疗剂(如上所述)。
因此，本文公开试剂盒，其包含：a)本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物；及b)说明书。在一个实施方案中，所述试剂盒用于治疗阿尔兹海默症或阿尔兹海默症相关症状。在一个实施方案中，所述试剂盒用于预防阿尔兹海默症。在一个实施方案中，所述试剂盒用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。在一个实施方案中，所述试剂盒用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物在制备用于治疗或预防阿尔兹海默症的试剂盒中的用途。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的试剂盒中的用途。本文还提供了本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA或包含本文所述的PKR抑制剂或具有16bp-26bp双链茎环结构的环形RNA的药物或药物组合物在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的试剂盒中的用途。
在一个实施方案中，所述的具有16bp-26bp双链茎环结构的环形RNA选自
circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。在一个实施方案中，所述具有16bp-26bp双链茎环结构的环形RNA为circPOLR2A。在一个实施方案中，所述circPOLR2A是人circPOLR2A。
在一个实施方案中，所述牛皮癣是静止期、缓解期或退行期牛皮癣。在一个实施方案中，所述牛皮癣是进展期、活动期或炎症期牛皮癣。在一个实施方案中，所述牛皮癣是非复发型牛皮癣或复发型牛皮癣，优选复发型牛皮癣。在一个实施方案中，所述牛皮癣是急性牛皮癣或慢性牛皮癣，优选慢性牛皮癣。在一个实施方案中，所述牛皮癣是轻度、中度、或重度牛皮癣，优选中/重度牛皮癣。在一个实施方案中，所述牛皮癣是S100A8阳性、S100A9阳性、以及S100A8和S100A9阳性牛皮癣。在一些实施方案中，所述牛皮癣选自斑块状牛皮癣、滴状牛皮癣、点状牛皮癣、反转型牛皮癣、脓疱性牛皮癣、掌跖脓疱病(Palmo-Plantar Pustulosis)、寻常型牛皮癣或红皮病性牛皮癣。在一个实施方案中，所述牛皮癣相关症状包括皮肤损害，例如皮疹、瘙痒、发红、肿胀、囊泡形成(微小水泡)、龟裂、渗液、结硬皮或鳞屑等。在一个实施方案中，所述牛皮癣相关症状包括或涉及炎性细胞因子(例如IFNβ、IL6、IL17A、IL23、RIG-I、TNFα等)过表达。在一个实施方案中，所述牛皮癣相关症状包括淋巴器官肿大。在一个实施方案中，所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
在一个实施方案中，所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。在一个实施方案中，所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或淀粉样蛋白(包括Aβ肽)的产生、组装、聚集或沉积。在一个实施方案中，所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力(包括空间记忆能力)丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。在一个实施方案中，所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施例1、构建全身组织稳定过表达环形RNA的小鼠模型
本实施例证明通过CRISPR/CAS9能成功构建稳定过表达环形RNA的小鼠模型。
以人体内源表达的环形RNA circPOLR2A为例，构建稳定过表达的小鼠模型。circPOLR2A序列是在circexplorer数据库(http://yanglab.github.io/CIRCexplorer/)中获得，其中circPOLR2A对应的具体DNA序列为：ATGGTTCCTCGCATGATTGTCACCCCCCAGAGCAATCGGCCTGTCATGGGTATTGTGCAGGACACACTCACAGCAGTGCGCAAATTCACCAAGAGAGACGTCTTCCTGGAGCGGGTGGAACGGCACATGTGTGATGGGGACATTGTTATCTTCAACCGGCAGCCAACTCTGCACAAAATGTCCATGATGGGGCATCGGGTCCGCATTCTCCCATGGTCTACCTT
TCGCTTGAATCTTAGTGTGACAACTCCGTACAATGCAGACTTTGACGGGGATGAGATGAACTTGCACCTGCCACAGTCTCTGGAGACGCGAGCAGAGATCCAGGAGCTGGCC(SEQ ID NO:1)，在如图1结果所示，通过NCBI数据库(https://pubmed.ncbi.nlm.nih.gov)进行序列比对，circPOLR2A序列在人鼠之间保守，但由于小鼠中成环外显子两侧缺少长散在序列(LINE,long interspersed nuclear elements)和短散在序列(SINE,short interspersed nuclear elements)，所以生成不保守，即小鼠体内无法生成表达内源的circPOLR2A。
为检测人体内源表达的环形RNA circPOLR2A是否能在小鼠中稳定生成和表达，通过CRISPR/CAS9在ROSA26位点敲入了过表达circPOLR2A的序列，通过FuGENE HD Transfection Reagent(Promega)将同源重组的Donor质粒和sgRNA转染到小鼠干细胞R1细胞中，经过Trizol抽提RNA，结合RT-PCR，挑选鉴定到了#3，#29两个单基因插入阳性的单克隆。如图2所示，通过qPCR对#29号单克隆进行每个细胞中circPOLR2A拷贝数的绝对定量分析，在三次重复实验中，每个#29克隆中每个R1细胞能稳定表达约300，550，430个circPOLR2A。
基于以上研究结果，我们分别构建了两组稳定过表达circPOLR2A以及对应线性linearPOLR2A的转基因小鼠(小鼠购自百奥赛图生物公司)，如图3所示，一组小鼠是由EF1α启动子驱动的表达，并由两个过表达的序列串联，分别进行circPOLR2A以及对应线性linearPOLR2A的过表达；另外一组小鼠由CAG启动子驱动的表达，包含一个过表达circPOLR2A或者linearPOLR2A的序列。
为检测两组不同启动子驱动过表达circPOLR2A以及对应线性linearPOLR2A的转基因小鼠中，各个组织中circPOLR2A或者linearPOLR2A的表达量，分别取三只野生型(WT)，单基因插入小鼠(WT/+)，双基因插入小鼠(+/+)的心脏组织，脾脏组织，肺组织，肾组织，脑组织，皮肤组织和肝脏组织，进行称重，并在Trizol中进行研磨，抽提各组织中总RNA，如图4结果所示。结合RT-qPCR计算每毫克组织中或者每微克总RNA中circPOLR2A或者linearPOLR2A的拷贝数。如图5结果所示，结合#29号R1单克隆细胞三次重复实验的平均拷贝数，以mactin为内参，计算两组不同启动子驱动的野生型(WT)，单基因插入小鼠(WT/+)，双基因插入小鼠(+/+)脾脏中circPOLR2A或者linearPOLR2A的表达量。同时结合Northern Blotting，进一步检测CAG启动子驱动的稳定过表达circPOLR2A转基因小鼠的各个组织中表达量，根据图6的结果所示，CAG启动子驱动过表达circPOLR2A小鼠在心脏组织，脾脏组织，肺组织，肝脏组织中的表达量较高，并且通过核酸外切酶RNaseR消化实验证明CAG启动子驱动的稳定过表达circPOLR2A小鼠模型的成功构建。
以上结果证明，通过CRISPR/CAS9基因编辑技术，人体内源表达的环形RNA circPOLR2A以及其对应的linearPOLR2A能够在转基因小鼠各组织中稳定表达。
实施例2、咪喹莫特诱导的牛皮癣小鼠模型中RNase L微激活、环形RNA表达下调、
PKR异常激活
2.1.咪喹莫特(Imiquimod，IMQ)诱导的小鼠模型模拟牛皮癣疾病表型
通过施用咪喹莫特诱导牛皮癣小鼠模型(Fits et al.,J Immunol,2009,PMID:19380832)。在第0天(D0)将小鼠背部进行剃毛，取5组小鼠在背部涂抹咪喹莫特(购于3M Pharmaceuticals公司)分别连续诱导1天、2天、3天、5天和8天，同时在对照组小鼠的背部涂抹凡士林(vaseline)，咪喹莫特与凡士林的施用剂量均为62.5mg/每只动物。取对应时间点的小鼠，处死后解剖分离小鼠脾脏，进行拍照，如图7及表1结果所示(其中表1统计了图7照片中脾脏占的像素点)，随着连续IMQ抹药诱导的时间变长，小鼠脾脏尺寸逐渐变大。
表1.IMQ处理后的脾脏大小(pixel^2)
2.2咪喹莫特(Imiquimod，IMQ)诱导的小鼠脾脏中RNase L被瞬时激活，小鼠内源环形RNA表达量下调
取5组小鼠分别在背部涂抹咪喹莫特(购于3M Pharmaceuticals公司)连续诱导1天、2天、3天、5天和8天，施用剂量为62.5mg/每只动物。取对应时间点的小鼠，处死后解剖分离小鼠脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入Trizol提取总RNA，进行RT-qPCR分别检测牛皮癣相关的细胞因子mIFNβ,mIL17A,mIL23,mIL6,mPKR的表达变化。如图8及表2-7结果(其中表2-7中所表示的表达量是以D0天其中一只小鼠为1，计算对应目标基因表达变化的倍数)所示，mIFNβ,mIL17A,mIL23表达量随着抹药时间的增加而增加，但mIL6和mPKR的表达量在D1时表达量最高，随着抹药时间的增加，而逐渐降低。同时，通过结合RctB连接和RT-qPCR检测tRNA-His-21的变化来进一步确定RNase L激活，发现RNase L被瞬时激活，且在D1时激活程度最高，随着抹药诱导时间的增加，RNase L激活程度逐渐降低。
表2.mIFNβ的表达变化
表3.mIL17A的表达变化
表4.mIL23的表达变化
表5.mIL6的表达变化
表6.mPKR的表达变化
表7.tRNA-His-21的表达变化
为了整体检测咪喹莫特诱导的小鼠脾脏细胞的整体变化情况，取不同抹药诱导时间点的小鼠脾脏总RNA进行高通量测序(RNA-Seq)，每组时间点包括4只小鼠，同时还检测了对照组涂抹凡士林(施用剂量为62.5mg/每只动物)处理8天的小鼠脾脏总RNA。如图9结果所示，不同时间咪喹莫特处理以及凡士林处理小鼠脾脏中，整体线性RNA水平以及环形RNA来源的线性亲本基因表达量变化不明显，但环形RNA表达量从咪喹莫特处理D1时表达量开始降低，并一直持续D8。
为了进一步检测咪喹莫特诱导的小鼠模型脾脏细胞中环形RNA的表达变化，结合RT-qPCR检测了mCnot2，mFam120A，mNco2在pre-mRNA，mRNA，circRNA水平上的表达变化。如图9及表8-10结果(其中表8-10中所表示的表达量是以D0天其中一只小鼠为1，计算对应目标基因表达变化的倍数)所示，与通过RNA-seq检测到结果一致，三个目标基因在pre-mRNA和mRNA上随着抹药时间的增加，表达量变化不明显，但环形RNA表达量从D1开始持续降低。
表8.Cnot2的表达变化
表9.Fam120a的表达变化
表10.Nco2的表达变化
2.3咪喹莫特(Imiquimod，IMQ)诱导的小鼠模型脾脏中PKR被异常激活
取三组野生型小鼠分别在背部不做处理、涂抹咪喹莫特(施用剂量为62.5mg/每只动物)连续处理8天或者涂抹凡士林(施用剂量为62.5mg/每只动物)连续处理8天，处死后解剖分离小鼠脾脏组织，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入RIPA buffer裂解细胞，在冰上孵育10分钟，加入蛋白质变性剂，100℃蛋白质变性10分钟，通过Western Blotting检测PKR的表达以及PKR磷酸化情况。如图10结果所示，咪喹莫特连续处理8天与未处理组相比，PKR蛋白表达量变化不明显，但PKR磷酸化水平升高，即PKR被异常激活。同时比较咪喹莫特或者凡士林连续诱导8天的小鼠脾脏细胞中PKR的表达量与磷酸化水平，两组小鼠脾脏细胞中PKR的表达量没有明显变化，但咪喹莫特组小鼠PKR磷酸化水平升高，对照凡士林处理组小鼠PKR没有被激活。说明咪喹莫特诱导的小鼠体内PKR的异常激活与连续抹药8天的处理动作无关，与咪喹莫特诱导的牛皮癣疾病表型有关。
2.4咪喹莫特(Imiquimod，IMQ)诱导的小鼠脾脏中不同免疫细胞亚型变化
在D0将小鼠背部进行剃毛，取5组小鼠分别在背部涂抹咪喹莫特(购于3M Pharmaceuticals公司)连续诱导1天、2天和5天，施用剂量为62.5mg/每只动物，处死小鼠后解剖取小鼠脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入DPBS漂洗细胞一次，1：200加入免疫细胞表面抗体进行荧光染色，4℃孵育30分钟，加入DPBS漂洗细胞一次，离心收集细胞沉淀，加入500μl的RIPM 1640培养基进行重悬用于流式细胞分选。
为了检测T细胞在咪喹莫特诱导的小鼠模型中细胞占比的变化，通过流式分析CD3+细胞，进一步分析CD4+或CD8+细胞，确定CD4+辅助性T细胞以及CD8+杀伤性T细胞在野生型小鼠中随着抹药时间增加，脾脏细胞不同免疫细胞亚型占比的变化。如图11及表11-14结果所示，CD4+辅助性T细胞和CD8+杀伤性T细胞随着抹药处理时间的增加，细胞量逐渐降低，说明T细胞在该牛皮癣模型小鼠中所占比例随药物诱导逐渐降低。
为了检测单核细胞以及树突状细胞在咪喹莫特诱导的小鼠模型中细胞占比的变化，通过流式分析CD45+细胞，进一步分析CD11b+或CD11c+细胞，来确定CD11b+单核细胞和CD11c+树突状细胞在咪喹莫特诱导的牛皮癣症状小鼠脾脏中细胞占比的变化。如图11及表11-14结果所示，CD11b+单核细胞和CD11c+树突状细胞随着抹药处理时间的增加，细胞比例逐渐增加，说明单核细胞和树突状细胞随着抹药处理时间的增加，在该牛皮癣模型小鼠中所占比例逐渐增加。
表11.CD11c+树突状细胞在免疫细胞亚型中的比例变化(％)
表12.CD4+T细胞在免疫细胞亚型中的比例变化(％)
表13.CD8+T细胞在免疫细胞亚型中的比例变化(％)
表14.CD11b+细胞在免疫细胞亚型中的比例变化(％)
如图11(b)结果所示，分别检测未处理组和咪喹莫特连续处理1天、2天以及5天的小鼠脾脏中各种免疫细胞亚型的变化，与图11(a)结果一致CD4+辅助性T细胞和CD8+
杀伤性T细胞随着抹药处理时间的增加，细胞占比逐渐降低；CD11b+单核细胞和CD11c+树突状细胞随着咪喹莫特处理时间的增加，细胞占比逐渐增加。
2.5咪喹莫特诱导的牛皮癣小鼠模型潜在的分子机制说明
随着咪喹莫特处理时间增加，在分子水平上RNase L的激活，环形RNA表达量的降低以及PKR的异常激活表明，RNase L-环形RNA-PKR相关分子途径在牛皮癣小鼠疾病模型中具有潜在关联，具体来说在第1天时RNase L被激活，同时环形RNA的表达量降低，与mPKR和mIL6的表达变化一致。在细胞水平上，抹药诱导第2天后，不同免疫亚型细胞的比例发生明显变化，由此推测RNase L的激活以及环形RNA的变化可能会影响到下游不同免疫细胞亚型的变化，说明调节环形RNA的表达水平可以作为一种全新靶点用于自身免疫疾病如牛皮癣(psoriasis)的分子诊断或干预治疗中。
实施例3、咪喹莫特诱导的过表达环形RNA小鼠中牛皮癣疾病表型减轻
3.1.咪喹莫特诱导过表达环形RNA或线性RNA小鼠模型
在D0时将小鼠背部进行剃毛，取对应稳定过表达circPOLR2A或linearPOLR2A转基因小鼠分别在背部抹药连续诱导1天、2天、3天、5天和8天。取对应处理时间点的小鼠，处死后解剖分离小鼠脾脏，进行称重，如图12结果所示，D0时，过表达circPOLR2A和linearPOLR2A小鼠脾脏重量相同，随着连续抹药的时间变长，整体上小鼠脾脏大小的逐渐变大，但在D5和D8时，过表达circPOLR2A小鼠相比于过表达linearPOLR2A小鼠脾脏重量增加不明显，说明过表达circPOLR2A在一定程度上有助于缓解牛皮癣(psoriasis)模型小鼠脾脏肿大的表型。
3.2咪喹莫特诱导的过表达环形RNA小鼠中牛皮癣相关标志物基因表达降低
在D0时将小鼠背部剃毛，取对应过表达circPOLR2A或linearPOLR2A小鼠分别在背部抹药连续处理1天、2天、3天、5天和8天。取对应处理时间点的小鼠脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入Trizol提取总RNA，通过RT-qPCR分别检测牛皮癣相关的细胞因子mIFNβ,mIL6,和基因mPKR的表达变化。如图12(b)及表16-18结果(其中表16-18中所表示的表达量是以D0天其中一只小鼠为1，计算对应目标基因表达变化的倍数)所示，在过表达linearPOLR2A小鼠模型中，mIFNβ表达量在D1和D2时比较高，而在过表达circPOLR2A小鼠模型中，mIFNβ表达量变化不明显，维持在低表达水平；在过表达linearPOLR2A小鼠模型中，mIL6表达量在D1时表达量最高，而过表达circPOLR2A小鼠模型中，mIL6表达量变化不明显，维持在低表达水平。同时，在重复实验中，过表达linearPOLR2A小鼠模型与野生型小鼠的mIL6表达量变化一致，在D1时表达量最高，而过表达circPOLR2A小鼠模型中，mIL6表达变化不明显，维持在低表达水平，说明过表达circPOLR2A在一定程度上有助于缓解牛皮癣(psoriasis)模型小鼠相关炎症因子或标志物基因表达水平。
表15.mIL6的表达变化
表16.mIFNβ的表达变化
表17.mPKR的表达变化
3.3咪喹莫特诱导的过表达环形RNA小鼠模型在脾脏免疫亚型细胞上的变化
在D0时，将小鼠背部进行剃毛，取对应过表达circPOLR2A或linearPOLR2A小鼠分别在背部抹药连续处理2天，处死小鼠后解剖分离小鼠脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入DPBS漂洗细胞一次，利用磁珠法分选得到B细胞，T细胞，以及单核细胞，加入Trizol提取各免疫细胞亚群的总RNA，通过RT-qPCR分别检测牛皮癣相关的标志基因mS100A8和mS100A9，及炎症因子mIL6和mTNFα的表达变化。
如图13及表19-30结果(其中表19-30中所表示的表达量是以其中一只过表达线性RNA小鼠为1，计算对应目标基因表达变化倍数)所示，B细胞、T细胞以及单核细胞中牛皮癣相关的标志基因mS100A8和mS100A9，炎症因子mIL6和mTNFα的表达变化不一致。S100A8/9属于钙结合蛋白，在应激状态下由角质形成细胞表达和释放，诱导中性粒细胞迁移，形成炎症反应(Walter et al.,Nat Commun,2013,PMID:23463003)。其中，在B细胞中，过表达circPOLR2A相比较于linearPOLR2A小鼠模型中，牛皮癣相关的标志基因mS100A8和mS100A9以及炎症因子mIL6表达量较低，mTNFα表达量变化不明显；在T细胞中，过表达circPOLR2A小鼠模型相比较于linearPOLR2A小鼠模型中，牛皮癣相关的标志基因mS100A8和mS100A9，炎症因子mIL6和mTNFα
表达量由于个体差异较大，无统计学差异；在单核细胞中，过表达circPOLR2A小鼠模型相比较于linearPOLR2A小鼠模型中，牛皮癣相关的标志基因mS100A8和mS100A9，由于个体差异较大，无统计学差异，炎症因子mIL6表达量较低，mTNFα表达量变化不明显。同时，在B细胞、T细胞和单核细胞中，野生型小鼠和过表达linearPOLR2A小鼠相比，牛皮癣相关的标志基因mS100A8和mS100A9，炎症因子mIL6和mTNFα表达量变化一致，无明显差异。
表18.B细胞中的S100A8的表达变化
表19.B细胞中的S100A9的表达变化
表20.B细胞中的IL6的表达变化
表21.B细胞中的TNFα的表达变化
表22.T细胞中的S100A8的表达变化
表23.T细胞中的S100A9的表达变化
表24.T细胞中的IL6的表达变化
表25.T细胞中的TNFα的表达变化
表26.单核细胞中的S100A8的表达变化
表27.单核细胞中的S100A9的表达变化
表28.单核细胞中的IL6的表达变化
表29.单核细胞中的TNFα的表达变化
3.4.环形RNA有助于缓解牛皮癣(psoriasis)模型小鼠疾病表型分子机制说明
在不同免疫细胞亚群中，过表达circPOLR2A小鼠模型相比于过表达linearPOLR2A小鼠模型，牛皮癣相关的标志基因mS100A8和mS100A9以及炎症因子mIL6表达变化有差异。取对应稳定过表达circPOLR2A或linearPOLR2A模型小鼠，处死后解剖分离小鼠脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞。加入DPBS漂洗细胞一次，和上述方法一致，利用磁珠法分选得到B细胞、T细胞以及单核细胞，转染相同质量(2μg)的常用的双链RNA病毒刺激模拟物poly(I:C)，4小时后，分别收集细胞，加入Trizol
试剂提取细胞的总RNA进行RT-qPCR检测细胞因子mIFNβ,mTNFα和mIL6的mRNA表达量。在B细胞和单核细胞中，在poly(I:C)的刺激下，过表达circPOLR2A的小鼠模型相比较于linearPOLR2A小鼠模型中，mIFNβ,mTNFα和mIL6表达量降低，然而在T细胞中，该变化不明显。结果如图14所示。
对野生型小鼠，过表达circPOLR2A和过表达linear POLR2A小鼠模型的脾脏细胞进行PKR表达量的检测，根据图15结果所示，PKR在B细胞和单核细胞中的表达量比T细胞中高，由此推测PKR的表达水平可能会影响到环形RNA参与不同免疫细胞亚群的天然免疫应答炎症反应调控中。
实施例4、体外合成的具有特定双链结构环形RNA的引入能够缓解咪喹莫特诱导牛皮癣疾病表型
为了进一步探究体外制备的含有特殊结构的环形RNA用于干预治疗牛皮癣的潜在可能，如图16结果所示，我们利用T4 RNA ligase的方法在体外合成并纯化circPOLR2A，通过Northern Blotting电泳的实验方法和RNase R消化的方式验证体外合成环形RNA circPOLR2A的环状结构的完整性和产物纯度。并利用体外SHAPE-MaP实验方法，对其二级结构进行了解析，结果如图16所示，通过T4 RNA ligase(购于NEB公司)合成的circPOLR2A(体外转录对应的DNA序列为：ATGGTTCCTCGCATGATTGTCACCCCCCAGAGCAATCGGCCTGTCATGGGTATTGTGCAGGACACACTCACAGCAGTGCGCAAATTCACCAAGAGAGACGTCTTCCTGGAGCGGGTGGAACGGCACATGTGTGATGGGGACATTGTTATCTTCAACCGGCAGCCAACTCTGCACAAAATGTCCATGATGGGGCATCGGGTCCGCATTCTCCCATGGTCTACCTTTCGCTTGAATCTTAGTGTGACAACTCCGTACAATGCAGACTTTGACGGGGATGAGATGAACTTGCACCTGCCACAGTCTCTGGAGACGCGAGCAGAGATCCAGGAGCTGGCC(SEQ ID NO:1))具有16-26bp的双链RNA结构区域(蓝色标记区域)。这种具有特殊双链RNA结构的环形RNA在体外同位素实验中能够抑制79bp dsRNA诱导的PKR磷酸化激活，因此可以作为PKR的抑制剂。通过尾静脉注射的方式将具有特殊双链RNA结构的circPOLR2A引入咪喹莫特诱导的自身免疫疾病牛皮癣小鼠模型中，发现疾病模型小鼠相关炎症反应有一定程度缓解。如图17结果所示，我们采用之前文献披露的器官选择性靶向RNA递送技术(SORT)(Chen et al.,Nat Nanotechnol,2020,PMID:32251383)，将五种不同的脂质体成分5A2-SC8/DOPE/cholesterol/DMG-PEG按照15/15/30/3/7摩尔比制备纳米颗粒，分别包裹5μg体外制备的具有特殊双链结构的环形RNA circPOLR2A及同序列的线性RNA，同时通过纳米颗粒包裹相同体积的PBS，在DPBS中透析30分钟之后，通过尾静脉注射到小鼠中。6小时后，涂抹咪喹莫特(施用剂量为62.5mg/每只动物)诱导牛皮癣疾病症状，连续处理2天后处死小鼠，解剖分离小鼠脾脏，进行称重，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞，加入Trizol试剂提取细胞的总RNA
进行RT-qPCR分别检测细胞因子mIFNβ,mTNFα和mIL6的mRNA表达量。这一系列实施例结果表明，体外制备的具有特殊双链结构环形RNA的引入，能够在一定程度上缓解咪喹莫特诱导的牛皮癣疾病表型。
为了提高环形RNA治疗咪喹莫特诱导的牛皮癣小鼠的效果，我们通过尾静脉注射纳米包裹的体外合成的环形RNA，来对牛皮癣模型的小鼠进行治疗。尾静注射纳米颗粒包裹的体外合成的环形RNA，24小时之后，处死小鼠，解剖分离小鼠肝脏，脾脏，肺和肾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞，加入Trizol试剂提取细胞的总RNA，肝脏，肺和肾脏进行组织研磨并加入Trizol试剂提取细胞的总RNA，通过Northern Blotting分析环形RNA递送靶向的器官，如图19A所示，我们发现环形RNA主要被递送到脾脏中。如图19B所示，体外合成的环形RNA相比于线形RNA在小鼠体内更稳定。尾静注射纳米颗粒包裹的体外合成的环形RNA和线性RNA，分别6小时、24小时、48小时处死小鼠，解剖分离小鼠，脾脏，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞，加入Trizol试剂提取细胞的总RNA，通过Northern Blotting进一步分析，线性RNA在24小时基本完全降解，环形RNA在48小时才会基本完全降解，总体而言，体外合成环形RNA与线形RNA相比在小鼠体内更加稳定。进一步分析，递送到小鼠体内的环形RNA是否还能保持双链的结构，如图19C我们通过SHAPE-MaP分析纳米颗粒递送前后环形RNA对应的SHAPE值，发现无明显变化，所以纳米颗粒包裹的环形RNA能保持完整的双链结构。
连续咪喹莫特抹药诱导两天，并在第1.5天分别尾静脉注射相同体积的生理盐水(PBS)，包裹0.5μg、5μg和15μg的circPOLR2A，24小时后，涂抹后处死小鼠，解剖分离小鼠脾脏，进行称重，将脾脏放在70μm的细胞滤网中进行研磨，并加入3倍细胞体积的红细胞裂解液将红细胞去除，收集得到淋巴细胞，加入RIPA试剂提取细胞的总蛋白，进一步分析PKR的磷酸化水平的变化。如图19D所示，注射包裹5μg和15μg的circPOLR2A的小鼠体内，PKR被明显抑制，说明体外合成的具有双链结构的环形RNA在咪喹莫特诱导的牛皮癣小鼠的模型的早起疾病发生中发挥重要的调控作用，并能起到治疗的效果。如图19E所示，通过石蜡切片和苏木精-伊红染色法(hematoxylin-eosin staining,HE staining)，测量在第1.5天分别尾静脉注射相同体积的生理盐水(PBS)，包裹0.5μg、5μg和15μg的circPOLR2A进行靶向脾脏递送后的小鼠表皮厚度，发现5μg和15μg的circPOLR2A递送组小鼠的表皮厚度有显著性降低，进一步说明体外合成的具有双链结构的环形RNA能够缓解咪喹莫特诱导的牛皮癣小鼠模型的疾病表型。
实施例5、PKR敲除(KO)可缓解咪喹莫特诱导的牛皮癣相关表型
由于PKR在牛皮癣的发病过程中，表达量呈现先升高后降低的变化趋势，所以我们想进一步探究PKR在小鼠咪喹莫特诱导的小鼠模型中的作用。如图20A所示，PKR
本底蛋白在咪喹莫特抹药诱导的第一天表达量显著上升，并在第二天表达量最高，后面随着抹药诱导的时间变长，PKR蛋白表达量也下降；PKR磷酸化蛋白在咪喹莫特抹药诱导第二天表达量最高，后面随着抹药诱导的时间变长，PKR磷酸化蛋白表达量也下降；PKR下游蛋白eIF2α在咪喹莫特抹药诱导的第一天表达量显著上升，并在第二天表达量最高，后面随着抹药诱导的时间变长，eIF2α蛋白表达量也下降；eIF2α磷酸化蛋白在咪喹莫特抹药诱导第二天表达量最高，后面随着抹药诱导的时间变长，eIF2α磷酸化蛋白表达量也下降；因此我们想进一步探究和PKR相同变化趋势的基因，如图20B所示，通过RNA-seq分析我们找到了和PKR相同变化趋势的基因和RIG-I，NOD，Toll，NF-kappa B以及TNF信号变化通路相关，我们进一步探究PKR与这些相同变化趋势的基因之间的关系，通过基因编辑CRISPR/CAS9技术构建了PKR敲除的C57/BL6小鼠品系。如图21A所示，PKR小鼠是通过CRISPR/CAS9技术对第三个外显子进行大片段的删除造成移码突变从而将PKR进行敲除。我们分别通过RNA-seq分析第三个exon的表达以及western blotting实验验证PKR KO小鼠的成功建立。我们发现咪喹莫特诱导的PKR KO小鼠中，第一天环形RNA表达量发生下降，如图21B所示。我们通过RNA-seq分析PKR KO小鼠和WT小鼠相比牛皮癣相关基因的表达变化，如图22所示，在咪喹莫特诱导的第一天，PKR KO小鼠和WT小鼠的脾脏中，IFNα和dsRNA sensor信号通路都在第一天表达量上升，但KO小鼠相比较于WT小鼠，这两个相关的信号通路表达量有所下降，说明PKR能过调控和PKR变化趋势相同的基因，包括IFNα和dsRNA sensor信号通路，PKR在咪喹莫特诱导的牛皮癣小鼠的模型的早起疾病发生中发挥重要的调控作用。
环形RNA作为PKR的抑制剂，我们一步比较过表达环形RNA的小鼠中和PKR变化趋势相同的基因变化，包括IFNα和dsRNA sensor信号通路，和野生型WT小鼠相比，IFNα相关的标志基因mIfi44、mIsg15、mMX2以及炎症因子mIL6表达量较低，并且有显著性差异，mIfih1h和mStat1表达量变化不明显，如图23所示。
实施例6、脑定位注射AAV2/9过表达circPOLR2A可缓解阿尔兹海默症相关表型
AAV作为目前最为安全且可行的基因过表达工具，已经有成功应用于治疗的范例。以AAV为过表达载体在5×FAD小鼠中进行了circPOLR2A过表达对AD疾病治疗作用的研究。首先构建了AAV过表达circPOLR2A及其对照线性POLR2A的质粒系统(图24A)。在该质粒系统中，POLR2A两个外显子的两端为两段完全反向互补序列和两段egfp序列。反向互补序列相互配对会促进外显子的反向剪接，从而成功表达circPOLR2A，同时两段egfp也会通过剪接形成完整的egfp mRNA，进一步翻译表达出eGFP荧光蛋白。而作为对照的线性POLR2A质粒去掉了3'端的完全反向互补序列，不能有效促进环化。通过经典剪接产生线性的POLR2A。在5xFAD小鼠海马中脑立体定位注射AAV病毒，三周后在海马区检测到了绿色荧光蛋白产生(图24B，比例尺为100μm)。这表明circPOLR2A的AAV过表达系统成功建立。
基于以上结果，在8月龄的5×FAD小鼠海马中分别注射了AAV2/9-L与AAV2/9-C，4周后收样检测。取注射区域即小鼠海马组织进行匀浆并抽提RNA，蛋白进行后续检测。在AAV-C注射小鼠中GFP表达，表明circPOLR2A生成。利用qPCR检测了circPOLR2A的绝对表达量，结果见表1。可见脑室注射的小鼠样品中circPOLR2A的表达量均比较高，但也有相对更大的个体差异。通过Northern Blot检测海马组织中成功表达了circPOLR2A，在线性对照组中也能看到极少量circPOLR2A通过自发的反向剪接产生(图25)。
表30
Western blot检测发现，Tau与PKR磷酸化水平相对AAV-L注射组降低，Aβ整体表达水平低(图26A)。RT-qPCR也检测发现AAV-C注射小鼠中相关免疫因子PKR、TNFα、IL6表达量显著降低(图26B)。
海马组织的切片免疫荧光染色显示GFP表达，表明circPOLR2A成功过表达。Tau蛋白磷酸化与Aβ斑表达量下降(图27A、C，比例尺为100μm)。这表明circPOLR2A过表达降低了AD的病理学表征，减弱了AD小鼠中枢神经系统中的炎症反应，进一步提供了以circPOLR2A回补缓解AD症状的可能性。
实施例7、尾静脉注射AAV-PHP.eB-circPOLR2A改善5xFAD小鼠相关疾病表型
在之前的研究结果中，初步验证了AAV过表达circPOLR2A挽回AD疾病表型的有效性。但是AAV的中枢神经系统原位注射有以下局限性：其一，脑立体定位注射是有创手术，开颅过程增加了小鼠颅内感染的风险。其二，这种注射方式仅能在注射位点高表达RNA，在AD这一疾病模型中，降低AD的疾病相关蛋白表达，提升记忆力需要全脑给药，这是原位注射无法实现的。其三，AAV脑定位注射实验过程复杂，在疾病的临床治疗和长期给药中是无法实现的。
因此，选择了小鼠尾静脉注射的方式实现小鼠全脑过表达circPOLR2A。在5×FAD小鼠尾静脉注射AAV-PHP.eB-circPOLR2A，4周后检测小鼠海马和皮层中均成功过表达circPOLR2A(图28，比例尺为650μm)，其绝对定量情况如下表2。取对应组织匀浆抽提RNA与蛋白质检测发现在过表达小鼠海马及皮层中相关免疫基因的表达均低于GFP表达的对照5×FAD小鼠，Aβ与PKR磷酸化水平也有所降低(图29)。海马组织的冷冻切片染色可见circPOLR2A过表达小鼠中Aβ蛋白斑载量减少，统计有显著差异(图30，比例尺为100μm)。
表31
除了分子水平的疾病靶标之外，AD常常在临床上表现为患者记忆力逐渐丧失。在5xFAD小鼠模型中同样表现有类似记忆力减退表型。对尾静脉注射4周后的小鼠的空间学习记忆能力进行了检测。在水迷宫实验中，各组小鼠游泳速度无明显差异，水中运动能力相似(图31A、B)。在前五天的空间学习能力检测中WT小鼠优于5×FAD小鼠，前三天的学习中circPOLR2A过表达小鼠优于GFP对照组5xFAD小鼠，第四天第五天二者无差异(图31C)。在第六天的空间记忆能力检测中WT小鼠在目标象限所处时间显著高于对照组5×FAD小鼠(图31D)，在原平台所在位置的穿梭次数显著高于对照组小鼠(图31E)。circPOLR2A过表达小鼠在目标象限所处时间也显著高于对照组5×FAD小鼠(图31D)，穿梭次数高于对照组(图31E)，这表明AAV尾静脉注射过表达circPOLR2A可以提高5xFAD小鼠的空间记忆能力。
综上所述，本实施例通过两种不同的AAV过表达circPOLR2A的方法在一定程度上缓解了阿尔兹海默症相关表型，提高了小鼠的空间记忆能力。这些实施例证明，具有特殊双链结构的环形RNA(以circPOLR2A为例)的回补可以在一定程度上缓解阿尔兹海默症的相关表型，为特殊结构的环形RNA适配体作为PKR抑制剂参与阿尔兹海默症的治疗提供可能。
实施方案：
实施方案1.circPOLR2A在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。
实施方案2.circPOLR2A在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。
实施方案3.circPOLR2A在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。
实施方案4.前述任一项的用途，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案5.前述任一项的用途，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案6.前述任一项的用途，其中所述牛皮癣是复发型牛皮癣。
实施方案7.前述任一项的用途，其中所述牛皮癣是慢性牛皮癣。
实施方案8.前述任一项的用途，其中所述牛皮癣是中/重度牛皮癣。
实施方案9.前述任一项的用途，其中所述牛皮癣是S100A8和/或S100A9阳性牛
皮癣。
实施方案10.前述任一项的用途，其中所述牛皮癣相关症状包括皮肤损害。
实施方案11.前述任一项的用途，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案12.前述任一项的用途，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案13.前述任一项的用途，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案14.前述任一项的用途，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案15.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案16.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案17.实施方案16的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案18.前述任一项的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案19.前述任一项的用途，其中所述药物包含包含circPOLR2A的纳米颗粒。
实施方案20.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案21.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的circPOLR2A。
实施方案22.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至约5mg/kg的circPOLR2A。
实施方案23.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案24.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案25.circPOLR2A在制备用于预防牛皮癣的药物中的用途。
实施方案26.具有16-26bp双链茎环结构的环形RNA在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。
实施方案27.具有16-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。
实施方案28.具有16-26bp双链茎环结构的环形RNA在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。
实施方案29.前述任一项的用途，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案30.前述任一项的用途，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案31.前述任一项的用途，其中所述牛皮癣是复发型牛皮癣。
实施方案32.前述任一项的用途，其中所述牛皮癣是慢性牛皮癣。
实施方案33.前述任一项的用途，其中所述牛皮癣是中/重度牛皮癣。
实施方案34.前述任一项的用途，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案35.前述任一项的用途，其中所述牛皮癣相关症状包括皮肤损害。
实施方案36.前述任一项的用途，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案37.前述任一项的用途，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案38.前述任一项的用途，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案39.前述任一项的用途，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案40.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案41.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案42.实施方案41的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案43.前述任一项的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案44.前述任一项的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案45.实施方案44的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案46.前述任一项的用途，其中所述药物包含包含具有16bp-26bp双链茎环结构的环形RNA的纳米颗粒。
实施方案47.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案48.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的具有16bp-26bp双链茎环结构的环形RNA。
实施方案49.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至
约5mg/kg的具有16bp-26bp双链茎环结构的环形RNA。
实施方案50.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案51.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案52.具有16-26bp双链茎环结构的环形RNA在制备用于预防牛皮癣的药物中的用途。
实施方案53.PKR抑制剂在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途。
实施方案54.PKR抑制剂在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途。
实施方案55.PKR抑制剂在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途。
实施方案56.前述任一项的用途，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案57.前述任一项的用途，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案58.前述任一项的用途，其中所述牛皮癣是复发型牛皮癣。
实施方案59.前述任一项的用途，其中所述牛皮癣是慢性牛皮癣。
实施方案60.前述任一项的用途，其中所述牛皮癣是中/重度牛皮癣。
实施方案61.前述任一项的用途，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案62.前述任一项的用途，其中所述牛皮癣相关症状包括皮肤损害。
实施方案63.前述任一项的用途，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案64.前述任一项的用途，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案65.前述任一项的用途，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案66.前述任一项的用途，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案67.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案68.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案69.实施方案68的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案70.前述任一项的用途，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案71.实施方案70的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案72.实施方案73的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案73.实施方案74的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案74.前述任一项的用途，其中所述药物包含包含PKR抑制剂的纳米颗粒。
实施方案75.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案76.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的PKR抑制剂。
实施方案77.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至约5mg/kg的PKR抑制剂。
实施方案78.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案79.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案80.PKR抑制剂在制备用于预防牛皮癣的药物中的用途。
实施方案81.circPOLR2A，其用于治疗对象的牛皮癣或牛皮癣相关症状。
实施方案82.circPOLR2A，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。
实施方案83.circPOLR2A，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。
实施方案84.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案85.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案86.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是复发型牛皮癣。
实施方案87.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是慢性
牛皮癣。
实施方案88.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是中/重度牛皮癣。
实施方案89.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案90.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣相关症状包括皮肤损害。
实施方案91.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案92.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案93.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案94.前述任一项的用于所述用途的circPOLR2A，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案95.前述任一项的用于所述用途的circPOLR2A，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案96.前述任一项的用于所述用途的circPOLR2A，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案97.实施方案96的用于所述用途的circPOLR2A，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案98.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A是人circPOLR2A。
实施方案99.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A包含在纳米颗粒中。
实施方案100.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案101.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A的剂量单元为约0.03mg至约300mg。
实施方案102.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A以约0.005mg/kg至约5mg/kg施用。
实施方案103.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案104.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案105.circPOLR2A，其用于预防牛皮癣。
实施方案106.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于治疗对象的牛皮癣或牛皮癣相关症状。
实施方案107.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。
实施方案108.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。
实施方案109.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案110.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案111.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是复发型牛皮癣。
实施方案112.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是慢性牛皮癣。
实施方案113.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是中/重度牛皮癣。
实施方案114.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案115.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣相关症状包括皮肤损害。
实施方案116.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案117.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案118.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案119.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案120.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案121.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案122.实施方案121的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案123.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形
RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案124.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案125.实施方案124的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述circPOLR2A是人circPOLR2A。
实施方案126.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA包含在纳米颗粒中。
实施方案127.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案128.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA的剂量单元为约0.03mg至约300mg。
实施方案129.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA以约0.005mg/kg至约5mg/kg施用。
实施方案130.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案131.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案132.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于预防牛皮癣。
实施方案133.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于治疗对象的牛皮癣或牛皮癣相关症状。
实施方案134.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状。
实施方案135.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展。
实施方案136.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药
物组合物，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案137.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案138.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣是复发型牛皮癣。
实施方案139.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣是慢性牛皮癣。
实施方案140.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣是中/重度牛皮癣。
实施方案141.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案142.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣相关症状包括皮肤损害。
实施方案143.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案144.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案145.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案146.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案147.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案148.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案149.实施方案148的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案150.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案151.实施方案150的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案152.实施方案150的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案153.实施方案152的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述circPOLR2A是人circPOLR2A。
实施方案154.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂包含在纳米颗粒中。
实施方案155.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案156.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂的剂量单元为约0.03mg至约300mg。
实施方案157.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂以约0.005mg/kg至约5mg/kg施用。
实施方案158.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案159.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案160.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于预防牛皮癣。
实施方案161.一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案162.一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案163.一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案164.前述任一项的方法，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案165.前述任一项的方法，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案166.前述任一项的方法，其中所述牛皮癣是复发型牛皮癣。
实施方案167.前述任一项的方法，其中所述牛皮癣是慢性牛皮癣。
实施方案168.前述任一项的方法，其中所述牛皮癣是中/重度牛皮癣。
实施方案169.前述任一项的方法，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案170.前述任一项的方法，其中所述牛皮癣相关症状包括皮肤损害。
实施方案171.前述任一项的方法，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案172.前述任一项的方法，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案173.前述任一项的方法，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案174.前述任一项的方法，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案175.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案176.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案177.实施方案176的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案178.前述任一项的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案179.前述任一项的方法，其中所述circPOLR2A包含在纳米颗粒中。
实施方案180.前述任一项的方法，其中所述circPOLR2A通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案181.前述任一项的方法，其中所述circPOLR2A的剂量单元为约0.03mg至约300mg。
实施方案182.前述任一项的方法，其中所述circPOLR2A以约0.005mg/kg至约5mg/kg的施用。
实施方案183.前述任一项的方法，其中所述circPOLR2A每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案184.前述任一项的方法，其中所述circPOLR2A每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案185.一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的circPOLR2A。
实施方案186.一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案187.一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案188.一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案189.前述任一项的方法，其中所述牛皮癣是静止期、缓解期或退行期牛
皮癣。
实施方案190.前述任一项的方法，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案191.前述任一项的方法，其中所述牛皮癣是复发型牛皮癣。
实施方案192.前述任一项的方法，其中所述牛皮癣是慢性牛皮癣。
实施方案193.前述任一项的方法，其中所述牛皮癣是中/重度牛皮癣。
实施方案194.前述任一项的方法，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案195.前述任一项的方法，其中所述牛皮癣相关症状包括皮肤损害。
实施方案196.前述任一项的方法，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案197.前述任一项的方法，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案198.前述任一项的方法，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案199.前述任一项的方法，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案200.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案201.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案202.实施方案201的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案203.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案204.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案205.实施方案204的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案206.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA包含在纳米颗粒中。
实施方案207.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案208.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA的剂量单元为约0.03mg至约300mg。
实施方案209.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA以约0.005mg/kg至约5mg/kg的施用。
实施方案210.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案211.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案212.一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案213.一种在对象中治疗牛皮癣或牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案214.一种在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案215.一种在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案216.前述任一项的方法，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
实施方案217.前述任一项的方法，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
实施方案218.前述任一项的方法，其中所述牛皮癣是复发型牛皮癣。
实施方案219.前述任一项的方法，其中所述牛皮癣是慢性牛皮癣。
实施方案220.前述任一项的方法，其中所述牛皮癣是中/重度牛皮癣。
实施方案221.前述任一项的方法，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
实施方案222.前述任一项的方法，其中所述牛皮癣相关症状包括皮肤损害。
实施方案223.前述任一项的方法，其中所述牛皮癣相关症状包括或涉及炎性细胞因子过表达。
实施方案224.前述任一项的方法，其中所述牛皮癣相关症状包括淋巴器官肿大。
实施方案225.前述任一项的方法，其中所述牛皮癣相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案226.前述任一项的方法，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
实施方案227.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案228.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案229.实施方案228的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞和树突状细胞。
实施方案230.前述任一项的方法，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案231.实施方案230的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案232.实施方案233的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案233.实施方案234的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案234.前述任一项的方法，其中所述PKR抑制剂包含在纳米颗粒中。
实施方案235.前述任一项的方法，其中所述PKR抑制剂通过静脉、皮下、肌肉、局部、体表、吸入、黏膜或口服施用。
实施方案236.前述任一项的方法，其中所述PKR抑制剂的剂量单元为约0.03mg至约300mg。
实施方案237.前述任一项的方法，其中所述PKR抑制剂以约0.005mg/kg至约5mg/kg的施用。
实施方案238.前述任一项的用方法途，其中所述PKR抑制剂每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案239.前述任一项的方法，其中所述PKR抑制剂每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案240.一种在对象中预防牛皮癣的方法，所述方法包括向对象施用预防有效量的PKR抑制剂。
实施方案241.circPOLR2A在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。
实施方案242.circPOLR2A在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。
实施方案243.circPOLR2A在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。
实施方案244.前述任一项的用途，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案245.实施方案244的用途，其中所述阿尔兹海默症的病理学表征选自Tau
蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案246.前述任一项的用途，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案247.前述任一项的用途，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案248.前述任一项的用途，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案249.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案250.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案251.实施方案250的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案252.前述任一项的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案253.前述任一项的用途，其中所述药物包含包含circPOLR2A的纳米颗粒。
实施方案254.前述任一项的用途，其中所述药物包含编码circPOLR2A的递送载体。
实施方案255.实施方案254的用途，其中所述递送载体为AAV载体。
实施方案256.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案257.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的circPOLR2A。
实施方案258.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至约5mg/kg的circPOLR2A。
实施方案259.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案260.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案261.circPOLR2A在制备用于预防阿尔兹海默症的药物中的用途。
实施方案262.具有16-26bp双链茎环结构的环形RNA在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。
实施方案263.具有16-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。
实施方案264.具有16-26bp双链茎环结构的环形RNA在制备用于在患有阿尔兹海
默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。
实施方案265.前述任一项的用途，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案266.实施方案265的用途，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案267.前述任一项的用途，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案268.前述任一项的用途，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案269.前述任一项的用途，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案270.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案271.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案272.实施方案271的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案273.前述任一项的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案274.前述任一项的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案275.实施方案274的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案276.前述任一项的用途，其中所述药物包含包含具有16bp-26bp双链茎环结构的环形RNA的纳米颗粒。
实施方案277.实施方案276的用途，其中所述药物包含编码具有16bp-26bp双链茎环结构的环形RNA的递送载体。
实施方案278.实施方案277的用途，其中所述递送载体为AAV载体。
实施方案279.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案280.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的具有16bp-26bp双链茎环结构的环形RNA。
实施方案281.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至
约5mg/kg的具有16bp-26bp双链茎环结构的环形RNA。
实施方案282.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案283.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案284.具有16-26bp双链茎环结构的环形RNA在制备用于预防阿尔兹海默症的药物中的用途。
实施方案285.PKR抑制剂在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。
实施方案286.PKR抑制剂在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。
实施方案287.PKR抑制剂在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。
实施方案288.前述任一项的用途，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案289.实施方案288的用途，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案290.前述任一项的用途，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案291.前述任一项的用途，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案292.前述任一项的用途，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案293.前述任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案294.前述任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案295.实施方案294的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案296.前述任一项的用途，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案297.实施方案296的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、
circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案298.实施方案296的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案299.实施方案298的用途，其中所述circPOLR2A是人circPOLR2A。
实施方案300.前述任一项的用途，其中所述药物包含包含PKR抑制剂的纳米颗粒。
实施方案301.前述任一项的用途，其中所述药物包含编码PKR抑制剂的递送载体。
实施方案302.实施方案301的用途，其中所述递送载体为AAV载体。
实施方案303.前述任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案304.前述任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的PKR抑制剂。
实施方案305.前述任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至约5mg/kg的PKR抑制剂。
实施方案306.前述任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案307.前述任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案308.PKR抑制剂在制备用于预防阿尔兹海默症的药物中的用途。
实施方案309.circPOLR2A，其用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状。
实施方案310.circPOLR2A，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。
实施方案311.circPOLR2A，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。
实施方案312.前述任一项的用于所述用途的circPOLR2A，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案313.实施方案312的用于所述用途的circPOLR2A，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案314.前述任一项的用于所述用途的circPOLR2A，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案315.前述任一项的用于所述用途的circPOLR2A，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案316.前述任一项的用于所述用途的circPOLR2A，其中所述阿尔兹海默症
相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案317.前述任一项的用于所述用途的circPOLR2A，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案318.前述任一项的用于所述用途的circPOLR2A，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案319.实施方案318的用于所述用途的circPOLR2A，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案320.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A是人circPOLR2A。
实施方案321.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A包含在纳米颗粒中。
实施方案322.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A编码在递送载体中。
实施方案323.实施方案322的用途，其中所述递送载体为AAV载体。
实施方案324.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案325.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A的剂量单元为约0.03mg至约300mg。
实施方案326.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A以约0.005mg/kg至约5mg/kg施用。
实施方案327.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案328.前述任一项的用于所述用途的circPOLR2A，其中所述circPOLR2A每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案329.circPOLR2A，其用于预防阿尔兹海默症。
实施方案330.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状。
实施方案331.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。
实施方案332.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。
实施方案333.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案334.实施方案333的用于所述用途的具有16-26bp双链茎环结构的环形
RNA，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案335.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案336.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案337.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案338.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案339.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案340.实施方案339的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案341.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案342.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案343.实施方案342的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述circPOLR2A是人circPOLR2A。
实施方案344.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA包含在纳米颗粒中。
实施方案345.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16bp-26bp双链茎环结构的环形RNA编码在递送载体中。
实施方案346.实施方案345的用途，其中所述递送载体为AAV载体。
实施方案347.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案348.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA的剂量单元为约0.03mg至约
300mg。
实施方案349.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA以约0.005mg/kg至约5mg/kg施用。
实施方案350.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案351.前述任一项的用于所述用途的具有16-26bp双链茎环结构的环形RNA，其中所述具有16-26bp双链茎环结构的环形RNA每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案352.具有16-26bp双链茎环结构的环形RNA或包含所述环形RNA的药物组合物，其用于预防阿尔兹海默症。
实施方案353.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状。
实施方案354.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状。
实施方案355.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展。
实施方案356.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案357.实施方案356的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案358.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案359.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案360.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案361.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案362.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案363.实施方案362的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案364.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案365.实施方案364的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案366.实施方案364的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案367.实施方案366的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述circPOLR2A是人circPOLR2A。
实施方案368.前述任一项的用于所述用途的PKR抑制剂，其中所述PKR抑制剂包含在纳米颗粒中。
实施方案369.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂编码在递送载体中。
实施方案370.实施方案369的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述递送载体为AAV载体。
实施方案371.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案372.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂的剂量单元为约0.03mg至约300mg。
实施方案373.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂以约0.005mg/kg至约5mg/kg施用。
实施方案374.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案375.前述任一项的用于所述用途的PKR抑制剂或包含PKR抑制剂的药物组合物，其中所述PKR抑制剂每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案376.PKR抑制剂或包含PKR抑制剂的药物组合物，其用于预防阿尔兹海默症。
实施方案377.一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案378.一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案379.一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的circPOLR2A。
实施方案380.前述任一项的方法，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案381.实施方案380的方法，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案382.前述任一项的方法，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案383.前述任一项的方法，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案384.前述任一项的方法，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案385.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案386.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案387.实施方案386的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案388.前述任一项的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案389.前述任一项的方法，其中所述circPOLR2A包含在纳米颗粒中。
实施方案390.前述任一项的方法，其中所述circPOLR2A编码在递送载体中。
实施方案391.实施方案390的方法，其中所述递送载体为AAV载体。
实施方案392.前述任一项的方法，其中所述circPOLR2A通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案393.前述任一项的方法，其中所述circPOLR2A的剂量单元为约0.03mg至约300mg。
实施方案394.前述任一项的方法，其中所述circPOLR2A以约0.005mg/kg至约5mg/kg的施用。
实施方案395.前述任一项的方法，其中所述circPOLR2A每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案396.前述任一项的方法，其中所述circPOLR2A每月一次施用、隔月一次
施用、每3个月一次施用、或每6个月一次施用。
实施方案397.一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的circPOLR2A。
实施方案398.一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案399.一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案400.一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案401.前述任一项的方法，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案402.实施方案401的方法，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案403.前述任一项的方法，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案404.前述任一项的方法，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案405前述任一项的方法，其中所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
实施方案406.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案407.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案408.实施方案407的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞和小胶质细胞。
实施方案409.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案410.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案411.实施方案410的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案412.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA包含在纳米颗粒中。
实施方案413.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA编码在递送载体中。
实施方案414.实施方案413的方法，其中所述递送载体为AAV载体。
实施方案415.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案416.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA的剂量单元为约0.03mg至约300mg。
实施方案417.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA以约0.005mg/kg至约5mg/kg的施用。
实施方案418.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案419.前述任一项的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案420.一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的具有16-26bp双链茎环结构的环形RNA。
实施方案421.一种在对象中治疗阿尔兹海默症或阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案422.一种在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案423.一种在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的方法，所述方法包括向对象施用治疗有效量的PKR抑制剂。
实施方案424.前述任一项的方法，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征。
实施方案425.实施方案424的方法，其中所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
实施方案426.前述任一项的方法，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
实施方案427.前述任一项的方法，其中所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
实施方案428.前述任一项的方法，其中所述阿尔兹海默症相关症状与PKR异常活
化有关或由PKR异常活化介导。
实施方案429.前述任一项的方法，其中所述对象的免疫细胞中的PKR被异常活化。
实施方案430.前述任一项的方法，其中所述对象的免疫细胞中的PKR被过度磷酸化。
实施方案431.实施方案430的方法，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细胞、树突状细胞、和小胶质细胞。
实施方案432.前述任一项的方法，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
实施方案433.实施方案432的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
实施方案434.实施方案433的方法，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
实施方案435.实施方案434的方法，其中所述circPOLR2A是人circPOLR2A。
实施方案436.前述任一项的方法，其中所述PKR抑制剂包含在纳米颗粒中。
实施方案437.前述任一项的方法，其中所述PKR抑制剂编码在递送载体中。
实施方案438.实施方案437的方法，其中所述递送载体为AAV载体。
实施方案439.前述任一项的方法，其中所述PKR抑制剂通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
实施方案440.前述任一项的方法，其中所述PKR抑制剂的剂量单元为约0.03mg至约300mg。
实施方案441.前述任一项的方法，其中所述PKR抑制剂以约0.005mg/kg至约5mg/kg的施用。
实施方案442.前述任一项的用方法途，其中所述PKR抑制剂每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
实施方案443.前述任一项的方法，其中所述PKR抑制剂每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
实施方案444.一种在对象中预防阿尔兹海默症的方法，所述方法包括向对象施用预防有效量的PKR抑制剂。
Claims (32)
- PKR抑制剂在制备用于治疗对象的牛皮癣或牛皮癣相关症状的药物中的用途，或在制备用于治疗对象的阿尔兹海默症或阿尔兹海默症相关症状的药物中的用途。
- PKR抑制剂在制备用于在患有牛皮癣的对象中缓解或减轻牛皮癣相关症状的药物中的用途，或者在制备用于在患有阿尔兹海默症的对象中缓解或减轻阿尔兹海默症相关症状的药物中的用途。
- PKR抑制剂在制备用于在患有牛皮癣的对象中阻止或延缓牛皮癣相关症状的出现或进展的药物中的用途，或者在制备用于在患有阿尔兹海默症的对象中阻止或延缓阿尔兹海默症相关症状的出现或进展的药物中的用途。
- 权利要求1-3任一项的用途，其中所述牛皮癣是静止期、缓解期或退行期牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣是进展期、活动期或炎症期牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣是复发型牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣是慢性牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣是中/重度牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣是S100A8和/或S100A9阳性牛皮癣。
- 权利要求1-3任一项的用途，其中所述牛皮癣相关症状包括皮肤损害。
- 权利要求1-3任一项的用途，其中所述牛皮癣相关症状或所述阿尔兹海默症相关症状包括或涉及炎性细胞因子过表达。
- 权利要求1-3任一项的用途，其中所述牛皮癣相关症状包括淋巴器官肿大。
- 权利要求1-3任一项的用途，其中所述牛皮癣相关症状或所述阿尔兹海默症相关症状与PKR异常活化有关或由PKR异常活化介导。
- 权利要求1-3任一项的用途，其中所述牛皮癣相关症状与RNase L异常活化有关或由RNase L异常活化介导。
- 权利要求1-3任一项的用途，其中所述阿尔兹海默症相关症状包括阿尔兹海默症的病理学表征，所述阿尔兹海默症的病理学表征选自Tau蛋白磷酸化、或Aβ肽的产生、组装、聚集或沉积。
- 权利要求1-3任一项的用途，其中所述阿尔兹海默症相关症状选自认知衰退、神经退化、记忆丧失、学习记忆能力丧失、意识模糊、判断力受损、人格改变、定向障碍或语言技能丧失。
- 权利要求1-3任一项的用途，其中所述对象的免疫细胞中的PKR被异常活化。
- 权利要求1-3任一项的用途，其中所述对象的免疫细胞中的PKR被过度磷酸化。
- 权利要求18的用途，其中所述免疫细胞选自T淋巴细胞、B淋巴细胞、单核细 胞、树突状细胞和小胶质细胞。
- 权利要求1-3任一项的用途，其中所述PKR抑制剂是具有16bp-26bp双链茎环结构的环形RNA。
- 权利要求20的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA选自circARID1B、circCAMSAP1、circCCNB1、circCNN2、circDHX34、circEPHB4、circEZH2、circFCHO2、circFGFR1、circFKBP8、circKIAA0368、circMBOAT2、circPIP5K1C、circPOLR2A、circPPP1CB、circPROSC、circPTK2、circPVT1、circRELL1、circSDHAF2、circSLC22A23、circSNHG4、circTBCD、circTMEM181、circUIMC1、circVAPB中的任一个或多个。
- 权利要求20的用途，其中所述具有16bp-26bp双链茎环结构的环形RNA是circPOLR2A。
- 权利要求1-3任一项的用途，其中所述circPOLR2A是人circPOLR2A。
- 权利要求1-3任一项的用途，其中所述药物包含包含PKR抑制剂的纳米颗粒。
- 权利要求1-3任一项的用途，其中所述药物包含编码所述PKR抑制剂的递送载体。
- 权利要求25的用途，其中所述递送载体为AAV载体。
- 权利要求1-3任一项的用途，其中所述药物被配制为用于通过静脉、皮下、肌肉、局部、体表、吸入、黏膜、颅内、鞘内或口服施用。
- 权利要求1-3任一项的用途，其中所述药物被配制为每剂量单元包含约0.03mg至约300mg的PKR抑制剂。
- 权利要求1-3任一项的用途，其中所述药物的单次施用量为约0.005mg/kg至约5mg/kg的PKR抑制剂。
- 权利要求1-3任一项的用途，其中所述药物被配制为用于每日一次施用、隔日一次施用、每周两次施用、每周一次施用、或每两周一次施用。
- 权利要求1-3任一项的用途，其中所述药物被配制为用于每月一次施用、隔月一次施用、每3个月一次施用、或每6个月一次施用。
- PKR抑制剂在制备用于预防牛皮癣或阿尔兹海默症的药物中的用途。
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