TREM for use in correcting missense mutations

Abstract

The present invention generally relates to tRNA-based effector molecules used to insert missense mutations into open reading frames (ORFs) of genes, for example, for the purpose of treating repeat elongation disorders. This disclosure features modified tRNA-based effector molecules (TREMs, e.g., TREM or TREM fragments), as well as related compositions and their use, for inserting missense mutations into open reading frames (ORFs) within genes. In some embodiments, the ORF comprises a missense mutation associated with repeat elongation disorder (RED).

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 63 / 458,888, filed on 12 April 2023. The entire contents of the said application are incorporated by reference. [Background technology]

[0002] Transfer RNA (tRNA) is a complex, naturally occurring RNA molecule that has several functions, including protein initiation and elongation. [Overview of the project] [Means for solving the problem]

[0003] This disclosure features modified tRNA-based effector molecules (TREMs, e.g., TREM or TREM fragments), related compositions, and their use for inserting missense mutations into open reading frames (ORFs) within genes. In some embodiments, the ORF contains a missense mutation associated with repeat extension disease (RED). As described herein, a TREM is a complex molecule capable of mediating various cellular processes. The TREMs disclosed herein include, for example, at least one modification (e.g., a non-native modification) on a component nucleotide (e.g., a base or sugar) or within an internucleotide region (e.g., the TREM backbone). In one embodiment, a TREM comprising the sequence of formula (A):[L1]x-[ASt domain 1]-[L2]x-[DH domain]-[L3]x-[ACH domain]-[VL domain]-[TH domain]-[L4]x-[ASt domain 2]-[L5]x (wherein independently, [L1] and [VL domain] are arbitrary, and x is independently 0 or 1 for each case) is provided herein. In some embodiments, the TREM comprises the sequence of formula (A-1):[L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2] (wherein independently, [L1] and [VL domain] are arbitrary). In one embodiment, one of [L1], [ASt domain 1], [L2]-[DH domain], [L3], [ACH domain], [VL domain], [TH domain], [L4], and [ASt domain 2] contains a nucleotide with a non-natural modification.

[0004] In one embodiment, TREM has the following: (a) the ability to assist in protein synthesis, (ii) the ability to be loaded by synthetases, (iii) the ability to be bound by elongation factors, (iv) the ability to introduce amino acids into peptide chains, (v) the ability to assist in elongation, or (vi) the ability to assist in initiation; (b) comprises at least X consecutive nucleotides without unnatural modifications, where X is greater than 3, 4, 5, 6, 7, 8, 9, or 10; c) containing at least three, but not all, nucleotides of a certain type (e.g., A, T, C, G, or U) that have the same unnatural modification; (d) containing at least X nucleotides of a certain type (e.g., A, T, C, G, or U) that do not have the unnatural modification (X = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 5 (e) nucleotides of a certain type (e.g., A, T, C, G, or U) that do not contain unnatural modifications, in the order of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74 (f) containing only nucleotides of a certain type (e.g., A, T, C, G, or U) that are not unnaturally modified, and / or (f) containing only nucleotides of a certain type (e.g., A, T, C, G, or U) that are not unnaturally modified, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80.

[0005] In certain embodiments, the TREM includes feature (a)(i). In certain embodiments, the TREM includes feature (a)(ii). In certain embodiments, the TREM includes feature (a)(iii). In certain embodiments, the TREM includes feature (a)(iv). In certain embodiments, the TREM includes feature (a)(v). In certain embodiments, the TREM includes feature (a)(vi). In certain embodiments, the TREM includes feature (b). In certain embodiments, the TREM includes feature (c). In certain embodiments, the TREM includes feature (d). In certain embodiments, the TREM includes feature (e). In certain embodiments, the TREM includes feature (f). In certain embodiments, the TREM includes all of features (a)-(f), or combinations thereof.

[0006] In certain embodiments, a TREM domain comprising a non-natural modification has a function, such as a domain function described herein.

[0007] In certain aspects, herein, the sequence of Formula B: [L1] y -[ASt domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x -[VL domain] y -[TH domain] y -[L4] y -[ASt domain 2] x is a TREM core fragment comprising where x = 1 and y = 0 or 1; and one of [ASt domain 1], [ACH domain], and [ASt domain 2] comprises nucleotides having a non-natural modification, a TREM core fragment is provided.

[0008] In some embodiments, TREM has the ability to assist in protein synthesis. In some embodiments, TREM has the ability to be modulated by synthetases. In some embodiments, TREM has the ability to be bound by elongation factors. In some embodiments, TREM has the ability to introduce amino acids into peptide chains. In some embodiments, TREM has the ability to assist in elongation. In some embodiments, TREM has the ability to assist in initiation.

[0009] In one embodiment, [ASt domain 1] and / or [ASt domain 2], including non-natural modifications, have the ability to initiate or elongate polypeptide chains.

[0010] In one embodiment, the [ACH domain], including unnatural modifications, has the ability to mediate pairing with codons.

[0011] In one embodiment, y=1 for one, two, three, four, five, six, all, or any combination of [L1], [L2], [DH domain], [L3], [VL domain], [TH domain], and [L4].

[0012] In one embodiment, y=0 for one, two, three, four, five, six, all, or any combination of [L1], [L2], [DH domain], [L3], [VL domain], [TH domain], and [L4].

[0013] In one embodiment, y=1 for linker[L1], and L1 contains a nucleotide having unnatural modifications.

[0014] In one embodiment, y=1 for linker [L2], and L2 contains a nucleotide having unnatural modifications.

[0015] In one embodiment, y=1 for the [DH domain (DHD)], and the DHD contains a nucleotide with unnatural modifications. In one embodiment, the DHD containing unnatural modifications has the ability to mediate recognition by aminoacyl-tRNA synthetase.

[0016] In one embodiment, y=1 for linker[L3], and L3 contains a nucleotide having unnatural modifications.

[0017] In one embodiment, y=1 for the [VL domain (VLD)], and the VLD contains a nucleotide having a non-natural modification.

[0018] In one embodiment, y=1 for the [TH domain (THD)], and the THD contains nucleotides with unnatural modifications. In one embodiment, the THD containing unnatural modifications has the ability to mediate ribosome recognition.

[0019] In one embodiment, y=1 for linker [L4], and L4 contains a nucleotide having unnatural modifications.

[0020] In another embodiment, the present disclosure relates to a TREM fragment comprising a portion of TREM, wherein TREM is an array of formula (A-1): The TREM fragment includes [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], and provides a TREM fragment that includes unnatural modifications.

[0021] In one embodiment, the TREM fragment includes one, two, three, or all or any combination of the following: (a) a TREM half (e.g., derived from a cleavage in the anticodon sequence, e.g., a 5' half or a 3' half); (b) a 5' fragment (e.g., derived from a cleavage in the DH domain or ACH domain, e.g., a fragment containing the 5' end); (c) a 3' fragment (e.g., derived from a cleavage in the TH domain, e.g., a fragment containing the 3' end); or (d) an internal fragment (e.g., derived from a cleavage in any one of the ACH domain, DH domain or TH domain).

[0022] In one embodiment, the TREM fragment comprises (a) a TREM half containing a nucleotide having an unnatural modification.

[0023] In one embodiment, the TREM fragment includes (b) a 5' fragment containing a nucleotide having an unnatural modification.

[0024] In one embodiment, the TREM fragment includes a 3' fragment containing a nucleotide having an unnatural modification (c).

[0025] In one embodiment, the TREM fragment includes an internal fragment comprising (d) a nucleotide having an unnatural modification.

[0026] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM domain comprises a plurality of nucleotides, each having an unnatural modification. In some embodiments, the unnatural modification includes nucleic acid base modification, sugar (e.g., ribose) modification, or skeletal modification. In some embodiments, the unnatural modification is sugar (e.g., ribose) modification. In some embodiments, the unnatural modification is 2'-ribose modification, e.g., 2'-OMe, 2'-halo (e.g., 2'-F), 2'-MOE, or 2'-deoxy modification. In some embodiments, the unnatural modification is skeletal modification, e.g., phosphorothioate modification.

[0027] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM sequence includes a CCA sequence at a terminal, e.g., the 3' terminal. In some embodiments, the TREM sequence does not include a CCA sequence at a terminal, e.g., the 3' terminal.

[0028] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a modification of the nucleotide base or backbone, for example, a modification selected from Table 5.

[0029] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a base modification selected from the modifications listed in Table 5.

[0030] In any embodiment of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a skeletal modification selected from the modifications listed in Table 5.

[0031] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is coded by one of the sequences listed in Table 1, for example, sequence numbers 1 to 451.

[0032] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is coded by a consensus sequence selected from any one of sequence numbers 562 to 621.

[0033] In some embodiments of any TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in any one of SEQ ID NOs. 625-693. In some embodiments, the TREM, TREM core fragment, or TREM fragment includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the TREM provided in any one of SEQ ID NOs. 625-693. In some embodiments, the TREM, TREM core fragment, or TREM fragment includes a sequence that differs by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nucleotide sequence of the TREM provided in any one of SEQ ID NOs. 625-693. In one embodiment, the TREM, TREM core fragment, or TREM fragment includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothioate modifications) compared to the TREM, TREM core fragment, or TREM fragment provided in any one of SEQ ID NOs.625-693.

[0034] In any embodiment of a TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is a TREM provided to any one of TREM numbers 1 to 69. In some embodiments, the TREM, TREM core fragment, or TREM fragment includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothioate modifications) compared to a TREM provided to any one of TREM numbers 1 to 69.

[0035] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment as disclosed herein.

[0036] In another embodiment, TREM or related compositions may be used, in particular, to modulate functional parameters (e.g., expression parameters and / or signaling parameters) of RNA corresponding to a nucleic acid sequence containing an endogenous open reading frame (ORF) having a repeat extension disease (RED) codon, or of a polypeptide encoded by such a nucleic acid sequence.

[0037] In another embodiment, a method is provided herein for modulating a functional parameter of mRNA corresponding to an endogenous open reading frame (ORF) containing a repeat extension disease (RED) codon, or a polypeptide encoded by such an endogenous open reading frame (ORF), comprising contacting the subject with a TREM, TREM core fragment, or TREM composition disclosed herein in an amount and / or for a sufficient amount of time to modulate the functional parameter of the mRNA or polypeptide, thereby modulating the functional parameter in the subject, wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a codon having a first sequence. In one embodiment, the functional parameter includes, for example, a signaling parameter and / or expression parameter as described herein.

[0038] In another embodiment, a method for regulating the expression of a protein within a cell is provided, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a repeat extension disease (RED) codon, and the method comprises contacting the cell with a TREM, TREM core fragment, or TREM composition comprising a TREM fragment disclosed herein in an amount and / or for a sufficient amount of time to regulate the expression of the encoded protein, thereby regulating the expression of the protein within the cell, wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with the RED codon. In one embodiment, the RED codon is CAG.

[0039] In another embodiment, a method for regulating the expression of a protein in a subject is provided herein, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a repeat extension disease (RED) codon, and the method comprises contacting the subject with a TREM composition comprising: (i) an anticodon pairing with a RED codon, (ii) an aminoacyl-tRNA synthetase specific to Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly, and (iii) a sequence of formula A, or (iv) an unnatural modification, in an amount and / or for a sufficient amount of time to regulate the expression of the encoded protein. In one embodiment, the RED codon is CAG. In one embodiment, the TREM composition comprises (i). In one embodiment, the TREM composition comprises (ii). In one embodiment, the TREM composition comprises (iii). In one embodiment, the TREM composition comprises (iv). In one embodiment, the TREM composition comprises two of (i) to (iv). In one embodiment, the TREM composition comprises three of (i) to (iv). In another embodiment, the TREM composition comprises each of (i) to (iv).

[0040] In another embodiment, the Disclosure provides a method for treating a subject having an endogenous open reading frame (ORF) containing a repeat extension disease (RED) codon, the method comprising: providing a TREM, a TREM core fragment, or a TREM composition comprising a TREM fragment (where the TREM comprises an anticodon that pairs with the RED codon in the ORF); and treating the subject by contacting the subject with the TREM, a TREM core fragment, or a composition comprising a TREM fragment in an amount sufficient to treat the subject and / or for a sufficient amount of time. In one embodiment, the RED codon is CAG.

[0041] In another embodiment, the Disclosure provides a method for treating a subject having a Repeat Elongation Disease (RED), comprising: a TREM composition comprising contacting the subject with the TREM, TREM core fragment, or TREM fragment composition in an amount and / or for a period of time sufficient to treat the subject; in some embodiment, the repeat elongation comprises a repeat motif (e.g., a RED codon) as described in Table 9; in some embodiment, RED is a disease or disorder as described herein.

[0042] In another aspect, the present disclosure provides a method for producing a TREM, a TREM core fragment, or a TREM fragment as disclosed herein, comprising ligating a first nucleotide to a second nucleotide to form a TREM.

[0043] In one embodiment, the TREM, TREM core fragment, or TREM fragment is non-natural (e.g., synthetic).

[0044] In one embodiment, TREM, TREM core fragment, or TREM fragment is prepared by cell-free solid-phase synthesis.

[0045] In another aspect, the Disclosure provides a method for regulating the intracellular tRNA pool, comprising providing a TREM, a TREM core fragment, or a TREM fragment as disclosed herein, and a method for contacting a cell with a TREM, a TREM core fragment, or a TREM fragment, thereby regulating the intracellular tRNA pool.

[0046] In some embodiments, the Disclosure provides a method for contacting cells, tissues, or subjects with a TREM, TREM core fragment, or TREM fragment as disclosed herein (for example, the TREM shown in Figure 1), comprising contacting cells, tissues, or subjects with a TREM, TREM core fragment, or TREM fragment, thereby bringing cells, tissues, or subjects into contact with a TREM, TREM core fragment, or TREM fragment.

[0047] In another aspect, the Disclosure provides a method for delivering a TREM, TREM core fragment, or TREM fragment (e.g., the TREM shown in Figure 1) to a cell, tissue, or subject, comprising providing the cell, tissue, or subject, and bringing the cell, tissue, or subject into contact with the TREM, TREM core fragment, or TREM fragment disclosed herein.

[0048] In one embodiment, the present disclosure is a method for regulating an intracellular tRNA pool comprising an endogenous open reading frame (ORF) having a codon having a first sequence, By choice, to acquire knowledge about the abundance of one or both of (i) and (ii), for example, to acquire knowledge about the relative amounts of (i) and (ii) within a cell, where (i) is a tRNA portion having an anticodon that pairs with a codon of an ORF having a first sequence (first tRNA portion), and (ii) is an isoacceptor tRNA portion having an anticodon that pairs with a codon other than the codon having the first sequence within the cell (second tRNA portion); Contacting a cell with a TREM, TREM core fragment, or TREM fragment (e.g., the TREM shown in Figure 1) disclosed herein, in an amount and / or for a sufficient amount of time to regulate the relative amounts of a first tRNA portion and a second tRNA portion within the cell, wherein the TREM, TREM core fragment, or TREM fragment has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having a first sequence; This allows for the regulation of the intracellular tRNA pool. This provides a method that includes this.

[0049] In another aspect, the present disclosure is a method for modulating the tRNA pool in an object having an ORF containing a codon having a first sequence, By choice, to acquire knowledge about the abundance of one or both of (i) and (ii), for example, to acquire knowledge about the relative amounts of (i) and (ii) in the subject, where (i) is a tRNA portion having an anticodon that pairs with a codon of an ORF having a first sequence (first tRNA portion), and (ii) is an isoacceptor tRNA portion having an anticodon that pairs with a codon other than the codon having the first sequence in the subject (second tRNA portion); Contacting a subject with a TREM, TREM core fragment, or TREM fragment (e.g., the TREM shown in Figure 1) disclosed herein, in an amount and / or for a sufficient amount of time to adjust the relative amounts of the first and second tRNA portions in the subject, wherein the TREM, TREM core fragment, or TREM fragment has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having a first sequence; This allows for the regulation of the tRNA pool in the target. This provides a method that includes this.

[0050] In one embodiment, the present disclosure is a method for regulating the tRNA pool in a subject having an endogenous ORF containing a synonymous codon (synonymous codon or SMC), To provide a composition comprising a TREM, a TREM core fragment, or a TREM fragment (for example, the TREM shown in Figure 1) disclosed herein, wherein the TREM, TREM core fragment, or TREM fragment comprises an isoacceptor-tRNA moiety having an anticodon sequence that pairs with SMC(TREM); The subject is brought into contact with the composition in an amount and / or for a sufficient amount of time to modulate the tRNA pool in the subject. This allows for the regulation of the tRNA pool in the target. This provides a method that includes this.

[0051] In another aspect, the present disclosure relates to a method for regulating an intracellular tRNA pool having an endogenous ORF containing a codon containing an SMC, To provide a composition comprising a TREM, a TREM core fragment, or a TREM fragment (for example, the TREM shown in Figure 1) disclosed herein, wherein the TREM, TREM core fragment, or TREM fragment comprises an isoacceptor-tRNA moiety having an anticodon sequence that pairs with SMC(TREM); To bring cells into contact with the composition in an amount and / or for a sufficient amount of time to regulate the intracellular tRNA pool, This provides a method that includes regulating the intracellular tRNA pool.

[0052] In one embodiment, the present disclosure is a method for regulating the expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an ORF, the ORF comprising a mutated codon, and the method is Cells are brought into contact with a composition comprising a TREM, a TREM core fragment, or a TREM fragment (e.g., the TREM shown in Figure 1) disclosed herein, in an amount and / or for a sufficient amount of time to regulate the expression of the encoded protein. Here, TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a mutated codon, This provides a method that includes regulating the expression of proteins within cells.

[0053] In another aspect, the present disclosure relates to a method for regulating the expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous ORF, the ORF comprising a mutated codon, and the method is The subject is brought into contact with a composition comprising a TREM, a TREM core fragment, or a TREM fragment (e.g., the TREM shown in Figure 1) in an amount and / or for a sufficient amount of time to modulate the expression of the encoded protein. Here, TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a mutated codon, This provides a method that includes regulating the expression of proteins within cells.

[0054] In some embodiment of any of the methods disclosed herein, the mutation in the ORF is a nonsense mutation resulting in an immature stop codon selected from, for example, UAA, UGA, or UAG. In some embodiment, the stop codon is UAA. In some embodiment, the stop codon is UGA. In some embodiment, the stop codon is UAG.

[0055] In one embodiment of any of the methods disclosed herein, the TREM includes an anticodon that pairs with a stop codon.

[0056] The TREMs described herein include TREM, TREM core fragments, and TREM fragments. TREM, TREM core fragments, or TREM fragments may be modified with unnatural modifications, for example, to increase the level and / or activity (e.g., stability) of the TREM. For example, pharmaceutical TREM compositions containing TREM having unnatural modifications can be administered to cells, tissues, or subjects, for example, in vitro or in vivo, to modulate their functions. This specification discloses TREM having unnatural modifications, TREM core fragments, or TREM fragments, TREM compositions, preparations, methods for preparing TREM compositions and preparations, and methods for using them.

[0057] In one embodiment, the TREM, TREM core fragment, and TREM fragment include unnatural modifications that improve the stability of the TREM, TREM core fragment, or TREM fragment, or enhance its activity.

[0058] Any additional features of the aforementioned TREM, TREM core fragments, TREM fragments, TREM compositions, preparations, methods for producing TREM compositions and preparations, and methods for using TREM compositions and preparations include one or more features described in the listed embodiments, drawings, descriptions, examples, or claims.

[0059] Those skilled in the art will be able to recognize or confirm, by conventional experimentation alone, numerous equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be included in the embodiments, drawings, description, examples, or claims listed below. [Brief explanation of the drawing]

[0060] [Figure 1-1] This table lists exemplary TREMs described herein, such as TREMs that can have a missense mutation (e.g., a RED codon inserted into the ORF of a gene) inserted into the ORF of a gene. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 1-5] Same as above. [Figure 1-6] Same as above. [Figure 1-7] Same as above. [Figure 2] This is a schematic diagram illustrating the intended function of TREM, which can insert missense mutations into the ORF of a gene. [Figure 3] This is a schematic diagram illustrating the design of the HTT reporter. The number of CAG repeats in HTT exon 1 was varied to reproduce the number of CAG repeats observed in healthy individuals and Huntington's disease patients. Abbreviations: CMV: Cytomegalovirus promoter; eGFP: Enhanced green fluorescent protein reporter. [Figure 4] This line plot shows the reduction in GFP spots in HEK293 cells treated with the displayed missense tRNA for 48 hours. [Figure 5] This graph illustrates the effectiveness of an exemplary missense TREM. [Figure 6] This graph shows the measurement results of HTT protein aggregates using a fluorescence microscope. A reporter plasmid was transfected into Hek293 cells, and imaging was performed using phase and GFP channels. [Figure 7]This graph shows the area of ​​GFP spots classified according to their frequency in HEK293 cells. [Figures 8A-8D] These are a series of fluorescence microscopy images showing aggregates in HEk293 cells transfected with 63Q and 105Q reporters, compared to cells transfected with an empty vector or 21Q reporters. [Figure 9] This graph shows the effect of missense TREM on HTT protein aggregation in HEK293 cells. [Figure 10] This graph shows that missense TREM inhibits aggregate formation. HEK293 cells were co-transfected with an ATXN7 10Q or 52Q reporter along with a missense TREM plasmid, and aggregate formation was measured using GFP fluorescence imaging. [Figure 11] This graph shows the effect of missense TREM on the ATXN3 reporter. The ATXN3 24Q reporter was transfected into HEK293 cells with a missense TREM plasmid, and aggregate formation was measured. [Figure 12] This graph shows the effect of missense TREM on cell health. HEK293 cells (Figure 12A) and U87 cells (Figure 12B) were transfected with missense TREM plasmids for 48 hours. [Figure 13] This is an immunoblot of cell lysates recovered from HEK293 cells transfected with control or missense TREM. [Figure 14] This graph shows the effect of autophagy on the removal of HTT 63QpolyQ protein aggregates from missense TREM-transfected cells. [Figure 15] This immunoblot shows the effect of autophagy inhibition on polyQ protein accumulation mediated by missense TREM. [Figure 16]This is an immunoblot of HEK293 cells transfected with exemplary missense TREM plasmids. Cells were transfected with different missense TREM plasmids, and after collecting the cell lysates, immunoblotting was performed using an anti-LC3B antibody. [Modes for carrying out the invention]

[0061] Repeat Elongation Disorders (REDs) are a group of human diseases caused by an increase in the length of polynucleotide repeat sequences in the genome that exceeds a critical threshold. One class of Repeat Elongation Disorders is characterized by an increase in the length of a dangerous codon (e.g., a Repeat Elongation Disorder codon) in the genome, which is then transcribed into mRNA containing RED codon repeats that exceed the critical threshold. For example, some REDs are characterized by a repeat of the CAG codon within the open reading frame of the major disease protein. This repeating CAG codon forms a polyglutamine (polyQ) sequence in the translated protein product. In the case of polyQ REDs, the polyQ protein forms insoluble aggregates in the cytoplasm, affecting cell viability through gain-of-function mechanisms. Non-exclusive examples of polyQ repeat elongation disorders include Huntington's disease (caused by CAG elongation in the HTT gene), SCA1 (caused by CAG elongation in the ATXN1 gene), SCA2 (caused by CAG elongation in the ATXN2 gene), SCA3 / MJD (caused by CAG elongation in the ATXN3 gene), SCA6 (caused by CAG elongation in the CACNA1A gene), SCA7 (caused by CAG elongation in the ATXN7 gene), SCA17 (caused by CAG elongation in the TBP gene), DRPLA (caused by CAG elongation in the ATN1 gene), and SBMA (caused by CAG elongation in the AR gene).

[0062] Since the aggregation of pathogenic polyQ proteins is a common feature of polyQ RED resulting from repeat elongation in unrelated genes, methods to suppress the aggregation of polyQ proteins in the cytoplasm may yield broad therapeutic effects. In some individuals, genetically encoded interruptions of CAG repeat lengths exceeding the pathogenicity threshold delay the onset of the disease or alleviate symptoms, suggesting that shortening the length of the polyQ protein produced from toxic mRNA may mitigate or reduce the severity of the disease in patients.

[0063] One method to shorten the length of polyQ proteins translated from toxic mRNA is to create tRNAs that decode CAG codons corresponding to different amino acids, thereby reducing the number of glutamine residues incorporated into the peptide chain. These tRNAs can be classified as missense tRNAs because they mistakenly incorporate amino acids into sense codons during the mRNA translation process.

[0064] This disclosure features tRNA-based effector molecules (TREMs) containing unnatural modifications and related methods. As disclosed herein, TREMs are complex molecules capable of mediating various cellular processes. For example, pharmaceutical TREM compositions, such as TREMs containing unnatural modifications, can be administered to cells, tissues, or subjects to modulate their functions.

[0065] definition "To acquire" or "to obtain," as the terms are used herein, means to obtain ownership of a value, e.g., a numerical value, by "directly acquiring" or "indirectly acquiring" a physical entity or value. "Directly acquiring" means to obtain a value by performing a process (e.g., performing an analytical method). "Indirectly acquiring" means to receive a value from another party or source (e.g., a third-party laboratory that directly acquired the value).

[0066] When the term "isoreceptor" is used herein, it refers to a plurality of molecules, each containing a different native anticodon sequence, and each of the plurality of molecules mediating the incorporation of the same amino acid, which is an amino acid that naturally corresponds to a plurality of anticodons.

[0067] When the term "modification" is used herein in relation to nucleotides, it refers to a modification of the chemical structure of the nucleotide in question, such as a covalent modification. The modification may be natural or unnatural. In some embodiments, the modification is unnatural. In some embodiments, the modification is natural. In some embodiments, the modification is synthetic. In some embodiments, the modification is one of the modifications shown in Table 5.

[0068] "Naturally occurring nucleotides," as the term is used herein, refer to nucleotides that do not contain unnatural modifications. In some embodiments, they include natural modifications.

[0069] When the term is used herein in relation to nucleotides, “unnatural modification” means (a) a modification that a cell, e.g., a human cell, does not produce on endogenous tRNA; or (b) a modification that a cell, e.g., a human cell, may produce on endogenous tRNA, but such a modification is located at a position where it does not occur on endogenous tRNA, e.g., the modification is in a domain, linker or arm, or in a domain, linker or arm where such a modification is not present in the nucleotide and / or in nature. In either case, the modification is added by synthesis, e.g., in a cell-free reaction, e.g., a solid-phase or liquid-phase synthesis reaction. In some embodiments, an unnatural modification is a modification that does not exist (in identity, location or position) when the TREM sequence is expressed in mammalian cells, e.g., the HEK293 cell line. Exemplary unnatural modifications are found in Table 5.

[0070] When the term is used herein, “unnaturally modified nucleotide” refers to a nucleotide that includes unnatural modifications on or to a sugar, nucleic acid base, or phosphate moiety.

[0071] When the term “nucleotide” is used herein, it refers to an entity comprising a sugar, typically a pentameric sugar; a nucleic acid base; and a phosphate-binding group. In some embodiments, the nucleotides include naturally occurring nucleotides (e.g., those naturally present in human cells), such as adenine, thymine, guanine, cytosine, or uracil nucleotides.

[0072] "Functional parameters" refer to expression parameters and / or signal transduction parameters. In some embodiments, functional parameters are expression parameters. Expression parameters include expression parameters of polypeptides or proteins encoded by an endogenous ORF having a first sequence; or expression parameters of RNA encoded by an endogenous ORF having a first sequence, such as messenger RNA. In some embodiments, expression parameters are (a) Protein translation; (b) Expression level (e.g., of polypeptides, proteins, or mRNA); (c) Post-translational modification of polypeptides or proteins; (d) Folding (for example, of polypeptides or proteins, or mRNA), (e) Structure (e.g., of polypeptides or proteins, or mRNA), (f) Transfer (e.g., of polypeptides or proteins), (g) Computation (e.g., of polypeptides or proteins, or mRNA), (h) Incorporation into supramolecular structures (e.g., polypeptides or proteins, or mRNA), e.g., incorporation into membranes, proteasomes, or ribosomes, (i) Incorporation into a multimer polypeptide, e.g., homodimer or heterodimer, and / or (j) Stability It may include.

[0073] In one embodiment, the functional parameter is a signal transduction parameter. The signal transduction parameter is (1) Regulation of signaling pathways, such as cellular signaling pathways, downstream or upstream of proteins encoded by an endogenous ORF having a first sequence; (2) Regulation of cell fate; (3) Regulation of ribosome occupation; (4) Regulation of protein translation; (5) mRNA stability regulation; (6) Protein folding and structural regulation; (7) Protein transduction or compartmentalization control; and / or (8) Regulation of protein stability It may include.

[0074] As used herein, the terms “repeat elongation disease” and “RED” refer to diseases associated with an increase in the length of polynucleotide repeat sequences in the genome beyond a critical threshold (e.g., repeat elongation). RED may be associated with, for example, trinucleotide repeat elongation or hexanucleotide repeat elongation.

[0075] As used herein, the terms “repeat elongation disease codon” and “RED codon” refer to (a) a specific amino acid that corresponds to a particular amino acid in protein synthesis (e.g., translation) and (b) a trinucleotide sequence (e.g., Table 9) that is abnormally, tandem, and repeated in repeat elongation diseases. For example, a normal human subject (e.g., a subject not diagnosed with or experiencing symptoms of Huntington's disease) may have <36 repeats of the RED codon CAG in the HTT gene. In some embodiments, a human subject with Huntington's disease may have at least 36 (e.g., at least 37, 38, 39, 40, 45, 50, 100, or more) repeats of the RED codon CAG in the HTT gene. RED codons are associated with abnormally long amino acid sequences, such as polyglutamine (polyQ) sequences, which can trigger protein misfolding and amyloid-like aggregation, potentially leading to severe cytotoxicity, for example, contributing to neurodegeneration.

[0076] When the term is used herein, “tRNA-based effector molecule” or “TREM” refers to an RNA molecule having the structure or properties of (a) to (v) below, which may be recombinant TREM, synthetic TREM, or TREM expressed from heterologous cells. The TREMs described herein are synthetic molecules and are prepared, for example, in cell-free reactions, e.g., solid-phase or liquid-phase synthesis reactions. TREMs are chemically different from endogenous tRNA molecules prepared in cells, e.g., mammalian cells, e.g., human cells, in terms of modifications, e.g., primary sequence, type, or position. TREMs may have several of the structures and functions of (a) to (v) (e.g., 2, 3, 4, 5, 6, 7, 8, 9).

[0077] In some embodiments, TREM is non-natural, as can be assessed by its structure or the method by which it is manufactured.

[0078] In one embodiment, the TREM includes one or more of the following structures or characteristics: (a') Any selected linker region of the consensus sequence provided in the “consensus sequence” interval, e.g., linker 1 region; (a) an amino acid-binding domain, e.g., an acceptor stem domain (AStD) (an AStD, for example, when present in other wild-type tRNA, contains an RNA sequence sufficient to mediate the acceptance of an amino acid, e.g., a cognate or non-cognate amino acid, and the transfer of an amino acid (AA) in polypeptide chain initiation or elongation). Typically, an AStD contains a 3'-terminal adenosine (CCA) for acceptor stem loading, which is part of synthetase recognition. In some embodiments, the AStD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring AStD, e.g., an AStD encoded by the nucleic acid in Table 1. In some embodiments, the TREM may contain a fragment or analogue of an AStD, e.g., an AStD encoded by the nucleic acid in Table 1, the fragment having AStD activity in one embodiment and not having AStD activity in another embodiment. (A person skilled in the art can appropriately determine the sequence corresponding to any of the domains, stems, loops, or other sequence features described herein that are derived from the nucleic acid-encoded sequences in Table 1. For example, a person skilled in the art can determine the sequence corresponding to the AStD derived from the nucleic acid-encoded tRNA sequence in Table 1.)

[0079] In one embodiment, AStD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, AStD is formula I ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, AStD is Equation II ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, AStD is Equation III ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; (a'-1) A linker containing residues R8-R9 of the consensus sequence provided in the "consensus sequence" interval, e.g., linker 2 region; (b) Dihydrouridine hairpin domain (DHD) (DHD contains an RNA sequence sufficient to act as a recognition site for aminoacyl-tRNA synthetase for amino acid loading of TREM, for example, when present in other wild-type tRNAs, mediating recognition by aminoacyl-tRNA synthetase). In embodiments, DHD mediates the stabilization of the tertiary structure of TREM. In some embodiments, DHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring DHD, e.g., DHD encoded by nucleic acids in Table 1. In some embodiments, TREM may contain a fragment or analogue of DHD, e.g., DHD encoded by nucleic acids in Table 1, the fragment having DHD activity in one embodiment and not having DHD activity in another embodiment.

[0080] In one embodiment, the DHD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, DHD is given by formula I ZZZ residue R 10 -R 11 -R 12 -R 13 -R 14-R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R<able>0000054< / able>comprises -R, where ZZZ represents any one of the 20 amino acids; In certain embodiments, DHD is the residue R of formula II ZZZ of residue R 10 -R 11 -R 12 -R 13 -R 14 -R<000006##>-R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 comprises -R, where ZZZ represents any one of the 20 amino acids; In certain embodiments, DHD is the residue R of formula III<000007##>of residue R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 comprises -R, where ZZZ represents any one of the 20 amino acids; (b’-1) The residue R of the consensus sequence provided in the "consensus sequence" region29 A linker, for example, linker 3 region; (c) An anticodon that binds to each codon in the mRNA, for example, an anticodon hairpin domain (ACHD) (ACHD contains, for example, a sequence sufficient to mediate (with or without wobbling) base pairing with a codon, such as an anticodon triplet, when present in other wild-type tRNAs; in certain embodiments, ACHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring ACHD, such as an ACHD encoded by the nucleic acids in Table 1). In certain embodiments, TREM may include an ACHD, for example, a fragment or analog of an ACHD encoded by the nucleic acids in Table 1, and the fragment in certain embodiments has ACHD activity and in other embodiments does not have ACHD activity.

[0081] In certain embodiments, ACHD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at 1, 2, 5, or 10 or fewer positions. In certain embodiments, ACHD has the formula I ZZZ residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 and contains ZZZ, which represents any of the 20 amino acids; In certain embodiments, ACHD has the formula II ZZZ residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, ACHD is Equation III ZZZ The residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 It contains, and ZZZ represents one of the 20 amino acids; (d) Variable loop domain (VLD) (The VLD contains an RNA sequence sufficient to act as a recognition site for aminoacyl-tRNA synthetase for aminoacyl-tRNA loading of TREM, for example, when present in other wild-type tRNAs, mediating the recognition of aminoacyl-tRNA synthetase). In embodiments, the VLD mediates the stabilization of the tertiary structure of TREM. In some embodiments, the VLD modulates, for example, the specificity of TREM with respect to its homologous amino acids, for example, increasing it, for example, the VLD modulates the homologous adapter function of TREM. In some embodiments, the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring VLDs, for example, VLDs encoded by nucleic acids in Table 1. In some embodiments, TREM may include a fragment or analogue of a VLD, for example, a VLD encoded by nucleic acids in Table 1, the fragment having VLD activity in one embodiment and not having VLD activity in another embodiment.

[0082] In one embodiment, the VLD is located below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval.

[0083] In one embodiment, the VLD is a residue of the consensus sequence provided in the "consensus sequence" interval -[R 47 ] X Including x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18 x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271); (e) Thymine hairpin domain (THD) (THD comprises an RNA sequence sufficient to mediate ribosome recognition when present in other wild-type tRNAs, for example, to act as a recognition site for ribosomes to form a TREM-ribosome complex during translation). In some embodiments, THD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring THD, for example, THD encoded by the nucleic acids in Table 1. In some embodiments, TREM may comprise a fragment or analogue of THD, for example, THD encoded by the nucleic acids in Table 1, the fragment having THD activity in one embodiment and not having THD activity in another embodiment.

[0084] In one embodiment, the THD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, THD is formula I ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, THD is given by formula II ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, THD is given by Equation III ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; (e'1) The residue R of the consensus sequence provided in the "consensus sequence" interval 72 A linker that includes, for example, linker 4 region; (f) Under physiological conditions, it comprises a stem structure and one or more loop structures, e.g., one, two, or three loops. The loops may comprise domains described herein, e.g., domains selected from (a) to (e). The loops may comprise one or more domains. In some embodiments, the stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring stem or loop structures, e.g., stem or loop structures encoded by nucleic acids in Table 1. In some embodiments, TREM may comprise fragments or analogues of stem or loop structures, e.g., stem or loop structures encoded by nucleic acids in Table 1, wherein the fragments in one embodiment have the activity of the stem or loop structure, while in other embodiments they do not; (g) Tertiary structure, e.g., L-shaped tertiary structure; (h) Adapter function, i.e., TREM mediates the acceptance of amino acids, such as its congener amino acids, and mediates the transfer of AAs in the initiation or elongation of polypeptide chains; (i) Homogeneic adapter function (TREM mediates the acceptance and incorporation of amino acids (e.g., homogeneic amino acids) that are naturally bound to the anticodon of the TREM that initiates or extends the polypeptide chain); (j) Non-homogeneic adapter function (TREM mediates the acceptance and incorporation of amino acids other than those naturally bound to the TREM anticodon (e.g., non-homogeneic amino acids) during polypeptide chain initiation or elongation); (k) Regulatory functions, such as epigenetic functions (e.g., gene silencing functions or signaling pathway regulation functions), cell fate regulation functions, mRNA stability regulation functions, protein stability regulation functions, protein transduction regulation functions, or protein compartmentalization functions; (l) Structures that enable ribosome binding; (m) Post-transcriptional modifications, e.g., naturally occurring post-transcriptional modifications; (n) Functional properties of tRNA, for example, the ability to inhibit any of the properties (h) to (k) possessed by tRNA; (o) The ability to regulate cell fate; (p) Ability to regulate ribosome occupation; (q) The ability to regulate protein translation; (r) Ability to regulate mRNA stability; (s) Ability to regulate protein folding and structure; (t) Ability to regulate protein transduction or compartmentalization; (u) the ability to regulate protein stability; or (v) The ability to regulate signaling pathways, such as cellular signaling pathways.

[0085] In one embodiment, TREM comprises a full-length tRNA molecule or a fragment thereof.

[0086] In one embodiment, TREM includes the following characteristics: (a) to (e).

[0087] In one embodiment, TREM includes the following characteristics: (a) and (c).

[0088] In one embodiment, TREM includes the following characteristics: (a), (c), and (h).

[0089] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (b).

[0090] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (e).

[0091] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), and (e).

[0092] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), (e), and (g).

[0093] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (m).

[0094] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (g).

[0095] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (b).

[0096] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (e).

[0097] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), and (e).

[0098] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), (e), and (q).

[0099] In one embodiment, TREM is (i) an amino acid-binding domain that binds to an amino acid (e.g., AStD as described in (a) of this specification); and (ii) comprising an anticodon that binds to each codon in the mRNA (e.g., ACHD as described in (c) herein).

[0100] In one embodiment, the TREM includes a mobile RNA linker that provides the covalent bonds of (i) and (ii).

[0101] In one embodiment, TREM mediates protein translation.

[0102] In some embodiments, the TREM includes a linker, e.g., an RNA linker, e.g., a mobile RNA linker, that provides a covalent bond between the first and second structures or domains. In some embodiments, the RNA linker includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ribonucleotides. The TREM may include one or more linkers; for example, in embodiments, the TREM comprising (a), (b), (c), (d), and (e) may have a first linker between the first and second domains, and a second linker between the third domain and another domain.

[0103] For a certain purpose, TREM contains the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2].

[0104] In one embodiment, TREM comprises an RNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof, or differs from it by 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 or fewer ribonucleotides. In one embodiment, TREM comprises an RNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof, or differs from it by 1, 2, 3, 4, 5, 10, or 15 or fewer ribonucleotides. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which includes an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which includes an RNA sequence encoded by a DNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0105] In one embodiment, the TREM is 76 to 90 nucleotides long. In the embodiment, the TREM or its fragment or functional fragment is 10 to 90 nucleotides, 10 to 80 nucleotides, 10 to 70 nucleotides, 10 to 60 nucleotides, 10 to 50 nucleotides, 10 to 40 nucleotides, 10 to 30 nucleotides, 10 to 20 nucleotides, 20 to 90 nucleotides, 20 to 80 nucleotides, 20 to 70 nucleotides, 20 to 60 nucleotides, 20 to 50 nucleotides, 20 to 40 nucleotides, 30 to 90 nucleotides, 30 to 80 nucleotides, 30 to 70 nucleotides, 30 to 60 nucleotides, or 30 to 50 nucleotides.

[0106] In one embodiment, TREM is aminoacylated, for example, by loading amino acids with aminoacyl-tRNA synthetase.

[0107] In one embodiment, the TREM is unloaded with amino acids, for example, an unloaded TREM (uTREM).

[0108] In some embodiments, the TREM contains tRNA that is shorter than the full length. In embodiments, the TREM may correspond to a naturally occurring or non-naturally occurring fragment of tRNA. Exemplary fragments include the TREM half (e.g., derived from a cleavage in the ACHD, e.g., an anticodon sequence, e.g., a 5' half or a 3' half); the 5' fragment (e.g., derived from a cleavage in the DHD or ACHD, e.g., a fragment containing the 5' end); the 3' fragment (e.g., derived from a cleavage in the THD, e.g., a fragment containing the 3' end); or the internal fragment (e.g., derived from a cleavage in one or more of the ACHD, DHD, or THD).

[0109] When the term "TREM core fragment" is used herein, the sequence of formula B:[L1] y -[ASt Domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x-[VL domain] y -[TH domain] y -[L4] y -[ASt Domain 2] x This refers to the part where x=1 and y=0 or 1 in the equation.

[0110] As used herein, "TREM fragment" refers to the portion of TREM, where TREM comprises the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2].

[0111] When the term is used herein, "congenital adapter function TREM" refers to a TREM that mediates initiation or extension by AA (congenital AA) that naturally binds to the anticodon of the TREM.

[0112] When the term is used herein, “reduced expression” refers to a reduction compared to a reference, for example, if modification of a control region or addition of a drug results in a reduction in the expression of the product in question, then that reduction is compared to other similar cells without modification or addition.

[0113] When the term is used herein, “external nucleic acid” refers to a nucleic acid sequence that is not present in the nearest sequence in a reference cell, e.g., the cell into which the external nucleic acid is introduced, or that differs from it by at least one nucleotide. In some embodiments, the external nucleic acid includes a nucleic acid encoding TREM.

[0114] "Foreign TREM" is used in this specification, (a) The reference cell, for example, the cell into which the foreign nucleic acid is introduced, has at least one nucleotide or one post-transcriptional modification that is different from the nearest sequence tRNA; (b) Whether it has been introduced into cells other than the transcribed cell; (c) Whether it is present in cells other than those that exist naturally; or (d) Refers to a TREM that has a non-wild-type expression profile, e.g., a level or distribution (e.g., it is expressed at a higher level than the wild type). In some embodiments, the expression profile may be mediated by a change introduced into the nucleic acid that modulates expression or by the addition of a drug that modulates the expression of an RNA molecule. In some embodiments, an exogenous TREM includes one, two, three, or four of characteristics (a) to (d).

[0115] Where used herein, “GMP-grade composition” refers to a composition that conforms to current Good Manufacturing Practices (cGMP) guidelines or other similar requirements. In some embodiments, a GMP-grade composition may be used as a pharmaceutical product.

[0116] As used herein, the terms “increase” and “decrease” refer to adjustments that result in an increase or decrease in the amount of a particular indicator of function, expression, or activity relative to a reference, respectively. For example, after administration of TREM to cells, tissues, or subjects as described herein, the amount of the indicator markers (e.g., protein translation, mRNA stability, protein folding) as described herein may increase or decrease by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%, 2×, 3×, 5×, or 10×, relative to the amount of the marker before administration or relative to the effect of a negative control drug. The indicator may be measured after administration at the time when the administration has had the listed effects, for example, at least 12 hours, 24 hours, 1 week, 1 month, 3 months, or 6 months after the start of treatment.

[0117] When the term is used herein, “increased expression” means an increase compared to a reference, for example, if modification of a control region or addition of a drug results in increased expression of the product of interest, it is considered increased compared to otherwise similar cells without modification or addition.

[0118] "Non-homogeneous adapter functional TREM" refers, as used herein, to a TREM that mediates initiation or extension by AAs other than AAs that naturally bind to the TREM's anticodon (non-homogeneous AAs). In some embodiments, a non-homogeneous adapter functional TREM is also called a misloaded TREM (mTREM).

[0119] "Non-natural sequence," as used herein, refers to a sequence in which adenine is replaced by a residue other than an adenine analog, cytosine is replaced by a residue other than a cytosine analog, guanine is replaced by a residue other than a guanine analog, and uracil is replaced by a residue other than a uracil analog. An analog refers to any possible derivative of ribonucleotide A, G, C, or U. In some embodiments, a sequence having a derivative of any one of ribonucleotides A, G, C, or U is a non-natural sequence.

[0120] When the term is used herein, “pharmaceutical TREM composition” refers to a TREM composition suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition contains pharmaceutical excipients. In some embodiments, TREM may be the sole active ingredient in the pharmaceutical TREM composition. In embodiments, the pharmaceutical TREM composition may contain, substantially no, or pharmaceutically acceptable amounts of, host cell proteins, DNA, e.g., host cell DNA, endotoxins, and bacteria.

[0121] "Post-transcriptional processing," as used herein with respect to the target molecule, e.g., TREM, RNA, or tRNA, refers to covalent modification of the target molecule. In some embodiments, the covalent modification occurs after transcription. In some embodiments, the covalent modification occurs concurrently with transcription. In some embodiments, the modification is performed in vivo, for example, in the cells used to produce TREM. In some embodiments, the modification is performed ex vivo, for example, on TREM isolated from or obtained from the cells that produced TREM. In some embodiments, the post-transcriptional modification is selected from the post-transcriptional modifications listed in Table 2.

[0122] "Synthetic TREM," as used herein, refers to TREM synthesized in a cell having an endogenous nucleic acid encoding TREM, or synthesized by means other than cellular synthesis, for example, synthetic TREM is synthesized by cell-free solid-phase synthesis. Synthetic TREM may have the same or different sequence or tertiary structure as natural tRNA.

[0123] When used herein, "recombinant TREM" refers to TREM expressed in a human-modified cell having modifications that mediate TREM production, for example, the cell containing an exogenous sequence encoding TREM or modifications that mediate TREM expression, such as transcriptional expression or post-transcriptional modifications. Recombinant TREM may have the same or different sequence, set of post-transcriptional modifications, or tertiary structure as a reference tRNA, for example, a native tRNA.

[0124] As used herein, “reference TREM” refers to naturally occurring TREMs.

[0125] When the term "tRNA" is used herein, it refers to transtransition ribonucleic acid that is naturally present in its natural state.

[0126] When the term "TREM composition" is used herein, it refers to a composition comprising multiple TREMs, multiple TREM core fragments, and / or multiple TREM fragments. A TREM composition may comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In some embodiments, the composition comprises only a single species of TREM, TREM core fragment, or TREM fragment. In some embodiments, the TREM composition comprises a first TREM, TREM core fragment, or TREM fragment species; and a second TREM, TREM core fragment, or TREM fragment species. In some embodiments, the TREM composition comprises X TREMs, TREM core fragments, or TREM fragment species (X = 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the TREMs, TREM core fragments, or TREM fragments have at least 70, 75, 80, 85, 90, or 95, or 100%, identity with the sequences encoded by nucleic acids in Table 1. A TREM composition may comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In some embodiments, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% dry weight TREM (for liquid compositions, dry weight refers to the weight after substantially all liquid has been removed, e.g., after freeze-drying). In some embodiments, the composition is liquid. In some embodiments, the composition is dry, e.g., freeze-dried material. In some embodiments, the composition is frozen composition. In some embodiments, the composition is sterile. In some embodiments, the composition contains at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g of TREM (e.g., measured by dry weight). In some embodiments, at least X% of the TREM in the TREM composition has non-natural modifications at selected positions, where X is 80, 90, 95, 96, 97, 98, 99, or 99.5.

[0127] In one embodiment, at least X% of the TREM in the TREM composition has a non-natural modification at a first position and a non-natural modification at a second position, where X is independently 80, 90, 95, 96, 97, 98, 99, or 99.5. In the embodiment, the modifications at the first and second positions are the same. In the embodiment, the modifications at the first and second positions are different. In the embodiment, the nucleotides at the first and second positions are the same, for example, both being adenine. In the embodiment, the nucleotides at the first and second positions are different, for example, one being adenine and the other being thymine.

[0128] In one embodiment, at least X% of the TREM in the TREM composition has a non-natural modification at the first position, and less than Y% has a non-natural modification at the second position, where X is 80, 90, 95, 96, 97, 98, 99, or 99.5, and Y is 20, 20, 5, 2, 1, .1, or .01. In several embodiments, the nucleotides at the first and second positions are the same, for example, both being adenine. In several embodiments, the nucleotides at the first and second positions are different, for example, one being adenine and the other being thymine.

[0129] TREM, TREM core fragments, and TREM fragments "tRNA-based effector molecule" or "TREM" refers to an RNA molecule having one or more of the characteristics described herein. A TREM may include, for example, unnatural modifications as shown in Tables 4, 5, 6, or 7.

[0130] In one embodiment, the TREM includes a TREM containing an array of formula A; a TREM core fragment containing an array of formula B; or a TREM fragment containing a portion of the TREM containing an array of formula A.

[0131] In one embodiment, TREM includes the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2]. In one embodiment, [VL domain] is optional. In one embodiment, [L1] is optional.

[0132] In one embodiment, the TREM core fragment is an array of formula B:[L1] y -[ASt Domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x -[VL domain] y -[TH domain] y -[L4] y -[ASt Domain 2] x The equation includes x=1 and y=0 or 1. In one embodiment, y=0. In another embodiment, y=1.

[0133] In one embodiment, the TREM fragment comprises a portion of TREM, where TREM comprises the sequence of formula A:[L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], and the TREM fragment comprises one, two, three or all or any combination of the following: a TREM half (e.g., derived from a cleavage in the anticodon sequence, e.g., a 5' half or a 3' half); a 5' fragment (e.g., derived from a cleavage in the DH domain or ACH domain, e.g., a fragment containing a 5' end); a 3' fragment (e.g., derived from a cleavage in the TH domain, e.g., a fragment containing a 3' end); or an internal fragment (e.g., derived from a cleavage in any one of the ACH domain, DH domain or TH domain). Examples of TREM fragments include TREM halves (e.g., derived from a cleavage in ACHD, e.g., a 5' TREM half or a 3' TREM half), 5' fragments (e.g., derived from a cleavage in DHD or ACHD, e.g., a fragment containing the 5' end), 3' fragments (e.g., derived from a cleavage in THD, e.g., a fragment containing the 3' end of a TREM), or internal fragments (e.g., derived from a cleavage in one or more of ACHD, DHD, or THD).

[0134] In some embodiments, the TREM, TREM core fragment, or TREM fragment may be loaded with an amino acid (e.g., a homogeneous amino acid); may be loaded with a non-homogeneous amino acid (e.g., a misloaded TREM (mTREM)); or may not be loaded with an amino acid (e.g., an unloaded TREM (uTREM)). In some embodiments, the TREM, TREM core fragment, or TREM fragment may be loaded with an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0135] In some embodiments, the unextended anticodon is an anticodon consisting of three or fewer nucleotides. In some embodiments, the unextended anticodon pairs with three or fewer codon nucleotides on the nucleic acid being translated.

[0136] In some embodiments, the TREM, TREM core fragment, or TREM fragment is a cognate TREM. In some embodiments, the TREM, TREM core fragment, or TREM fragment is a non-cognate TREM. In some embodiments, the TREM, TREM core fragment, or TREM fragment recognizes codons provided in Table 2 or Table 3.

[0137] [Table 2]

[0138] [Table 3]

[0139] In one embodiment, the TREM includes a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 1, for example, one of the SEQ ID NOs. 1 to 451 disclosed in Table 1. In another embodiment, the TREM includes an RNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, one of the RNA sequences encoded by one of the SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, the TREM includes an RNA sequence encoded by a DNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of the DNA sequences provided in Table 1, e.g., SEQ ID NOs 1 to 451 disclosed in Table 1.

[0140] In one embodiment, a TREM, TREM core fragment, or TREM fragment contains at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence disclosed in Table 1, for example, at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by any one of SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, a TREM, TREM core fragment, or TREM fragment contains at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, an RNA sequence encoded by any one of SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, the TREM, TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of the SEQ ID NOs. 1 to 451 disclosed in Table 1.

[0141] In one embodiment, the TREM core fragment or TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the DNA sequence provided in Table 1, for example, the RNA sequence encoded by any one of SEQ ID NOs. In one embodiment, the TREM core fragment or TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, the RNA sequence encoded by any one of SEQ ID NOs. In one embodiment, the TREM core fragment or TREM fragment includes at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 98%, or 99% of an RNA sequence encoded by a DNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of the DNA sequences provided in Table 1, e.g., SEQ ID NOs 1 to 451 disclosed in Table 1.

[0142] In one embodiment, the TREM core fragment or TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, or 60 nt (but less than the full length) of an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the DNA sequence provided in Table 1, for example, an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 60% identical to the DNA sequence provided in Table 1, for example, an60% identical to the DNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at In one embodiment, the TREM core fragment or TREM fragment includes at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence having at least 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, 99%, or 100% identity with any one of SEQ ID NOs. 1 to 451 disclosed in Table 1.

[0143] In one embodiment, the TREM core fragment or TREM fragment includes a sequence of lengths of 10-90 ribonucleotides (rnt), 10-80 rnt, 10-70 rnt, 10-60 rnt, 10-50 rnt, 10-40 rnt, 10-30 rnt, 10-20 rnt, 20-90 rnt, 20-80 rnt, 20-70 rnt, 20-60 rnt, 20-50 rnt, 20-40 rnt, 30-90 rnt, 30-80 rnt, 30-70 rnt, 30-60 rnt, or 30-50 rnt.

[0144] [Table 1-1]

[0145] Table 1-2

[0146] Table 1-3

[0147] Table 1-4

[0148] Table 1-5

[0149] Table 1-6

[0150] Table 1-7

[0151] Table 1-8

[0152] Table 1-9

[0153] Table 1-10

[0154] Table 1-11

[0155] Table 1-12

[0156] Table 1-13

[0157] Table 1-14

[0158] Table 1-15

[0159] Table 1-16

[0160] Table 1-17

[0161] Table 1-18

[0162] Table 1-19

[0163] Table 1-20

[0164] Table 1-21

[0165] Table 1-22

[0166] Table 1-23

[0167] Table 1-24

[0168] Table 1-25

[0169] Table 1-26

[0170] Table 1-27

[0171] Table 1-28

[0172] Table 1-29

[0173] Table 1-30

[0174] Table 1-31

[0175] Table 1-32

[0176] [Table 1-33]

[0177] [Table 1-34]

[0178] [Table 1-35]

[0179] [Table 1-36]

[0180] [Table 1-37]

[0181] non-natural modification The TREMs, TREM core fragments, or TREM fragments described herein include unnatural modifications, such as those listed in Table 5. These unnatural modifications may be prepared according to methods known in the art. Exemplary methods for preparing unnatural modifications are provided in Examples 4 and 5.

[0182] In one embodiment, a non-native modification is a modification that cells, such as human cells, do not produce on endogenous tRNA.

[0183] In some embodiments, the non-native modification is a modification that a cell, such as a human cell, may make on endogenous tRNA, but such a modification is located at a position where it does not occur on native tRNA. In some embodiments, the non-native modification is located in a domain, linker, or arm where such a modification does not occur naturally. In some embodiments, the non-native modification is located at a position within a domain, linker, or arm where such a modification does not occur naturally. In some embodiments, the non-native modification is located on a nucleotide where such a modification does not occur naturally. In some embodiments, the non-native modification is located on a nucleotide at a position within a domain, linker, or arm where such a modification does not occur naturally.

[0184] In some embodiments, the TREMs, TREM core fragments, or TREM fragments described herein include the modifications shown in Table 5, or combinations thereof. The modifications shown in Table 5 are either not naturally present in RNA or are naturally present, and are used herein for synthetic TREMs, TREM core fragments, or TREM fragments at positions not found in nature.

[0185] [Table 5-1]

[0186] [Table 5-2]

[0187] [Table 5-3]

[0188] [Table 5-4]

[0189] [Table 5-5]

[0190]

Table 5-6

[0191]

Table 5-7

[0192]

Table 5-8

[0193]

Table 5-9

[0194]

Table 5-10

[0195]

Table 5-11

[0196]

Table 5-12

[0197]

Table 5-13

[0198]

Table 5-14

[0199] TREM, TREM core fragment and TREM fragment fusion In some embodiments, the TREM, TREM core fragment, and TREM fragment disclosed herein include additional parts, such as a fusion portion. In some embodiments, the fusion portion may be used for purification to modify the folding of the TREM, TREM core fragment, and TREM fragment, or as a targeting portion. In some embodiments, the fusion portion may include a tag, a linker, be cleavable, or include a binding site for an enzyme. In some embodiments, the fusion portion may be located at the N-terminus or C-terminus of the TREM, TREM core fragment, and TREM fragment. In some embodiments, the fusion portion may be encoded by the same or different nucleic acid molecules encoding the TREM, TREM core fragment, and TREM fragment.

[0200] TREM Consensus Array In one embodiment, the TREM disclosed herein includes a consensus sequence provided herein.

[0201] In one embodiment, the TREM disclosed herein is of formula I ZZZ The consensus array ( ZZZ (where represents one of 20 amino acids, and formula I corresponds to all species.)

[0202] In one embodiment, the TREM disclosed herein is Equation II ZZZ The consensus array ( ZZZ Formula II includes one of 20 amino acids (wherein formula II corresponds to mammals).

[0203] In one embodiment, the TREM disclosed herein is Equation III ZZZ The consensus array ( ZZZ (where represents one of 20 amino acids, and formula III corresponds to human).

[0204] In one embodiment, ZZZrepresents any one of 20 amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0205] In certain embodiments, the TREM disclosed herein is as follows: a) Under physiological conditions, residue R0 forms a linker region, e.g., the linker 1 region; b) Under physiological conditions, residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 form a stem region, e.g., the AStD stem region; c) Under physiological conditions, residues R8-R9 form a linker region, e.g., the linker 2 region; d) Under physiological conditions, residues -R 10 -R 11 -R 12 -R 13 -R 14 R 15 -R 16 -R 17 -R [[ID=4​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 This forms a stem-loop region, for example, an AC arm region; g) Under physiological conditions, residue-[R 47 ] x This includes, for example, a variable region as described herein; h) Under physiological conditions, residue-R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 This forms a stem-loop region, for example, a T-arm region; or i) Under physiological conditions, residue R 72 This forms a linker region, for example, a linker 4 region. Includes characteristics selected from.

[0206] Alanine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ALA The array (sequence number 562), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ala is, R0 = non-existence; R 14 , R 57 = Independently A or non-existent; R 26= A, C, G or non-existent; R5, R6, R 15 , R 16 , R 21 , R 30 , R 31 , R 32 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 48 , R 49 , R 50 , R 58 , R 59 , R 63 , R 64 , R 66 , R 67 = Independently N or non-existent; R 11 , R 35 , R 65 = Independently A, C, U, or non-existent; R1, R9, R 20 , R 38 , R 40 , R 51 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 22 , R 25 , R 27 , R 29 , R 46 , R 53 , R 72 = Independently A, G, U, or non-existent; R 24 , R 69 = Independently A, U, or non-existent; R 70 , R 71 = Independently C or non-existent; R3, R4 = independently C, G, or non-existent; R 12 , R 33 , R 36 , R 62 , R 68 = Independently C, G, U, or non-existent; R 13, R 17 , R 28 , R 39 , R 55 , R 60 , R 61 = Independently C, U, or non-existent; R 10 , R 19 , R 23 = Independently G or non-existent; R2 = G, U, or non-existent; R8, R 18 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; Here, for example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~2 3, x=1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~ 12, x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~ 271, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x= 1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x= (18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0207] In one embodiment, the TREM disclosed herein is Equation II ALA The array (sequence number 563) is included, R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61-R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ala is, R0, R 18 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R 15 , R 26 , R 64 = Independently A, C, G, or non-existent; R 16 , R 31 , R 50 , R 59 = Independently N or non-existent; R 11 , R 32 , R 37 , R 41 , R 43 , R 45 , R 49 , R 65 , R 66 = Independently A, C, U, or non-existent; R1, R5, R9, R 25 , R 27 , R 38 , R 40 , R 46 , R 51 , R 56 = Independently A, G, or non-existent; R7, R 22 , R 29 , R 42 , R 44 , R 53 , R 63 , R 72 = Independently A, G, U, or non-existent; R6, R 35 , R 69 = Independently A, U, or non-existent; R 55 , R 60 , R 70 , R 71 = Independently C or non-existent; R3 = C, G, or non-existent; R 12 , R 36 , R 48 = Independently C, G, U, or non-existent; R 13 , R 17 , R 28 , R 30 , R 34 , R 39 , R 58 , R 61 , R 62 , R 67 , R 68 = Independently C, U, or non-existent; R4, R 10 , R 19 , R 20 , R 23 , R 52 = Independently G or non-existent; R2, R8, R 33 = Independently G, U, or non-existent; R 21 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0208] In one embodiment, the TREM disclosed herein is Equation III ALA Includes the array (sequence number 564), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ala is, R0, R 18 = non-existent; R 14 , R 24 , R 57 , R 72 = Independently A or non-existent; R 15 , R 26 , R64 = Independently A, C, G, or non-existent; R 16 , R 31 , R 50 = Independently N or non-existent; R 11 , R 32 , R 37 , R 41 , R 43 , R 45 , R 49 , R 65 , R 66 = Independently A, C, U, or non-existent; R5, R9, R 25 , R 27 , R 38 , R 40 , R 46 , R 51 , R 56 = Independently A, G, or non-existent; R7, R 22 , R 29 , R 42 , R 44 , R 53 , R 63 = Independently A, G, U, or non-existent; R6, R 35 = Independently A, U, or non-existent; R 55 , R 60 , R 61 , R 70 , R 71 = Independently C or non-existent; R 12 , R 48 , R 59 = Independently C, G, U, or non-existent; R 13 , R 17 , R 28 , R 30 , R 34 , R 39 , R 58 , R 62 , R 67 , R 68 = Independently C, U, or non-existent; R1, R2, R3, R4, R 10 , R 19 , R20 , R 23 , R 52 = Independently G or non-existent; R 33 , R 36 = Independently G, U, or non-existent; R8, R 21 , R 54 , R 69 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0209] Arginine TREM Consensus Sequence In one embodiment, the TREM disclosed herein is of formula I ARG Includes the sequence (sequence number 565), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 57 = A or non-existent; R9, R 27 = Independently A, C, G, or non-existent; R1, R2, R3, R4, R5, R6, R7, R 11 , R 12 , R 16 , R 21 , R 22 , R 23 , R 25 , R 26 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 51 , R 58 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 = Independently N or non-existent; R 13 , R 17 , R 41 = Independently A, C, U, or non-existent; R 19 , R 20 , R 24 , R 40 , R 56 = Independently A, G, or non-existent; R 14 , R 15 , R 72= Independently A, G, U, or non-existent; R 18 = A, U, or non-existent; R 38 = C or non-existent; R 35 , R 43 , R 61 = Independently C, G, U, or non-existent; R 28 , R 55 , R 59 , R 60 = Independently C, U, or non-existent; R0, R 10 , R 52 = Independently G or non-existent; R8, R 39 = Independently G, U, or non-existent; R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0210] In one embodiment, the TREM disclosed herein is Equation II ARG (Sequence number 566) array, R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 18 = non-existent; R 24 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R3, R7, R 34 , R50 = independently A, C, G or non-existent; R2, R5, R6, R 12 , R 26 , R 32 , R 37 , R 44 , R 58 , R 66 , R 67 , R 68 , R 70 = independently N or non-existent; R 49 , R 71 = independently A, C, U or non-existent;<O009180>R1, R 15 , R 19 , R 25 , R 27 , R 40 , R 45 , R 46 , R 56 , R 72 = independently A, G or non-existent; R 14 , R 29 , R 63 = independently A, G, U or non-existent; R 16 , R 21 = independently A, U or non-existent; R 38 , R 61 = independently C or non-existent; R 33 [[ID=I3]], R 48 = independently C, G or non-existent; R4, R9, R 11 , R 43 , R 62 , R 64 , R 69 = independently C, G, U or non-existent; R 13 , R 22 , R 28 , R 30 , R 31 , R 35 , R 55 , R 60 , R 65 = independently C, U or non-existent; R0, R 10, R 20 , R 23 , R 51 , R 52 = Independently G or non-existent; R8, R 39 , R 42 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0211] In one embodiment, the TREM disclosed herein has the formula III ARG (SEQ ID NO: 567), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R[[ID=1​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 18 = non-existent; R 15 , R 21 , R 24 , R 41 , R 57 = Independently A or non-existent; R 34 , R 44 = Independently A, C, or non-existent; R3, R5, R 58 = Independently A, C, G, or non-existent; R2, R6, R 66 , R 70 = Independently N or non-existent; R 37 , R 49 = Independently A, C, U, or non-existent; R1, R 25 , R 29 , R 40 , R 45 , R 46 , R 50 = Independently A, G, or non-existent; R 14 , R 63 , R 68 = Independently A, G, U, or non-existent; R 16 = A, U, or non-existent; R 38 , R 61 = Independently C or non-existent; R7, R 11 , R 12 , R 26 , R 48 = Independently C, G, or non-existent; R 64 , R 67 , R 69 = Independently C, G, U, or non-existent; R4, R 13, R 22 , R 28 , R 30 , R 31 , R 35 , R 43 , R 55 , R 60 , R 62 , R 65 , R 71 = Independently C, U, or non-existent; R0, R 10 , R 19 , R 20 , R 23 , R 27 , R 33 , R 51 , R 52 , R 56 , R 72 = Independently G or non-existent; R8, R9, R 32 , R 39 , R 42 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0212] Asparagine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ASN The array (sequence number 568), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent; R 41 = A or non-existent; R 14 , R 48 , R 56= Independently A, C, G, or non-existent; R2, R4, R5, R6, R 12 , R 17 , R 26 , R 29 , R 30 , R 31 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 65 , R 66 , R 67 , R 68 , R 70 , R 71 = Independently N or non-existent; R 11 , R 13 , R 22 , R 42 , R 55 , R 59 = Independently A, C, U, or non-existent; R9, R 15 , R 24 , R 27 , R 34 , R 37 , R 51 , R 72 = Independently A, G, or non-existent; R1, R7, R 25 , R 69 = Independently A, G, U, or non-existent; R 40 , R 57 = Independently A, U, or non-existent; R 60 = C or non-existent; R 33 = C, G, or non-existent; R 21 , R 32 , R 43 , R 64 = Independently C, G, U, or non-existent; R3, R 16 , R 28 , R 35 , R 36 , R 61= Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 52 = Independently G or non-existent; R 54 = G, U, or non-existent; R8, R 23 , R 38 , R 39 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0213] In one embodiment, the TREM disclosed herein is Equation II ASN Includes the sequence (sequence number 569), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent, R 24 , R 41 , R 46 , R 62 = Independently A or non-existent; R 59 = A, C, or non-existent; R 14 , R 56 , R 66 = Independently A, C, G, or non-existent; R 17 , R 29 = Independently N or non-existent; R 11 , R 26 , R 42 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 12 , R 15 , R 25 , R 34 , R 37 , R 48 , R 51 , R 67 , R 68 , R 69 , R 70 , R 72 = Independently A, G, or non-existent; R 44 , R 45 , R 58 = Independently A, G, U, or non-existent; R 40 , R 57 = Independently A, U, or non-existent; R5, R 28 , R 60 = Independently C or non-existent; R 33 , R 65 = Independently C, G, or non-existent; R 21 , R 43 , R 71 = Independently C, G, U, or non-existent; R3, R6, R 13 , R 22 , R 32 , R 35 , R 36 , R 61 , R 63 , R 64 = Independently C, U, or non-existent; R7, R 10 , R 19 , R 20 , R 27 , R 49 , R 52 = Independently G or non-existent; R 54 = G, U, or non-existent; R2, R4, R8, R 16 , R 23 , R 30 , R 31 , R 38 , R 39 , R 50 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0214] In one embodiment, the TREM disclosed herein is Equation III ASN Includes the sequence (sequence number 570), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent, R 24 , R 40 , R 41 , R 46 , R 62 = Independently A or non-existent; R 59= A, C, or non-existent; R 14 , R 56 , R 66 = Independently A, C, G, or non-existent; R 11 , R 26 , R 42 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 12 , R 15 , R 34 , R 37 , R 48 , R 51 , R 67 , R 68 , R 69 , R 70 = Independently A, G, or non-existent; R 44 , R 45 , R 58 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R5, R 28 , R 60 = Independently C or non-existent; R 33 , R 65 = Independently C, G, or non-existent; R 17 , R 21 , R 29 = Independently C, G, U, or non-existent; R3, R6, R 13 , R 22 , R 32 , R 35 , R 36 , R 43 , R 61 , R 63 , R 64 , R 71 = Independently C, U, or non-existent; R7, R 10 , R 19 , R 20 , R 25 , R 27 , R 49 , R 52 , R 72= Independently G or non-existent; R 54 = G, U, or non-existent; R2, R4, R8, R 16 , R 23 , R 30 , R 31 , R 38 , R 39 , R 50 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0215] Aspartate TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ASP Includes the sequence (sequence number 571), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66-R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0 = non-existence, R 24 , R 71 = Independently A, C, or non-existent; R 33 , R 46 = Independently A, C, G, or non-existent; R2, R3, R4, R5, R6, R 12 , R 16 , R 22 , R 26 , R 29 , R 31 , R 32 , R 44 , R 48 , R 49 , R 58 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 13 , R 21 , R 34 , R 41 , R 57 , R 65 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 20 , R 27 , R 37 , R 40 , R 51 , R 56 , R 72 = Independently A, G, or non-existent; R7, R 25 , R 42 = Independently A, G, U, or non-existent; R 39 = C or non-existent; R50 , R 62 = Independently C, G, or non-existent; R 30 , R 43 , R 45 , R 55 , R 70 = Independently C, G, U, or non-existent; R8, R 11 , R 17 , R 18 , R 28 , R 35 , R 53 , R 59 , R 60 , R 61 = Independently C, U, or non-existent; R 19 , R 52 = Independently G or non-existent; R1 = G, U, or non-existent; R 23 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0216] In one embodiment, the TREM disclosed herein is Equation II ASP Includes the sequence (sequence number 572), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0, R 17 , R 18 , R 23 = Independently non-existent; R9, R 40 = Independently A or non-existent; R 24 , R 71= Independently A, C, or non-existent; R 67 , R 68 = Independently A, C, G, or non-existent; R2, R6, R 66 = Independently N or non-existent; R 57 , R 63 = Independently A, C, U, or non-existent; R 10 , R 14 , R 27 , R 33 , R 37 , R 44 , R 46 , R 51 , R 56 , R 64 , R 72 = Independently A, G, or non-existent; R7, R 12 , R 26 , R 65 = Independently A, U, or non-existent; R 39 , R 61 , R 62 = Independently C or non-existent; R3, R 31 , R 45 , R 70 = Independently C, G, or non-existent; R4, R5, R 29 , R 43 , R 55 = Independently C, G, U, or non-existent; R8, R 11 , R 13 , R 30 , R 32 , R 34 , R 35 , R 41 , R 48 , R 53 , R 59 , R 60 = Independently C, U, or non-existent; R 15 , R 19 , R 20 , R 25 , R 42 , R 50 , R 52= Independently G or non-existent; R1, R 22 , R 49 , R 58 , R 69 = Independently G, U, or non-existent; R 16 , R 21 , R 28 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0217] In one embodiment, the TREM disclosed herein is Equation III ASP Includes the sequence (sequence number 573), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0, R 17 , R 18 , R 23 = non-existent, R9, R 12 , R 40 , R 65 , R 71 = Independently A or non-existent; R2, R 24 , R 57 = Independently A, C, or non-existent; R6, R 14 , R 27 , R 46 , R 51 , R 56 , R 64 , R 67 , R 68 = Independently A, G, or non-existent; R3, R 31 , R 35 , R 39 , R 61 , R 62 = Independently C or non-existent; R 66 = C, G, or non-existent; R5, R8, R 29 , R 30 , R 32 , R 34 , R 41 , R 43 , R 48 , R 55 , R 59 , R 60 , R 63 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 20 , R 25 , R 33 , R 37 , R 42 , R 44 , R 45 , R49 , R 50 , R 52 , R 69 , R 70 , R 72 = Independently G or non-existent; R 22 , R 58 = Independently G, U, or non-existent; R1, R4, R7, R 11 , R 13 , R 16 , R 21 , R 26 , R 28 , R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0218] Cysteine ​​TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I CYS Includes the array (sequence number 574), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19-R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0 = non-existence, R 14 , R 39 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R 10 , R 15 , R 27 , R 33 , R 62 = Independently A, C, G, or non-existent; R3, R4, R5, R6, R 12 , R 13 , R 16 , R 24 , R 26 , R 29 , R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 65 = A, C, U, or non-existent; R9, R 25 , R 37 , R 40 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 20 , R 51 = Independently A, G, U, or non-existent; R 18 , R 38 , R 55 = Independently C or non-existent; R2 = C, G, or non-existent; R 21 , R 28 , R 43 , R 50 = Independently C, G, U, or non-existent; R 11 , R 22 , R 23 , R 35 , R 36 , R59 , R 60 , R 61 , R 71 , R 72 = Independently C, U, or non-existent; R1, R 19 = Independently G or non-existent; R 17 = G, U, or non-existent; R8, R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0219] In one embodiment, the TREM disclosed herein is Equation II CYS Includes the sequence (sequence number 575), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0, R 18 , R 23 = non-existent; R 14 , R 24 , R 26 , R 29 , R 39 , R 41 , R 45 , R 57 = Independently A or non-existent; R 44 = A, C, or non-existent; R 27 , R 62 = Independently A, C, G, or non-existent; R 16 = A, C, G, U, or non-existent; R 30 , R 70 = Independently A, C, U, or non-existent; R5, R7, R9, R 25 , R 34 , R 37 , R 40 , R 46 , R 52 , R 56 , R 58 , R 66 = Independently A, G, or non-existent; R 20 , R 51 = Independently A, G, U, or non-existent; R 35 , R 38 , R 43 , R 55 , R 69 = Independently C or non-existent; R2, R4, R 15 = Independently C, G, or non-existent; R 13 = C, G, U, or non-existent; R6, R 11 , R28 , R 36 , R 48 , R 49 , R 50 , R 60 , R 61 , R 67 , R 68 , R 71 , R 72 = Independently C, U, or non-existent; R1, R3, R 10 , R 19 , R 33 , R 63 = Independently G or non-existent; R8, R 17 , R 21 , R 64 = Independently G, U, or non-existent; R 12 , R 22 , R 31 , R 32 , R 42 , R 53 , R 54 , R 65 = Independently U or non-existent; R 59 =U, or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0220] In one embodiment, the TREM disclosed herein is Equation III CYS Includes the sequence (sequence number 576), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 26 , R 29 , R 34 , R 39 , R 41 , R45 , R 57 , R 58 = Independently A or non-existent; R 44 , R 70 = Independently A, C, or non-existent; R 62 = A, C, G or non-existent; R 16 =N or nonexistent; R5, R7, R9, R 20 , R 40 , R 46 , R 51 , R 52 , R 56 , R 66 = Independently A, G, or non-existent; R 28 , R 35 , R 38 , R 43 , R 55 , R 67 , R 69 = Independently C or non-existent; R4, R 15 = Independently C, G, or non-existent; R6, R 11 , R 13 , R 30 , R 48 , R 49 , R 50 , R 60 , R 61 , R 68 , R 71 , R 72 = Independently C, U, or non-existent; R1, R2, R3, R 10 , R 19 , R 25 , R 27 , R 33 , R 37 , R 63 = Independently G or non-existent; R8, R 21 , R 64 = Independently G, U, or non-existent; R 12 , R 17 , R 22 , R 31 , R32 , R 36 , R 42 , R 53 , R 54 , R 59 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0221] Glutamine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLN Includes the sequence (sequence number 577), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R9, R 26 , R 27 , R 33 , R 56 = Independently A, C, G, or non-existent; R2, R4, R5, R6, R 12 , R 13 , R 16 , R 21 , R 22 , R 25 , R 29 , R 30 , R 31 , R 32 , R 34 , R 41 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 17 , R 23 , R 43 , R 65 , R 71 = Independently A, C, U, or non-existent; R 15 , R 40 , R 51 , R 52 = Independently A, G, or non-existent; R1, R7, R 72 = Independently A, G, U, or non-existent; R3, R 11 , R 37 , R 60, R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R 10 , R 19 , R 20 = Independently G or non-existent; R 39 = G, U, or non-existent; R8, R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0222] In one embodiment, the TREM disclosed herein is Equation II GLN The array (sequence number 578), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 57 = Independently A or non-existent; R 17 , R 71= Independently A, C, or non-existent; R 25 , R 26 , R 33 , R 44 , R 46 , R 56 , R 69 = Independently A, C, G, or non-existent; R4, R5, R 12 , R 22 , R 29 , R 30 , R 48 , R 49 , R 63 , R 67 , R 68 = Independently N or non-existent; R 31 , R 43 , R 62 , R 65 , R 70 = Independently A, C, U, or non-existent; R 15 , R 27 , R 34 , R 40 , R 41 , R 51 , R 52 = Independently A, G, or non-existent; R2, R7, R 21 , R 45 , R 50 , R 58 , R 66 , R 72 = Independently A, G, U, or non-existent; R3, R 13 , R 32 , R 37 , R 42 , R 60 , R 64 = Independently C, G, U, or non-existent; R6, R 11 , R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R9, R 10 , R 19 , R 20= Independently G or non-existent; R1, R 16 , R 39 = Independently G, U, or non-existent; R8, R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0223] In one embodiment, the TREM disclosed herein is Equation III GLNThe array of (Array No. 579), R0 - R1 - R2 - R3 - R4 - R5 - R6 - R7 - R8 - R9 - R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 ​-R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 41 , R 57 = Independently A or non-existent; R 17 , R 71 = Independently A, C, or non-existent; R5, R 25 , R 26 , R 46 , R 56 , R 69 = Independently A, C, G, or non-existent; R4, R 22 , R 29 , R 30 , R 48 , R 49 , R 63 , R 68 = Independently N or non-existent; R 43 , R 62 , R 65 , R 70 = Independently A, C, U, or non-existent; R 15 , R 27 , R 33 , R 34 , R 40 , R 51 , R 52 = Independently A, G, or non-existent; R2, R7, R 12 , R 45 , R 50 , R 58 , R 66 = Independently A, G, U, or non-existent; R 31 = A, U, or non-existent; R 32 , R 44 , R 60 = Independently C, G, or non-existent; R3, R 13 , R 37, R 42 , R 64 , R 67 = Independently C, G, U, or non-existent; R6, R 11 , R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R9, R 10 , R 19 , R 20 = Independently G or non-existent; R1, R 21 , R 39 , R 72 = Independently G, U, or non-existent; R8, R 16 , R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0224] Glutamate TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLU The array (sequence number 580), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Glu is, R0 = non-existence; R 34 , R 43 , R 68 , R 69 = Independently A, C, G, or non-existent; R1, R2, R5, R6, R9, R12 , R 16 , R 20 , R 21 , R 26 , R 27 , R 29 , R 30 , R 31 , R 32 , R 33 , R 41 , R 44 , R 45 , R 46 , R 48 , R 50 , R 51 , R 58 , R 63 , R 64 , R 65 , R 66 , R 70 , R 71 = Independently N or non-existent; R 13 , R 17 , R 23 , R 61 = Independently A, C, U, or non-existent; R 10 , R 14 , R 24 , R 40 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 15 , R 25 , R 67 , R 72 = Independently A, G, U, or non-existent; R 11 , R 57 = Independently A, U, or non-existent; R 39 = C, G, or non-existent; R3, R4, R 22 , R 42 , R 49 , R 55 , R 62 = Independently C, G, U, or non-existent; R 18 , R 28 , R 35 , R 37 , R 53 , R 59, R 60 = Independently C, U, or non-existent; R 19 =G or non-existent; R8, R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0225] In one embodiment, the TREM disclosed herein is Equation II GLU The array (sequence number 581), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Glu is, R0, R 18 , R 23 = non-existent, R 17 , R 40 = Independently A or non-existent; R 26 , R 27 , R 34 , R 43 , R 68 , R 69 , R 71 = Independently A, C, G, or non-existent; R1, R2, R5, R 12 , R 21 , R 31 , R 33 , R 41 , R 45 , R 48 , R 51 , R 58 , R 66 , R 70 = Independently N or non-existent; R 44 , R 61 = Independently A, C, U, or non-existent; R9, R 14 , R 24 , R 25 , R 52 , R 56 , R 63 = Independently A, G, or non-existent; R7, R 15 , R 46 , R 50 , R 67 , R 72 = Independently A, G, U, or non-existent; R 29 , R 57 = Independently A, U, or non-existent; R 60 = C or non-existent; R 39 = C, G, or non-existent; R3, R6, R 20 , R 30 , R 32 , R 42 , R55 , R 62 , R 65 = Independently C, G, U, or non-existent; R4, R8, R 16 , R 28 , R 35 , R 37 , R 49 , R 53 , R 59 = Independently C, U, or non-existent; R 10 , R 19 = Independently G or non-existent; R 22 , R 64 = Independently G, U, or non-existent; R 11 , R 13 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0226] In one embodiment, the TREM disclosed herein is Equation III GLU The array (sequence number 582), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Glu is, R0, R 17 , R 18 , R 23 = non-existent, R 14 , R 27 , R 40 , R 71 = Independently A or non-existent; R44 = A, C, or non-existent; R 43 = A, C, G or non-existent; R1, R 31 , R 33 , R 45 , R 51 , R 66 = Independently N or non-existent; R 21 , R 41 = Independently A, C, U, or non-existent; R7, R 24 , R 25 , R 50 , R 52 , R 56 , R 63 , R 68 , R 70 = Independently A, G, or non-existent; R5, R 46 = Independently A, G, U, or non-existent; R 29 , R 57 , R 67 , R 72 = Independently A, U, or non-existent; R2, R 39 , R 60 = Independently C or non-existent; R3, R 12 , R 20 , R 26 , R 34 , R 69 = Independently C, G, or non-existent; R6, R 30 , R 42 , R 48 , R 65 = Independently C, G, U, or non-existent; R4, R 16 , R 28 , R 35 , R 37 , R 49 , R 53 , R 55 , R 58 , R 61 , R 62 = Independently C, U, or non-existent; R9, R 10 , R19 , R 64 = Independently G or non-existent; R 15 , R 22 , R 32 = Independently G, U, or non-existent; R8, R 11 , R 13 , R 36 , R 38 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0227] Glycine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLY The array (sequence number 583), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65-R 66 -R is 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a bonucleotide residue, and the consensus regarding Gly is, R0 = non-existence; R 24 = A or non-existent; R3, R9, R 40 , R 50 , R 51 = Independently A, C, G, or non-existent; R4, R5, R6, R7, R 12 , R 16 , R 21 , R 22 , R 26 , R 29 , R 30 , R 31 , R 32 , R 34 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 = Independently N or non-existent; R 59 = A, C, U, or non-existent; R1, R 10 , R 14 , R 15 , R 27 , R 56 = Independently A, G, or non-existent; R 20 , R 25 = Independently A, G, U, or non-existent; R 57 , R 72 = Independently A, U, or non-existent; R38 , R 39 , R 60 = Independently C or non-existent; R 52 = C, G, or non-existent; R2, R 19 , R 37 , R 54 , R 55 , R 61 , R 62 , R 69 , R 70 = Independently C, G, U, or non-existent; R 11 , R 13 , R 17 , R 28 , R 35 , R 36 , R 71 = Independently C, U, or non-existent; R8, R 18 , R 23 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0228] In one embodiment, the TREM disclosed herein is Equation II GLY Includes the array (sequence number 584), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gly is, R0, R 18 , R 23 = non-existent, R 24 , R 27 , R 40 , R 72 = Independently A or non-existent; R 26= A, C, or non-existent; R3, R7, R 68 = Independently A, C, G, or non-existent; R5, R 30 , R 41 , R 42 , R 44 , R 49 , R 67 = Independently A, C, G, U or non-existent; R 31 , R 32 , R 34 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R 12 , R 16 , R 22 , R 25 , R 29 , R 46 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R 17 , R 38 , R 39 , R 60 , R 61 , R 71 = Independently C or non-existent; R6, R 52 , R 64 , R 66 = Independently C, G, or non-existent; R2, R4, R 37 , R 48 , R 55 , R 65 = Independently C, G, U, or non-existent; R 13 , R 35 , R 43 , R 62 , R 69 = Independently C, U, or non-existent; R1, R 19 , R 20 , R51 , R 70 = Independently G or non-existent; R 21 , R 45 , R 63 = Independently G, U, or non-existent; R8, R 11 , R 28 , R 36 , R 53 , R 54 , R 58 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0229] In one embodiment, the TREM disclosed herein is Equation III GLY The array (sequence number 585), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gly is, R0, R 18 , R 23 = non-existent, R 24 , R 27 , R 40 , R 72 = Independently A or non-existent; R 26 = A, C, or non-existent; R3, R7, R 49 , R 68 = Independently A, C, G, or non-existent; R5, R 30 , R 41 , R 44 , R 67 = Independently N or non-existent; R 31 , R 32 , R 34 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R 12 , R 25 , R 29 , R 42 , R 46 = Independently A, G, U, or non-existent; R 16 , R 57 = Independently A, U, or non-existent; R 17 , R 38 , R 39 , R 60 , R 61 , R 71 = Independently C or non-existent; R6, R 52 , R64 , R 66 = Independently C, G, or non-existent; R 37 , R 48 , R 65 = Independently C, G, U, or non-existent; R2, R4, R 13 , R 35 , R 43 , R 55 , R 62 , R 69 = Independently C, U, or non-existent; R1, R 19 , R 20 , R 51 , R 70 = Independently G or non-existent; R 21 , R 22 , R 45 , R 63 = Independently G, U, or non-existent; R8, R 11 , R 28 , R 36 , R 53 , R 54 , R 58 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0230] Histidine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I HIS The array (sequence number 586), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding His is, R 23 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R 72= A, C, or non-existent; R9, R 27 , R 43 , R 48 , R 69 = Independently A, C, G, or non-existent; R3, R4, R5, R6, R 12 , R 25 , R 26 , R 29 , R 30 , R 31 , R 34 , R 42 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 = Independently N or non-existent; R 13 , R 21 , R 41 , R 44 , R 65 = Independently A, C, U, or non-existent; R 40 , R 51 , R 56 , R 70 = Independently A, G, or non-existent; R7, R 32 = Independently A, G, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R 11 , R 16 , R 33 , R 64 = Independently C, G, U, or non-existent; R2, R 17 , R 22 , R 28 , R 35 , R 53 , R 59 , R 61 , R 71 = Independently C, U, or non-existent; R1, R 10 , R15 , R 19 , R 20 , R 37 , R 39 , R 52 = Independently G or non-existent; R0 = G, U, or non-existence; R8, R 18 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0231] In one embodiment, the TREM disclosed herein is Equation II HIS The array (sequence number 587), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding His is, R0, R 17 , R 18 , R 23 = non-existent; R7, R 12 , R 14 , R 24 , R 27 , R 45 , R 57 , R 58 , R 63 , R 67 , R 72 = Independently A or non-existent; R3 = A, C, U, or non-existent; R4, R 43 , R 56 , R 70 = Independently A, G, or non-existent; R 49 = A, U, or non-existent; R2, R 28 , R 30 , R 41 , R 42 , R 44 , R 48 , R 55 , R 60 , R 66 , R 71 = Independently C or non-existent; R 25 = C, G, or non-existent; R9 = C, G, U, or non-existent; R8, R 13 , R 26 , R 33 , R 35 , R 50 , R 53 , R 61 , R 68 = Independently C, U, or non-existent; R1, R6, R 10 , R 15 , R 19 , R 20 , R32 , R 34 , R 37 , R 39 , R 40 , R 46 , R 51 , R 52 , R 62 , R 64 , R 69 = Independently G or non-existent; R 16 = G, U, or non-existent; R5, R 11 , R 21 , R 22 , R 29 , R 31 , R 36 , R 38 , R 54 , R 59 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0232] In one embodiment, the TREM disclosed herein is Equation III HIS The array (sequence number 588), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding His is, R0, R 17 , R 18 , R 23 = non-existent; R7, R 12 , R 14 , R 24 , R 27 , R 45 , R 57, R 58 , R 63 , R 67 , R 72 = Independently A or non-existent; R3 = A, C, or non-existence; R4, R 43 , R 56 , R 70 = Independently A, G, or non-existent; R 49 = A, U, or non-existent; R2, R 28 , R 30 , R 41 , R 42 , R 44 , R 48 , R 55 , R 60 , R 66 , R 71 = Independently C or non-existent; R8, R9, R 26 , R 33 , R 35 , R 50 , R 61 , R 68 = Independently C, U, or non-existent; R1, R6, R 10 , R 15 , R 19 , R 20 , R 25 , R 32 , R 34 , R 37 , R 39 , R 40 , R 46 , R 51 , R 52 , R 62 , R 64 , R 69 = Independently G or non-existent; R5, R 11 , R 13 , R 16 , R 21 , R 22 , R 29 , R 31 , R 36 , R 38 , R 53 , R 54 , R 59 , R65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0233] Isoleucine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ILE The array (sequence number 589), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13-R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ile is, R 23 = non-existent; R38 , R 41 , R 57 , R 72 = Independently A or non-existent; R1, R 26 = Independently A, C, G, or non-existent; R0, R3, R4, R6, R 16 , R 31 , R 32 , R 34 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 59 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 22 , R 61 , R 65 = Independently A, C, U, or non-existent; R9, R 14 , R 15 , R 24 , R 27 , R 40 = Independently A, G, or non-existent; R7, R 25 , R 29 , R 51 , R 56 = Independently A, G, U, or non-existent; R 18 , R 54 = Independently A, U, or non-existent; R 60 = C or non-existent; R2, R 52 , R 70 = Independently C, G, or non-existent; R5, R 12 , R 21 , R 30 , R 33, R 71 = independently C, G, U or non-existent; R 11 , R 13 , R 17 , R 28 , R 35 , R 53 , R 55 = independently C, U or non-existent; R 10 , R 19 , R 20 = independently G or non-existent; R8, R 36 , R 39 = independently U or non-existent; [R 47 x = N or non-existent; For example, x = 1 to 271 (for example, x = 1 to 250, x = 1 to 225, x = 1 to 200, x = 1 to 175, x =​​TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0234] In one embodiment, the TREM disclosed herein is Equation II ILE (Array of sequence number 590) R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ile is, R0, R 18 , R 23 = non-existent, R 24 , R 38 , R 40 , R 41 , R 57 , R 72 = Independently A or non-existent; R 26 , R 65 = Independently A, C, or non-existent; R 58 , R 59 , R 67 = Independently N or non-existent; R 22 = A, C, U, or non-existent; R6, R9, R 14 , R 15 , R 29 , R 34 , R 43 , R 46 , R 48 , R 50 , R 51 , R 63 , R 69 = Independently A, G, or non-existent; R 37 , R 56 = Independently A, G, U, or non-existent; R 54 = A, U, or non-existent; R 28 , R 35 , R 60 , R 62 , R 71 = Independently C or non-existent; R2, R 52 , R 70= Independently C, G, or non-existent; R5 = C, G, U, or non-existent; R3, R4, R 11 , R 13 , R 17 , R 21 , R 30 , R 42 , R 44 , R 45 , R 49 , R 53 , R 55 , R 61 , R 64 , R 66 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 25 , R 27 , R 31 , R 68 = Independently G or non-existent; R7, R 12 , R 32 = Independently G, U, or non-existent; R8, R 16 , R 33 , R 36 , R 39 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0235] In one embodiment, the TREM disclosed herein is Equation III ILE The array (sequence number 591), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ile is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R 72= Independently A or non-existent; R 26 , R 65 = Independently A, C, or non-existent; R 22 , R 59 = Independently A, C, U, or non-existent; R6, R9, R 15 , R 34 , R 43 , R 46 , R 51 , R 56 , R 63 , R 69 = Independently A, G, or non-existent; R 37 = A, G, U, or non-existent; R 13 , R 28 , R 35 , R 44 , R 55 , R 60 , R 62 , R 71 = Independently C or non-existent; R2, R5, R 70 = Independently C, G, or non-existent; R 58 , R 67 = Independently C, G, U, or non-existent; R3, R4, R 11 , R 17 , R 21 , R 30 , R 42 , R 45 , R 49 , R 53 , R 61 , R 64 , R 66 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 25 , R 27 , R 29 , R 31 , R 32 , R 48 , R 50 , R 52 , R 68 = Independently G or non-existent; R7, R 12 = Independently G, U, or non-existent; R8, R 16 , R 33 , R 36 , R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0236] Methionine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula IMET (Array number 592)'s array, R0 - R1 - R2 - R3 - R4 - R5 - R6 - R7 - R8 - R9 - R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 [[ID=2--]]-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 [[ID=4--]]-R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R​71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Met is, R0, R 23 = non-existent; R 14 , R 38 , R 40 , R 57 = Independently A or non-existent; R 60 = A, C, or non-existent; R 33 , R 48 , R 70 = Independently A, C, G, or non-existent; R1, R3, R4, R5, R6, R 11 , R 12 , R 16 , R 17 , R 21 , R 22 , R 26 , R 27 , R 29 , R 30 , R 31 , R 32 , R 42 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 , R 71 = Independently N or non-existent; R 18 , R 35 , R 41 , R 59 , R 65 = Independently A, C, U, or non-existent; R9, R 15 , R 51 = Independently A, G, or non-existent; R7, R 24 , R 25 , R 34 , R 53 , R56 = Independently A, G, U, or non-existent; R 72 = A, U, or non-existent; R 37 = C or non-existent; R 10 , R 55 = Independently C, G, or non-existent; R2, R 13 , R 28 , R 43 , R 64 = Independently C, G, U, or non-existent; R 36 , R 61 = Independently C, U, or non-existent; R 19 , R 20 , R 52 = Independently G or non-existent; R8, R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0237] In one embodiment, the TREM disclosed herein is Equation II MET Includes the sequence (sequence number 593), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Met is, R0, R 18 , R 22 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R72 = Independently A or non-existent; R 59 , R 60 , R 62 , R 65 = Independently A, C, or non-existent; R6, R 45 , R 67 = Independently A, C, G, or non-existent; R4 = N or does not exist; R 21 , R 42 = Independently A, C, U, or non-existent; R1, R9, R 27 , R 29 , R 32 , R 46 , R 51 = Independently A, G, or non-existent; R 17 , R 49 , R 53 , R 56 , R 58 = Independently A, G, U, or non-existent; R 63 = A, U, or non-existent; R3, R 13 , R 37 = Independently C or non-existent; R 48 , R 55 , R 64 , R 70 = Independently C, G, or non-existent; R2, R5, R 66 , R 68 = Independently C, G, U, or non-existent; R 11 , R 16 , R 26 , R 28 , R 30 , R 31 , R 35 , R 36 , R 43 , R 44 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 12 , R15 , R 19 , R 20 , R 25 , R 33 , R 52 , R 69 = Independently G or non-existent; R7, R 34 , R 50 = Independently G, U, or non-existent; R8, R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0238] In one embodiment, the TREM disclosed herein is Equation III MET The array (sequence number 594), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Met is, R0, R 18 , R 22 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R 72 = Independently A or non-existent; R 59 , R 62 , R 65 = Independently A, C, or non-existent; R6, R 67 = Independently A, C, G, or non-existent; R4, R 21 = Independently A, C, U, or non-existent; R1, R9, R 27 , R 29 , R 32 , R 45 , R 46 , R 51 = Independently A, G, or non-existent; R 17 , R 56 , R 58 = Independently A, G, U, or non-existent; R 49 , R 53 , R 63 = Independently A, U, or non-existent; R3, R 13 , R 26 , R 37 , R 43 , R 60 = Independently C or non-existent; R2, R 48 , R 55 , R 64 , R 70 = Independently C, G, or non-existent; R5, R66 = Independently C, G, U, or non-existent; R 11 , R 16 , R 28 , R 30 , R 31 , R 35 , R 36 , R 42 , R 44 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 12 , R 15 , R 19 , R 20 , R 25 , R 33 , R 52 , R 69 = Independently G or non-existent; R7, R 34 , R 50 , R 68 = Independently G, U, or non-existent; R8, R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0239] Leucine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I LEU The array (sequence number 595), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Leu is, R0 = non-existence; R 38 , R 57 = Independently A or non-existent; R 60 = A, C, or non-existent; R1, R13 , R 27 , R 48 , R 51 , R 56 = Independently A, C, G, or non-existent; R2, R3, R4, R5, R6, R7, R9, R 10 , R 11 , R 12 , R 16 , R 23 , R 26 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 17 , R 18 , R 21 , R 22 , R 25 , R 35 , R 55 = Independently A, C, U, or non-existent; R 14 , R 15 , R 39 , R 72 = Independently A, G, or non-existent; R 24 , R 40 = Independently A, G, U, or non-existent; R 52 , R 61 , R 64 , R 71 = Independently C, G, U, or non-existent; R36 , R 53 , R 59 = Independently C, U, or non-existent; R 19 =G or non-existent; R 20 = G, U, or non-existent; R8, R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0240] In one embodiment, the TREM disclosed herein is Equation IILEU (Array No. 596) array, R0 - R1 - R2 - R3 - R4 - R5 - R6 - R7 - R8 - R9 - R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R​71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Leu is, R0 = non-existence, R 38 , R 57 , R 72 = Independently A or non-existent; R 60 = A, C, or non-existent; R4, R5, R 48 , R 50 , R 56 , R 69 = Independently A, C, G, or non-existent; R6, R 33 , R 41 , R 43 , R 46 , R 49 , R 58 , R 63 , R 66 , R 70 = Independently N or non-existent; R 11 , R 12 , R 17 , R 21 , R 22 , R 28 , R 31 , R 37 , R 44 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 14 , R 15 , R 24 , R 27 , R 34 , R 39 = Independently A, G, or non-existent; R7, R 29 , R 32 , R 40 , R 45 = Independently A, G, U, or non-existent; R 25 = A, U, or non-existent; R 13 = C, G, or non-existent; R2, R3, R 16 , R 26, R 30 , R 52 , R 62 , R 64 , R 65 , R 67 , R 68 = Independently C, G, U, or non-existent; R 18 , R 35 , R 42 , R 53 , R 59 , R 61 , R 71 = Independently C, U, or non-existent; R 19 , R 51 = Independently G or non-existent; R 10 , R 20 = Independently G, U, or non-existent; R8, R 23 , R 36 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0241] In one embodiment, the TREM disclosed herein is Equation III LEU The array (sequence number 597), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Leu is, R0 = non-existence, R 38 , R 57 , R 72 = Independently A or non-existent; R 60 = A, C, or non-existent; R4, R5, R 48 , R50 , R 56 , R 58 , R 69 = Independently A, C, G, or non-existent; R6, R 33 , R 43 , R 46 , R 49 , R 63 , R 66 , R 70 = Independently N or non-existent; R 11 , R 12 , R 17 , R 21 , R 22 , R 28 , R 31 , R 37 , R 41 , R 44 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 14 , R 15 , R 24 , R 27 , R 34 , R 39 = Independently A, G, or non-existent; R7, R 29 , R 32 , R 40 , R 45 = Independently A, G, U, or non-existent; R 25 = A, U, or non-existent; R 13 = C, G, or non-existent; R2, R3, R 16 , R 30 , R 52 , R 62 , R 64 , R 67 , R 68 = Independently C, G, U, or non-existent; R 18 , R 35 , R 42 , R 53 , R 59 , R 61 , R 65 , R 71 = Independently C, U, or non-existent; R 19 , R 51 = Independently G or non-existent; R 10 , R 20 , R 26 = Independently G, U, or non-existent; R8, R 23 , R 36 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0242] Lysine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I LYS Includes the sequence (sequence number 598), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Lys is, R0 = non-existence, R 14 = A or non-existent; R 40 , R 41 = Independently A, C, or non-existent; R 34 , R 43 , R 51 = Independently A, C, G, or non-existent; R1, R2, R3, R4, R5, R6, R7, R 11 , R 12 , R 16 , R 21 , R 26 , R 30 , R 31 , R 32 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 13 , R 17 , R 59 , R 71 = Independently A, C, U, or non-existent; R9, R 15 , R 19 , R 20 , R 25 , R 27 , R 52 , R 56 = Independently A, G, or non-existent; R 24 , R 29 , R72 = Independently A, G, U, or non-existent; R 18 , R 57 = Independently A, U, or non-existent; R 10 , R 33 = Independently C, G, or non-existent; R 42 , R 61 , R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 36 , R 37 , R 53 , R 55 , R 60 = Independently C, U, or non-existent; R8, R 22 , R 23 , R 38 , R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0243] In one embodiment, the TREM disclosed herein is Equation II LYS Includes the array (sequence number 599), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Lys is, R0, R 18 , R 23 = non-existent, R 14 = A or non-existent; R 40 , R 41 , R 43 = Independently A, C, or non-existent; R3, R7 = independently A, C, G, or non-existence; R1, R6, R 11 , R 31 , R 45 , R 48 , R 49 , R 63 , R 65 , R 66 , R 68 = Independently N or non-existent; R2, R 12 , R 13 , R 17 , R 44 , R 67 , R 71 = Independently A, C, U, or non-existent; R9, R 15 , R 19 , R 20 , R 25 , R 27 , R 34 , R 50 , R 52 , R 56 , R 70 , R 72 = Independently A, G, or non-existent; R5, R 24 , R 26 , R 29 , R 32 , R 46 , R 69 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R 10 , R 61 = Independently C, G, or non-existent; R4, R 16 , R 21 , R 30 , R 58 , R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 36 , R 37 , R 42 , R 53 , R 55 , R 59 , R 60, R 62 = Independently C, U, or non-existent; R 33 , R 51 = Independently G or non-existent; R8 = G, U, or non-existence; R 22 , R 38 , R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0244] In one embodiment, the TREM disclosed herein is Equation III LYS Includes the sequence (sequence number 600), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68-R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Lys is, R0, R 18 , R 23 = non-existent, R9, R 14 , R 34 , R 41 = Independently A or non-existent; R 40 = A, C, or non-existent; R1, R3, R7, R 31 = Independently A, C, G, or non-existent; R 48 , R 65 , R 68 = Independently N or non-existent; R2, R 13 , R 17 , R 44 , R 63 , R 66 = Independently A, C, U, or non-existent; R5, R 15 , R 19 , R 20 , R 25 , R 27 , R 29 , R 50 , R 52 , R 56 , R 70 , R 72 = Independently A, G, or non-existent; R6, R 24 , R 32 , R 49 = Independently A, G, U, or non-existent; R 12 , R 26 , R 46 , R 57 = Independently A, U, or non-existent; R 11 , R 28 , R 35 , R 43 = Independently C or non-existent; R 10 , R45 , R 61 = Independently C, G, or non-existent; R4, R 21 , R 64 = Independently C, G, U, or non-existent; R 37 , R 53 , R 55 , R 59 , R 60 , R 62 , R 67 , R 71 = Independently C, U, or non-existent; R 33 , R 51 = Independently G or non-existent; R8, R 30 , R 58 , R 69 = Independently G, U, or non-existent; R 16 , R 22 , R 36 , R 38 , R 39 , R 42 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0245] Phenylalanine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I PHE The array (sequence number 601), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19-R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Phe is, R0, R 23 = non-existent; R9, R 14 , R 38 , R 39 , R 57 , R 72= Independently A or non-existent; R 71 = A, C, or non-existent; R 41 , R 70 = Independently A, C, G, or non-existent; R4, R5, R6, R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 16 , R 61 , R 65 = Independently A, C, U, or non-existent; R 15 , R 26 , R 27 , R 29 , R 40 , R 56 = Independently A, G, or non-existent; R7, R 51 = Independently A, G, U, or non-existent; R 22 , R 24 = Independently A, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R2, R3, R 21 , R 33 , R 43 , R 50 , R 64 = Independently C, G, U, or non-existent; R 11 , R 12 , R 13 , R 17 , R 28 , R 35 , R 36 , R59 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 25 , R 37 , R 52 = Independently G or non-existent; R1 = G, U, or non-existent; R8, R 18 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0246] In one embodiment, the TREM disclosed herein is Equation II PHE The array (sequence number 602), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66-R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Phe is, R0, R 18 , R 23 = non-existent; R 14 , R 24 , R 38 , R 39 , R 57 , R 72 = Independently A or non-existent; R 46 , R 71 = Independently A, C, or non-existent; R4, R 70 = Independently A, C, G, or non-existent; R 45 = A, C, U, or non-existent; R6, R7, R 15 , R 26 , R 27 , R 32 , R 34 , R 40 , R 41 , R 56 , R 69 = Independently A, G, or non-existent; R 29 = A, G, U, or non-existent; R5, R9, R 67 = Independently A, U, or non-existent; R 35 , R 49 , R 55 , R 60 = Independently C or non-existent; R 21 , R 43 , R 62 = Independently C, G, or non-existent; R2, R 33 , R 68 = Independently C, G, U, or non-existent; R3, R 11 , R 12 , R13 , R 28 , R 30 , R 36 , R 42 , R 44 , R 48 , R 58 , R 59 , R 61 , R 66 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 25 , R 37 , R 51 , R 52 , R 63 , R 64 = Independently G or non-existent; R1, R 31 , R 50 = Independently G, U, or non-existent; R8, R 16 , R 17 , R 22 , R 53 , R 54 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0247] In one embodiment, the TREM disclosed herein is Equation III PHE The array (sequence number 603), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Phe is, R0, R 18 , R 22 , R 23 = non-existent; R5, R7, R 14 , R 24 , R 26 , R 32 , R 34 , R38 , R 39 , R 41 , R 57 , R 72 = Independently A or non-existent; R 46 = A, C, or non-existent; R 70 = A, C, G or non-existent; R4, R6, R 15 , R 56 , R 69 = Independently A, G, or non-existent; R9, R 45 = Independently A, U, or non-existent; R2, R 11 , R 13 , R 35 , R 43 , R 49 , R 55 , R 60 , R 68 , R 71 = Independently C or non-existent; R 33 = C, G, or non-existent; R3, R 28 , R 36 , R 48 , R 58 , R 59 , R 61 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 21 , R 25 , R 27 , R 29 , R 37 , R 40 , R 51 , R 52 , R 63 , R 64 = Independently G or non-existent; R8, R 12 , R 16 , R 17 , R 30 , R 31 , R 42 , R 44 , R 50 , R 53 , R54 , R 65 , R 66 , R 67 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0248] Proline TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I PRO The array (sequence number 604), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Pro is, R0 = non-existence R 14 , R 57 = Independently A or non-existent; R 70 , R 72 = Independently A, C, or non-existent; R9, R 26 , R 27 = Independently A, C, G, or non-existent; R4, R5, R6, R 16 , R 21 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 = Independently N or non-existent; R 35 , R 65 = Independently A, C, U, or non-existent; R 24 , R 40 , R 56 = Independently A, G, or non-existent; R7, R 25 , R 51 = Independently A, G, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R1, R3, R 71 = Independently C, G, or non-existent; R 11 , R 12 , R 20 , R 69= Independently C, G, U, or non-existent; R 13 , R 17 , R 18 , R 22 , R 23 , R 28 , R 59 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 38 , R 39 , R 52 , = independently G or non-existent; R2 = independently G, U, or non-existent; R8, R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0249] In one embodiment, the TREM disclosed herein is Equation II PRO The array (sequence number 605), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Pro is, R0, R 17 , R 18 , R 22 , R 23 = non-existent; R 14 , R 45 , R 56 , R 57 , R 58 , R65 , R 68 = Independently A or non-existent; R 61 = A, C, G or non-existent; R 43 =N or nonexistent; R 37 = A, C, U, or non-existent; R 24 , R 27 , R 33 , R 40 , R 44 , R 63 = Independently A, G, or non-existent; R3, R 12 , R 30 , R 32 , R 48 , R 55 , R 60 , R 70 , R 71 , R 72 = Independently C or non-existent; R5, R 34 , R 42 , R 66 = Independently C, G, or non-existent; R 20 = C, G, U, or non-existent; R 35 , R 41 , R 49 , R 62 = Independently C, U, or non-existent; R1, R2, R6, R9, R 10 , R 15 , R 19 , R 26 , R 38 , R 39 , R 46 , R 50 , R 51 , R 52 , R 64 , R 67 , R 69 = Independently G or non-existent; R 11 , R 16 = Independently G, U, or non-existent; R4, R7, R8, R 13 , R 21 , R25 , R 28 , R 29 , R 31 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0250] In one embodiment, the TREM disclosed herein is Equation III PRO The array (sequence number 606), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Pro is, R0, R 17 , R 18 , R 22 , R 23 = non-existent; R 14 , R 45 , R 56 , R 57 , R 58 , R 65 , R 68 = Independently A or non-existent; R 37 = A, C, U, or non-existent; R 24 , R 27 , R 40 = Independently A, G, or non-existent; R3, R5, R 12 , R 30 , R 32 , R 48 , R 49 , R 55 , R 60 , R 61 , R 62 , R 66 , R 70 , R 71 , R 72 = Independently C or non-existent; R 34 , R 42 = Independently C, G, or non-existent; R 43 = C, G, U, or non-existent; R 41 = C, U, or non-existent; R1, R2, R6, R9, R 10 , R 15 , R 19 , R 20 , R 26 , R 33 , R 38 , R 39 , R 44 , R 46 , R 50 , R 51 , R 52 , R 63 , R 64 , R 67, R 69 = Independently G or non-existent; R 16 = G, U, or non-existent; R4, R7, R8, R 11 , R 13 , R 21 , R 25 , R 28 , R 29 , R 31 , R 35 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0251] Serine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I SER The array (sequence number 607), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ser is, R0 = non-existence; R 14 , R 24 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R2, R3, R4, R5, R6, R7, R9, R 10 , R 11 , R 12 , R 13 , R 16 , R 21 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 18 = A, C, U, or non-existent; R 15 , R 40, R 51 , R 56 = Independently A, G, or non-existent; R1, R 29 , R 58 , R 72 = Independently A, G, U, or non-existent; R 39 = A, U, or non-existent; R 60 = C or non-existent; R 38 = C, G, or non-existent; R 17 , R 22 , R 23 , R 71 = Independently C, G, U, or non-existent; R8, R 35 , R 36 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R 19 , R 20 = Independently G or non-existent; R 52 = G, U, or non-existent; R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0252] In one embodiment, the TREM disclosed herein is Equation II SER The array (sequence number 608), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ser is, R0, R 23 = non-existent, R 14 , R 24 , R 41 , R 57 = Independently A or non-existent; R 44 = A, C, or non-existent; R 25 , R 45 , R 48 = Independently A, C, G, or non-existent; R2, R3, R4, R5, R 37 , R 50 , R 62 , R 66 , R 67 , R 69 , R 70 = Independently N or non-existent; R 12 , R 28 , R 65 = Independently A, C, U, or non-existent; R9, R 15 , R 29 , R 34 , R 40 , R 56 , R 63 = Independently A, G, or non-existent; R7, R 26 , R 30 , R 33 , R 46 , R 58 , R 72 = Independently A, G, U, or non-existent; R 39 = A, U, or non-existent; R 11 , R 35 , R 60 , R 61 = Independently C or non-existent; R 13 , R 38 = Independently C, G, or non-existent; R6, R 17 , R 31 , R 43 , R 64 , R 68 = Independently C, G, U, or non-existent; R 36 , R 42 , R 49 , R 55 , R 59 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20, R 27 , R 51 = Independently G or non-existent; R1, R 16 , R 32 , R 52 = Independently G, U, or non-existent; R8, R 18 , R 21 , R 22 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0253] In one embodiment, the TREM disclosed herein is Equation III SER Includes the sequence (sequence number 609), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ser is, R0, R 23 = non-existent, R 14 , R 24 , R 41 , R 57 , R 58 = Independently A or non-existent; R 44 = A, C, or non-existent; R 25 , R 48 = Independently A, C, G, or non-existent; R2, R3, R5, R 37 , R 66 , R 67 , R 69 , R 70 = Independently N or non-existent; R 12 , R 28 , R 62 = Independently A, C, U, or non-existent; R7, R9, R 15 , R 29 , R 33 , R 34 , R 40 , R 45 , R 56 , R 63 = Independently A, G, or non-existent; R4, R 26 , R 46 , R 50 = Independently A, G, U, or non-existent; R 30 , R 39 = Independently A, U, or non-existent; R 11 , R 17 , R 35 , R 60 , R 61 = Independently C or non-existent; R 13 , R 38= Independently C, G, or non-existent; R6, R 64 = Independently C, G, U, or non-existent; R 31 , R 42 , R 43 , R 49 , R 55 , R 59 , R 65 , R 68 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 27 , R 51 , R 52 = Independently G or non-existent; R1, R 16 , R 32 , R 72 = Independently G, U, or non-existent; R8, R 18 , R 21 , R 22 , R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0254] Threonine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I THR The array (sequence number 610), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Thr is, R0, R 23 = non-existent; R 14 , R 41 , R 57 = Independently A or non-existent; R 56 , R70 = Independently A, C, G, or non-existent; R4, R5, R6, R7, R 12 , R 16 , R 26 , R 30 , R 31 , R 32 , R 34 , R 37 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 72 = Independently N or non-existent; R 13 , R 17 , R 21 , R 35 , R 61 = Independently A, C, U, or non-existent; R1, R9, R 24 , R 27 , R 29 , R 69 = Independently A, G, or non-existent; R 15 , R 25 , R 51 = Independently A, G, U, or non-existent; R 40 , R 53 = Independently A, U, or non-existent; R 33 , R 43 = Independently C, G, or non-existent; R2, R3, R 59 = Independently C, G, U, or non-existent; R 11 , R 18 , R 22 , R 28 , R 36 , R 54 , R 55 , R60 , R 71 = Independently C, U, or non-existent; R 10 , R 20 , R 38 , R 52 = Independently G or non-existent; R 19 = G, U, or non-existent; R8, R 39 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0255] In one embodiment, the TREM disclosed herein is Equation II THR Includes the sequence (sequence number 611), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Thr is, R0, R 18 , R 23 = non-existent, R 14 , R 41 , R 57 = Independently A or non-existent; R9, R 42 , R 44 , R 48 , R 56 , R 70 = Independently A, C, G, or non-existent; R4, R6, R 12 , R 26 , R 49 , R 58 , R 63 , R 64 , R 66 , R 68 = Independently N or non-existent; R 13 , R 21 , R 31 , R 37 , R 62 = Independently A, C, U, or non-existent; R1, R 15 , R 24 , R 27 , R 29 , R 46 , R 51 , R 69 = Independently A, G, or non-existent; R7, R 25 , R 45 , R 50 , R 67 = Independently A, G, U, or non-existent; R 40 , R 53 = Independently A, U, or non-existent; R 35 = C or non-existent; R 33 , R 43 = Independently C, G, or non-existent; R2, R3, R5, R 16 , R 32 , R 34 , R 59 , R 65 , R 72 = Independently C, G, U, or non-existent; R 11 , R 17 , R 22 , R 28 , R 30 , R 36 , R 55 , R 60 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 38 , R 52 = Independently G or non-existent; R8, R 39 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0256] In one embodiment, the TREM disclosed herein is Equation III THR The array (sequence number 612), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Thr is, R0, R 18 , R 23 = non-existent, R 14 , R 40 , R 41 , R 57 = Independently A or non-existent; R 44= A, C, or non-existent; R9, R 42 , R 48 , R 56 = Independently A, C, G, or non-existent; R4, R6, R 12 , R 26 , R 58 , R 64 , R 66 , R 68 = Independently N or non-existent; R 13 , R 21 , R 31 , R 37 , R 49 , R 62 = Independently A, C, U, or non-existent; R1, R 15 , R 24 , R 27 , R 29 , R 46 , R 51 , R 69 = Independently A, G, or non-existent; R7, R 25 , R 45 , R 50 , R 63 , R 67 = Independently A, G, U, or non-existent; R 53 = A, U, or non-existent; R 35 = C or non-existent; R2, R 33 , R 43 , R 70 = Independently C, G, or non-existent; R5, R 16 , R 34 , R 59 , R 65 = Independently C, G, U, or non-existent; R3, R 11 , R 22 , R 28 , R 30 , R 36 , R 55 , R 60 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 38 , R 52 = Independently G or non-existent; R 32 = G, U, or non-existent; R8, R 17 , R 39 , R 54 , R 72 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0257] Tryptophan TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I TRP The array (sequence number 613), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Trp is, R0 = non-existence; R 24 , R 39 , R 41 , R 57 = Independently A or non-existent; R2, R3, R 26 , R 27 , R 40 , R 48 = Independently A, C, G, or non-existent; R4, R5, R6, R 29 , R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 49 , R 51 , R 58 , R 63 , R 66 , R 67 , R 68 = Independently N or non-existent; R 13 , R 14 , R 16 , R 18 , R 21 , R 61 , R 65 , R 71 = Independently A, C, U, or non-existent; R1, R9, R 10 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R7, R 25 , R 72 = Independently A, G, U, or non-existent; R 37, R 38 , R 55 , R 60 = Independently C or non-existent; R 12 , R 35 , R 43 , R 64 , R 69 , R 70 = Independently C, G, U, or non-existent; R 11 , R 17 , R 22 , R 28 , R 59 , R 62 = Independently C, U, or non-existent; R 19 , R 20 , R 52 = Independently G or non-existent; R8, R 23 , R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0258] In one embodiment, the TREM disclosed herein is Equation II TRP The array (sequence number 614), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Trp is, R0, R 18 , R 22 , R 23 = non-existent; R 14 , R 24 , R 39 , R 41 , R 57 , R 72= Independently A or non-existent; R3, R4, R 13 , R 61 , R 71 = Independently A, C, or non-existent; R6, R 44 = Independently A, C, G, or non-existent; R 21 = A, C, U, or non-existent; R2, R7, R 15 , R 25 , R 33 , R 34 , R 45 , R 56 , R 63 = Independently A, G, or non-existent; R 58 = A, G, U, or non-existent; R 46 = A, U, or non-existent; R 37 , R 38 , R 55 , R 60 , R 62 = Independently C or non-existent; R 12 , R 26 , R 27 , R 35 , R 40 , R 48 , R 67 = Independently C, G, or non-existent; R 32 , R 43 , R 68 = Independently C, G, U, or non-existent; R 11 , R 16 , R 28 , R 31 , R 49 , R 59 , R 65 , R 70 = Independently C, U, or non-existent; R1, R9, R 10 , R 19 , R 20 , R 50 , R 52 , R 69 = Independently G or non-existent; R2, R8, R 29 , R 30 , R 42 , R 51 , R 64 , R 66 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0259] In one embodiment, the TREM disclosed herein is Equation III TRP The array (sequence number 615), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Trp is, R0, R 18 , R 22 , R 23 = non-existent; R 14 , R 24 , R 39 , R 41 , R 57 , R 72 = Independently A or non-existent; R3, R4, R 13 , R 61 , R 71 = Independently A, C, or non-existent; R6, R 44 = Independently A, C, G, or non-existent; R 21 = A, C, U, or non-existent; R2, R7, R 15 , R 25 , R 33 , R 34 , R 45 , R 56 , R 63 = Independently A, G, or non-existent; R 58 = A, G, U, or non-existent; R 46 = A, U, or non-existent; R 37 , R 38 , R 55 , R 60 , R 62 = Independently C or non-existent; R 12 , R 26 , R 27 , R 35 , R 40 , R 48 , R 67 = Independently C, G, or non-existent; R 32 , R 43 , R 68 = Independently C, G, U, or non-existent; R 11 , R 16 , R 28 , R 31 , R 49 , R 59 , R 65 , R 70 = Independently C, U, or non-existent; R1, R9, R 10 , R 19 , R 20 , R 50 , R 52 , R 69 = Independently G or non-existent; R2, R8, R 29 , R 30 , R 42 , R 51 , R 64 , R 66 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0260] Tyrosine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I TYR The array (sequence number 616), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Tyr is, R0 = non-existence R 14 , R 39 , R 57 = Independently A or non-existent; R 41 , R 48 , R51 , R 71 = Independently A, C, G, or non-existent; R3, R4, R5, R6, R9, R 10 , R 12 , R 13 , R 16 , R 25 , R 26 , R 30 , R 31 , R 32 , R 42 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 22 , R 65 = Independently A, C, U, or non-existent; R 15 , R 24 , R 27 , R 33 , R 37 , R 40 , R 56 = Independently A, G, or non-existent; R7, R 29 , R 34 , R 72 = Independently A, G, U, or non-existent; R 23 , R 53 = Independently A, U, or non-existent; R 35 , R 60 = Independently C or non-existent; R 20 = C, G, or non-existent; R1, R2, R 28 , R 61 , R 64 = Independently C, G, U, or non-existent; R 11 , R 17 , R 21, R 43 , R 55 = Independently C, U, or non-existent; R 19 , R 52 = Independently G or non-existent; R8, R 18 , R 36 , R 38 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0261] In one embodiment, the TREM disclosed herein is Equation II TYR The array (sequence number 617), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Tyr is, R0, R 18 , R 23 = non-existent, R7, R9, R 14 , R 24 , R 26 , R 34 , R 39 , R 57 = Independently A or non-existent; R 44 , R 69 = Independently A, C, or non-existent; R 71 = A, C, G or non-existent; R 68 =N or nonexistent; R 58 = A, C, U, or non-existent; R 33 , R 37 , R 41 , R 56 , R 62 , R 63 = Independently A, G, or non-existent; R6, R 29 , R 72 = Independently A, G, U, or non-existent; R 31 , R 45 , R 53 = Independently A, U, or non-existent; R 13 , R 35 , R 49 , R 60 = Independently C or non-existent; R 20 , R 48 , R 64 , R 67 , R 70 = Independently C, G, or non-existent; R1, R2, R5, R 16 , R 66 = Independently C, G, U, or non-existent; R11 , R 21 , R 28 , R 43 , R 55 , R 61 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 25 , R 27 , R 40 , R 51 , R 52 = Independently G or non-existent; R3, R4, R 30 , R 32 , R 42 , R 46 = Independently G, U, or non-existent; R8, R 12 , R 17 , R 22 , R 36 , R 38 , R 50 , R 54 , R 59 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0262] In one embodiment, the TREM disclosed herein is Equation III TYR Includes the array (sequence number 618), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Tyr is, R0, R 18 , R 23 = non-existent, R7, R9, R 14 , R 24 , R 26 , R 34 , R 39 , R 57 , R72 = Independently A or non-existent; R 44 , R 69 = Independently A, C, or non-existent; R 71 = A, C, G or non-existent; R 37 , R 41 , R 56 , R 62 , R 63 = Independently A, G, or non-existent; R6, R 29 , R 68 = Independently A, G, U, or non-existent; R 31 , R 45 , R 58 = Independently A, U, or non-existent; R 13 , R 28 , R 35 , R 49 , R 60 , R 61 = Independently C or non-existent; R5, R 48 , R 64 , R 67 , R 70 = Independently C, G, or non-existent; R1, R2 = independently C, G, U, or non-existent; R 11 , R 16 , R 21 , R 43 , R 55 , R 66 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 20 , R 25 , R 27 , R 33 , R 40 , R 51 , R 52 = Independently G or non-existent; R3, R4, R 30 , R 32 , R 42 , R 46= Independently G, U, or non-existent; R8, R 12 , R 17 , R 22 , R 36 , R 38 , R 50 , R 53 , R 54 , R 59 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0263] Valin TREM consensus array In one embodiment, the TREM disclosed herein is of formula I VAL The array (sequence number 619), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Val is, R0, R 23 = non-existent; R 24 , R 38 , R 57 = Independently A or non-existent; R9, R 72 = Independently A, C, G, or non-existent; R2, R4, R5, R6, R7, R 12 , R 15 , R 16 , R 21 , R 25 , R 26 , R 29 , R 31 , R 32 , R 33 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 17 , R 35 , R 59 = Independently A, C, U, or non-existent; R 10 , R 14 , R 27 , R 40 , R 52 , R 56 = Independently A, G, or non-existent; R1, R3, R 51 , R 53 = Independently A, G, U, or non-existent; R 39 = C or non-existent; R 13 , R 30 , R 55 = Independently C, G, U, or non-existent; R 11 , R 22 , R 28 , R 60 , R 71 = Independently C, U, or non-existent; R 19 =G or non-existent; R 20 = G, U, or non-existent; R8, R 18 , R 36 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0264] In one embodiment, the TREM disclosed herein is Equation II VAL The array (sequence number 620), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Val is, R0, R 18 , R 23 = non-existent; R 24 , R 38 , R 57 = Independently A or non-existent; R 64 , R 70 , R72 = Independently A, C, G, or non-existent; R 15 , R 16 , R 26 , R 29 , R 31 , R 32 , R 43 , R 44 , R 45 , R 49 , R 50 , R 58 , R 62 , R 65 = Independently N or non-existent; R6, R 17 , R 34 , R 37 , R 41 , R 59 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 27 , R 40 , R 46 , R 51 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 12 , R 25 , R 33 , R 53 , R 63 , R 66 , R 68 = Independently A, G, U, or non-existent; R 69 = A, U, or non-existent; R 39 = C or non-existent; R5, R 67 = Independently C, G, or non-existent; R2, R4, R 13 , R 48 , R 55 , R 61 = Independently C, G, U, or non-existent; R 11 , R 22 , R 28 , R 30 , R 35 , R 60 , R71 = Independently C, U, or non-existent; R 19 =G or non-existent; R1, R3, R 20 , R 42 = Independently G, U, or non-existent; R8, R 21 , R 36 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0265] In one embodiment, the TREM disclosed herein is Equation III VAL The array (sequence number 621), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Val is, R0, R 18 , R 23 = non-existent; R 24 , R 38 , R 40 , R 57 , R 72 = Independently A or non-existent; R 29 , R 64 , R 70 = Independently A, C, G, or non-existent; R 49 , R 50 , R 62 = Independently N or non-existent; R 16 , R 26 , R 31 , R 32 , R 37 , R 41 , R 43 , R 59 , R 65 = Independently A, C, U, or non-existent; R9, R 14 , R 27 , R 46 , R 52 , R 56 , R 66 = Independently A, G, or non-existent; R7, R 12 , R 25 , R 33 , R 44 , R 45 , R 53 , R 58 , R 63 , R 68 = Independently A, G, U, or non-existent; R 69 = A, U, or non-existent; R 39 = C or non-existent; R5, R 67 = Independently C, G, or non-existent; R2, R4, R 13 , R 15 , R 48 , R 55 = Independently C, G, U, or non-existent; R6, R 11 , R 22 , R 28 , R 30 , R 34 , R 35 , R 60 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 51 = Independently G or non-existent; R1, R3, R 20 , R 42 = Independently G, U, or non-existent; R8, R 17 , R 21 , R 36 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0266] Variable domain consensus array In one embodiment, the TREM disclosed herein is R 47The variable region includes a variable region at a certain position. In one embodiment, the variable region is the length of 1 to 271 ribonucleotides (e.g., 1 to 250, 1 to 225, 1 to 200, 1 to 175, 1 to 150, 1 to 125, 1 to 100, 1 to 75, 1 to 50, 1 to 40, 1 to 30, 1 to 29, 1 to 28, 1 to 27, 1 to 26, 1 to 25, 1 to 24, 1 to 23, 1 to 22, 1 to 21, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 10 to 271, 20 to 271, 30 to 271, 40 to 271 These are 50-271, 60-271, 70-271, 80-271, 100-271, 125-271, 150-271, 175-271, 200-271, 225-271, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, or 271 ribonucleotides. In one embodiment, the variable region includes one, all, or a combination of adenine, cytosine, guanine, or uracil.

[0267] In one embodiment, the variable region includes a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence as disclosed in Table 4, for example, one of sequence numbers 452-561 disclosed in Table 4.

[0268] [Table 4-1]

[0269] [Table 4-2]

[0270] [Table 4-3]

[0271] [Table 4-4]

[0272] Corresponding nucleotide position To determine whether a selected nucleotide position in the candidate sequence corresponds to a selected position in the reference sequence (e.g., SEQ ID NO: 622, SEQ ID NO: 623, SEQ ID NO: 624), perform one or more of the following evaluations.

[0273] Rating A: 1. Align the candidate sequences with the consensus sequences in Tables 9 and 10. Select the consensus sequence that has the most aligned positions (and at least 60% of the positions of the aligned candidate sequences).

[0274] Alignment is performed as follows: Candidate sequences and isodecoder consensus sequences from Tables 10A-10B are aligned based on a global pairwise alignment calculated using the Needleman-Wunsch algorithm, with the following settings: match score, mismatch penalty: -1, gap start penalty: -1, gap extension penalty: -0.5, and no penalty for terminal gaps. Next, the alignment with the highest overall alignment score is used to determine the similarity (%) between the candidate sequence and the consensus sequence by counting the number of matching positions within the alignment, dividing it by the larger of the number of non-N base pairs in the candidate sequence or the consensus sequence, and multiplying the quotient by 100. If multiple alignments (of the candidate sequence and a single consensus sequence) have the same score, the similarity (%) is the highest similarity (%) calculated from the alignments with the same score. This process is repeated for each candidate sequence and each iso-decoder consensus sequence remaining in Tables 10A-10B, and the alignment showing the highest similarity (%) is selected. If this alignment has a similarity (%) of 60% or more, it is considered a valid alignment and is used to associate positions in the candidate sequences with positions in the consensus sequences; otherwise, the candidate sequence is considered not to match any of the iso-decoder consensus sequences. If ties occur at this point, all typified consensus sequences are advanced to step 2 of the analysis.

[0275] 2. Using the selected consensus sequence from Step 1, determine the consensus sequence position number to align with the selected position (e.g., modified position) in the candidate sequence. Next, assign the position number of the matched position in the consensus sequence to the selected position in the candidate sequence. In other words, the selected position in the candidate sequence is numbered according to the numbering of the consensus sequence. If there are ties in the consensus sequence in Step 1 and different position numbers result in Step 2, all such position numbers are advanced to Step 5.

[0276] 3. Align the consensus sequence and reference sequence selected in Step 1. The alignment is performed using the method described in Step 1.

[0277] 4. From the alignment in Step 3, determine the position number of the consensus sequence that matches the selected position in the reference sequence (e.g., the corrected position). Next, assign the position number of the matched position in the consensus sequence to the selected position in the reference sequence. In other words, the selected position in the reference sequence is numbered according to the numbering of the consensus sequence. If ties occur at this point, all consensus sequences with ties are advanced to Step 5 of the analysis.

[0278] 5. If the position number values ​​determined for the reference sequence in step 2 are the same as the position number values ​​determined for the candidate sequence in step 4, then those positions are defined as corresponding.

[0279] Rating B The reference sequence (for example, the TREM sequence described herein) and the candidate sequence are aligned with each other. The alignment is performed as follows:

[0280] The reference sequence and candidate sequence are aligned based on a global pairwise alignment calculated using the Needleman-Wunsch algorithm, with the following settings: match score, mismatch penalty: -1, gap start penalty: -1, gap extension penalty: -0.5, and no penalty for terminal gaps. Next, the alignment with the highest overall alignment score is used to determine the similarity (%) between the candidate sequence and the reference sequence. This is achieved by counting the number of matching positions within the alignment, dividing it by the larger of the number of non-N base pairs in the candidate sequence or consensus sequence, and multiplying the quotient by 100. If multiple alignments have the same score, the similarity (%) is taken as the highest similarity (%) calculated from the alignments with the same score. If this alignment has a similarity (%) of 60% or higher, it is considered a valid alignment and is used to associate the positions of the candidate sequence with the positions of the reference sequence. Otherwise, the candidate sequence is considered not to match the reference sequence.

[0281] If a selected nucleotide position in a reference sequence (e.g., a modification position) pairs with a selected nucleotide position in a candidate sequence (e.g., a modification position), then those positions are defined as corresponding.

[0282] Rating C: Candidate sequences are assigned nucleotide position numbers based on the Comprehensive tRNA Numbering System (CtNS) (also known as the tRNAviz method), which is used as a global numbering system for tRNA molecules (for example, as described in Lin et al., Nucleic Acids Research, 47:W1, pages W542-W547, 2 July 2019). Alignment is performed as follows:

[0283] 1. Candidate sequences are assigned nucleotide positions based on the tRNAviz method. In the case of novel sequences not present in the tRNAviz database, the numbering of the closest related sequence in the database is applied. For example, if TREM differs from a sequence in the database at any given nucleotide position, the numbering of a tRNA having a wild-type sequence at that given position is used.

[0284] 2. Nucleotide positions are assigned to the reference sequence according to the method described in 1.

[0285] 3. If the position number values ​​determined for the reference array in step 1 are the same as the position number values ​​determined for the candidate array in step 2, then those positions are defined as corresponding.

[0286] If the selected positions in the reference sequence and the candidate sequence are found to correspond in at least one of evaluations A, B, and C, then those positions are defined as corresponding. For example, if two positions are found to correspond in evaluation A but not in evaluation B or C, those positions are defined as corresponding. Similarly, if two positions are found to correspond in evaluation B but not in evaluation A or C, those positions are defined as corresponding. Furthermore, if two positions are found to correspond in evaluation C but not in evaluation A or B, those positions are defined as corresponding.

[0287] The numbering above is for explanatory purposes only and does not imply a required order. If multiple evaluations are performed, they may be carried out in any order.

[0288] [Table 6-1]

[0289] [Table 6-2]

[0290] [Table 6-3]

[0291] [Table 6-4]

[0292] [Table 7-1]

[0293] [Table 7-2]

[0294] [Table 7-3]

[0295] [Table 7-4]

[0296] [Table 8]

[0297] Repeat growth disorder (RED) TREM compositions disclosed herein can be used to treat RED, for example, as described herein. RED as described herein is characterized by elongation of nucleic acid sequences (e.g., RED codons) within the genome. For example, RED may be a trinucleotide repeat disorder (e.g., a disorder involving a RED codon) or a hexanucleotide repeat disorder. Non-limiting examples of RED are shown in Table 9.

[0298] In one embodiment, the subject has the RED listed in Table 9. In one embodiment, the cells are, for example, those with the RED listed in Table 9, and are obtained, for example, from a subject having them.

[0299] For example, RED can be selected from the left column of Table 9. Alternatively, RED may be selected from the left column of Table 9, and in some embodiments, the trinucleotide sequence (e.g., RED codon) or hexanucleotide sequence may be present in one of the genes selected from the middle column of Table 9, e.g., the genes provided in the middle column of Table 9. In some embodiments, the RED codon or hexanucleotide sequence may be present in the gene corresponding to RED provided in the left column of Table 9. In some embodiments, the RED codon or hexanucleotide sequence may be a repeat motif selected from the right column of Table 9. For example, RED may be selected from the left column of Table 9, the RED codon may be present in the gene provided in the corresponding middle column (e.g., in the same row) of Table 9, and the RED codon may be a repeat motif provided in the corresponding right column of Table 9.

[0300] In one embodiment, the RED codon is a repeat motif provided in the right column of Table 9, and the repeat extension is not present in the gene provided in Table 9.

[0301] [Table 9]

[0302] In another aspect, the Disclosure concerns a method of treating a disease or disorder in cells or subjects by administering TREM (e.g., TREM as described herein) to the cells or subjects. Illustrative diseases or disorders include RED, for example, the REDs listed in Table 9.

[0303] In some embodiments, the disease or disorder is a polyglutamine (polyQ) disease. PolyQ diseases are characterized by repeat elongation of the RED codon CAG, which results in abnormally large segments of consecutive glutamine residues, triggering protein misfolding and amyloid-like aggregation, leading to severe cytotoxicity that contributes to neurodegeneration. In some embodiments, the disease or disorder is Huntington's disease. Huntington's disease is a hereditary neurodegenerative disease. Typical symptoms usually begin between the ages of 30 and 50 and include ataxia and unsteady gait, eventually progressing to the ataxia and involuntary movements characteristic of chorea. In some embodiments, Huntington's disease is characterized by repeat elongation within the HTT gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CAG. In some embodiments, Huntington's disease is characterized by at least 36 (e.g., at least 37, 38, 39, 40, 45, 50, 100, or more) repeats of the RED codon CAG in the HTT gene. In some embodiments, Huntington's disease is characterized by approximately 36 to 250 (e.g., approximately 37 to 200, 38 to 150, 39 to 100, 40 to 75, or 50) repeats of the RED codon CAG in the HTT gene.

[0304] In some embodiments, polyQ disease is spinocerebellar degeneration (SCA) (e.g., SCA1, SCA2, SCA3, SCA7, SCA8, and SCA17). SCA is a progressive, degenerative genetic disorder characterized by neurological symptoms such as dysarthria, hypermetric saccades, and ataxia of gait and stance. Approximately 150,000 people in the United States are diagnosed with SCA. There is no known effective treatment or therapy.

[0305] In some embodiments, the polyQ disorder is SCA1. SCA1 is an autosomal dominant genetic disorder that typically leads to death within 10 to 30 years of symptom onset. SCA1 is usually diagnosed in subjects aged 30 to 40 years. In some embodiments, SCA1 is characterized by repeat elongation within the ATXN1 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CAG. In some embodiments, SCA1 is characterized by at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, or more) repeats of the RED codon CAG within the ATXN1 gene. SCA1 polyQ toxicity causes, for example, degeneration of neurons (e.g., Purkinje neurons) in the cerebellum and spinal cord.

[0306] In some embodiments, polyQ disease is SCA2. SCA2 is a fatal, progressive, genetic disorder in which polyQ toxicity causes neurodegeneration in the cerebellum, inferior olivary nucleus, and pons, among other areas. Symptoms of SCA2 include ataxia, parkinsonism, and dementia. In some embodiments, SCA2 is characterized by repeat elongation within the ATXN2 gene. In some embodiments, the repeat elongation includes repeats of the RED codon CAG. In some embodiments, SCA2 is characterized by at least 32 (e.g., at least 33, 34, 35, 40, 45, 50, 55, or more) repeats of the RED codon CAG within the ATXN2 gene.

[0307] In some embodiments, the polyQ disorder is SCA3. SCA3 is an autosomal dominant disorder that causes progressive cerebellar ataxia. Symptoms of SCA3 include gaze-induced nystagmus, upper motor neuron degeneration, and slow saccades. In some embodiments, SCA3 is characterized by repeat elongation within the ATXN3 gene. In some embodiments, the repeat elongation includes repeats of the RED codon CAG. In some embodiments, SCA3 is characterized by at least 45 (e.g., at least 50, 55, 60, 65, 70, 75, or 80 or more) repeats of the RED codon CAG within the ATXN3 gene. In some embodiments, SCA3 is characterized by approximately 61–87 (e.g., approximately 62–86, 63–85, 64–80, 65–75, or 70) repeats of the RED codon CAG within the ATXN3 gene. SCA3 polyQ toxicity causes neurodegeneration, primarily in the rhomboencephalon.

[0308] In some embodiments, the polyQ disease is SCA7. Symptoms of SCA7 include macular degeneration, upper motor neuron degeneration, and slow saccades. In some embodiments, SCA7 is characterized by repeat elongation within the ATXN7 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CAG. In some embodiments, SCA7 is characterized by at least 11 (e.g., at least 12, 13, 14, 15, 20, 25, 30, 40, 45, 50, or more) repeats of the RED codon CAG within the ATXN7 gene. The polyQ toxicity of SCA7 is, for example, the formation of intranuclear inclusions that cause macular degeneration in the retina and, for example, neurodegeneration in the cerebellum and brainstem.

[0309] In some embodiments, polyQ disorder is SCA8. Symptoms of SCA8 include horizontal nystagmus, dysarthria, mild aspiration, and ataxia. In some embodiments, SCA8 is characterized by repeat elongation in the ATXN8b gene or ATXN8OS. In some embodiments, the repeat elongation includes repeats of the RED codon CAG or CTG. In some embodiments, SCA8 includes repeat elongation within the ATXN8b gene, and the repeat elongation includes repeats of the RED codon CAG. In some embodiments, SCA8 is characterized by at least 51 (e.g., at least 52, 53, 54, 55, 60, 65, 70, 75, 100, or more) repeats of the RED codon CAG within the ATXN8b gene. In some embodiments, SCA8 is characterized by approximately 71 to 1300 (e.g., approximately 72 to 1200, 73 to 1100, 74 to 1000, 75 to 750, 100 to 500, or 300) repeats of the RED codon CAG within the ATXN8b gene. SCA8polyQ toxicity causes neurodegeneration. In some embodiments, SCA8 includes a repeat extension within the ATXN8OS gene, the repeat extension including a repeat of the RED codon CTG. In some embodiments, SCA8 is characterized by at least 51 (e.g., at least 52, 53, 54, 55, 60, 65, 70, 75, 100, or more) repeats of the RED codon CTG within the ATXN8OS gene. In some embodiments, SCA8 is characterized by approximately 71–1300 (e.g., approximately 72–1200, 73–1100, 74–1000, 75–750, 100–500, or 300) repeats of the RED codon CTG within the ATXN8OS gene. ATXN8OS mRNA containing the elongated repeat sequence accumulates in cerebellar cortical neurons as ribonuclear inclusions that colocalize with the RNA-binding protein MBNL1, indicating that these transcripts can dysregulate brain gene pathways in a manner similar to that involved in myotonic dystrophy type 1 (DM1) (Daughters et al. PloS Genet. 5:e1000600, 2009).

[0310] In some embodiments, the polyQ disorder is SCA17. SCA17 is one of the most heterogeneous forms of autosomal dominant cerebellar ataxia and has a broad clinical spectrum that can mimic other movement disorders such as Huntington's disease, dystonia, and parkinsonism. Symptoms may include gait and lower limb ataxia as well as dysarthria, in addition to parkinsonism, choreiform movements, dystonia, epilepsy, cognitive symptoms, and psychiatric symptoms. In some embodiments, SCA17 is characterized by repeat elongation within the TBP gene. In some embodiments, SCA17 is characterized by at least 41 (e.g., at least 42, 43, 44, 45, 50, 55, 60, 65, 70, or more) repeats of the RED codon CAG within the TBP gene. SCA17 polyQ toxicity causes neurodegeneration.

[0311] In some embodiments, polyQ disease is dentatorubral-pallidoluysian atrophy (DRPLA). DRPLA is an autosomal dominant spinocerebellar degeneration, also known as Holeyr syndrome and Naito-Oyanagi disease. Symptoms of DRPLA include ataxia, chorea athetosis, dementia, seizures, myoclonus, cervical dystonia, corneal endothelial degeneration, autism, and surgery-resistant obstructive sleep apnea. In some embodiments, DRPLA is characterized by repeat elongation within the ATN1 gene. In some embodiments, this repeat elongation includes a repeat sequence of the RED codon CAG. In some embodiments, DRPLA is characterized by at least 36 (e.g., at least 37, 38, 39, 40, 45, 50, or more) repeats of the RED codon CAG within the ATN1 gene. In some embodiments, DRPLA is characterized by approximately 49–88 (e.g., approximately 50–87, 55–86, 60–85, 65–80, or 70–75) repeats of the RED codon CAG within the ATN1 gene. DRPLA polyQ toxicity causes intranuclear inclusions and neuronal degeneration in central nervous system tissues, for example, throughout the brain and spinal cord.

[0312] In some embodiments, the polyQ disease is spinal and bulbar muscular atrophy (SBMA), a rare adult-onset X-linked recessive lower motor neuron disease. Symptoms of SBMA include dysarthria, dysphagia, denervation of the muscles, and degeneration of the bulbar and lower motor neurons. In some embodiments, SBMA is characterized by repeat elongation within the AR gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CAG. In some embodiments, SBMA is characterized by at least 35 (e.g., at least 40, 45, 50, 55, 60, 65, 70, or more) repeats of the RED codon CAG within the AR gene. The polyQ toxicity of SBMA causes neurodegeneration, for example, in the anterior horn of the spinal cord and the brainstem.

[0313] In some embodiments, polyQ disease is glutaminase deficiency, an autosomal recessive genetic disorder that develops in childhood. Glutaminase deficiency is associated with epilepsy and is characterized by intractable seizures, respiratory failure, brain abnormalities, and neonatal death. In some embodiments, glutaminase deficiency is characterized by repeat elongation within the GLS gene. In some embodiments, the repeat elongation includes repeats of the RED codon CAG. In some embodiments, glutaminase deficiency is characterized by at least 35 (e.g., at least 40, 45, 50, 55, 60, 65, 70, or more) repeats of the RED codon CAG within the GLS gene.

[0314] In some embodiments, RED is Fragile X syndrome (FRAXA). FRAXA is an X-linked dominant genetic disorder characterized by mild to moderate intellectual disability. Symptoms of FRAXA include autism, language development delay, and hyperactivity. In some embodiments, FRAXA is characterized by repeat elongation within the FMR1 gene. In some embodiments, the repeat elongation includes repeats of the RED codon CGG. In some embodiments, FRAXA is characterized by at least 54 (e.g., at least 55, 60, 65, 70, 75, 100, or more) repeats of the RED codon CGG within the FMR1 gene. In some embodiments, FRAXA is characterized by at least 230 (e.g., 240, 250, 300, or more) repeats of the RED codon CGG within the FMR1 gene.

[0315] In some embodiments, RED is Fragile X-associated tremor / ataxia syndrome (FXTAS). FXTAS is a late-onset neurodegenerative disease most frequently diagnosed in male pre-mutation carriers of FRAXA aged 50 years or older. Symptoms include cerebellar ataxia, motion tremor, parkinsonism, cognitive decline, and autonomic nervous system dysfunction. In some embodiments, FXTAS is characterized by repeat extensions within the FMR1 gene. In some embodiments, this repeat extension includes the RED codon CGG repeat. In some embodiments, FXTAS is characterized by at least 54 (e.g., at least 55, 60, 65, 70, 75, 100, or more) repeats of the RED codon CGG within the FMR1 gene. In some embodiments, FXTAS is characterized by approximately 55 to 200 (e.g., approximately 60 to 175, 75 to 150, or 100 to 125) repeats of the RED codon CGG within the FMR1 gene.

[0316] In some embodiments, RED is fragile X-related premature ovarian failure (FXPOI). FXPOI is the most common known genetic cause of ovarian failure in women with a normal chromosome number (46,XX), accounting for 5–10% of cases of premature ovarian failure. Symptoms may include repeated elevations of follicle-stimulating hormone and menstrual abstinence for at least 4–6 months. In some embodiments, FXPOI is characterized by repeat elongation within the FMR1 gene. In some embodiments, this repeat elongation includes repeats of the RED codon CGG. In some embodiments, FXPOI is characterized by approximately 55–199 (e.g., approximately 60–175, 75–150, or 100–125) repeats of the RED codon CGG within the FMR1 gene. In some embodiments, FXPOI is characterized by approximately 70–100 (e.g., approximately 75–95, 80–90, or 85) repeats of the RED codon CGG within the FMR1 gene.

[0317] In some embodiments, RED is myotonic dystrophy type 1 (DM1). DM1 is an autosomal dominant muscular dystrophy that causes symptoms such as delayed post-contraction muscle relaxation (myotonia), ptosis, hypersomnia, and abnormalities in the electrical activity of the heart, such as arrhythmias or conduction blocks. In some embodiments, DM1 is characterized by repeat elongation within the DMPK gene. In some embodiments, the repeat elongation includes repeats of the RED codon CTG. In some embodiments, DM1 is characterized by at least 35 (e.g., at least 40, 45, 50, 55, 60, 65, or more) repeats of the RED codon CTG within the DMPK gene. In some embodiments, DM1 is characterized by at least 50 (e.g., at least 100, 150, 200, or more) repeats of the RED codon CTG within the DMPK gene.

[0318] In some embodiments, RED is a disease or disorder characterized by repeat elongation of the RED codon GCN (where N may be A, C, T, or G), resulting in an abnormally long polyalanine (polyA) sequence in the resulting protein. Such RED may be classified as polyA RED. Similar to polyQ repeat elongation, this abnormally long polyA sequence promotes protein aggregation, such as intranuclear inclusions, which contribute to cell death and neurodegeneration. In some embodiments, polyA RED is selected from blepharoptosis, ptosis, and blepharofibrillary syndrome (BPES), cleidocranial dysplasia (CCD), congenital central hypoventilation syndrome (CHS), holoprosencephalopathy 5 (HPE), synpolydactyly type 1 (SPD1), and X-linked intellectual disability (e.g., X-linked hypopituitarism).

[0319] In some embodiments, polyA RED is BPES. BPES is a rare autosomal dominant genetic disorder characterized by symptoms such as narrow horizontal palpebral fissure (palpebral fissure), drooping eyelids (ptosis), and a fold of skin running from the nasal ala to the lower eyelid (palpebral fissure). Types 1 and 2 of BPES are distinguished by the presence or absence of symptoms of early ovarian failure in women (type 1) or (type 2), which often leads to menopausal symptoms and infertility in patients as young as 15 years of age. In some embodiments, BPES is characterized by repeat elongation within the FOXL2 gene. In some embodiments, this repeat elongation includes repeats of the RED codon GCN. In some embodiments, BPES is characterized by at least 15 (e.g., at least 20, 25, 30, 35, 40, 45, 50, or more) repeats of the RED codon GCN within the FOXL2 gene.

[0320] In some embodiments, polyA RED is CCD. CCD is an autosomal dominant congenital anomaly that primarily affects bones and teeth. The clavicle is typically underdeveloped or absent, causing the shoulders to form too close together, and the anterior part of the skull closes abnormally late, resulting in a shorter-than-average skull. Other symptoms may include a protruding forehead, wide-set eyes, dental abnormalities, scoliosis, decreased bone density, and a flat nose. In some embodiments, CCD is characterized by repeat elongation within the RUNX2 gene. In some embodiments, the repeat elongation includes repeats of the RED codon GCN. In some embodiments, CCD is characterized by at least 15 (e.g., at least 20, 25, 30, 35, 40, 45, 50, or more) repeats of the RED codon GCN within the RUNX2 gene.

[0321] In some embodiments, polyA RED is CHS. CHS is a congenital sleep-related respiratory disorder that causes ineffective respiration, apnea, or respiratory arrest during sleep (mild form) and while awake (severe form) due to impaired autonomic respiratory control. In some embodiments, CHS is characterized by repeat elongation within the PHOX2B gene. In some embodiments, the repeat elongation includes repeats of the RED codon GCN. In some embodiments, CHS is characterized by at least 15 (e.g., at least 20, 25, 30, 35, 40, 45, 50, or more) repeats of the RED codon GCN within the PHOX2B gene.

[0322] In some embodiments, polyA RED is HPE. HPE is a congenital head defect in which the forebrain does not develop into two hemispheres between 18 and 28 days of gestation. The symptoms of HPE can vary from mild (no facial defects, no organ defects, olfactory dysfunction, or only a single central incisor) to severe (cyclopia). In some embodiments, HPE is characterized by repeat elongation within the ZIC2 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon GCN. In some embodiments, HPE is characterized by at least 7 (e.g., at least 8, 9, 10, or more) repeats of the RED codon GCN within the ZIC2 gene.

[0323] In some embodiments, polyA RED is SPD1. SPD1 is an autosomal dominant genetic disorder characterized by the co-occurrence of syndactyly and polydactyly. In some embodiments, SPD1 is characterized by repeat elongation within the HOXD13 gene. In some embodiments, this repeat elongation includes a repeat of the RED codon GCN. In some embodiments, SPD1 is characterized by at least 7 (e.g., at least 8, 9, 10, or more) repeats of the RED codon GCN within the HOXD13 gene.

[0324] In some embodiments, polyA RED is an X-linked intellectual disability, such as a medical disorder associated with X-linked recessive inheritance, which causes intellectual disability. Non-exclusive examples of such disorders include Coffin-Lowry syndrome, CCD3X syndrome, MASA syndrome, MECP2 duplication syndrome, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and X-linked alpha-thalassemia intellectual disability syndrome. In some embodiments, the X-linked intellectual disability is characterized by repeat elongation within the ARX gene. In some embodiments, the repeat elongation includes a repeat of the RED codon GCN. In some embodiments, the X-linked disorder is characterized by at least 7 (e.g., at least 8, 9, 10, or more) repeats of the RED codon GCN within the ARX gene. PolyA repeat elongation in the ARX protein reduces both the concentration and function of the ARX protein in cells, which is associated with impaired normal development and migration of interneurons. The subsequent deterioration of interneuronal function is likely to be the underlying cause of the neurological problems characteristic of X-linked intellectual disability.

[0325] In some embodiments, polyA RED is X-linked hypopituitarism. X-linked hypopituitarism is an X-linked intellectual disability in which a mutation in the SOX3 gene causes the disorder and has a variable phenotype including growth hormone deficiency due to hypopituitarism. In some embodiments, X-linked hypopituitarism is characterized by repeat elongation within the SOX3 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon GCN. In some embodiments, X-linked hypopituitarism is characterized by at least 7 (e.g., at least 8, 9, 10, or more) repeats of the RED codon GCN within the SOX3 gene.

[0326] In some embodiments, RED is oculopharyngeal distal myopathy type 2, i.e., an autosomal dominant inherited disorder characterized by progressive muscle weakness. In some embodiments, oculopharyngeal distal myopathy type 2 is characterized by repeat elongation within the GIPC1 gene. In some embodiments, the repeat elongation includes repeats of the RED codon CGG. In some embodiments, oculopharyngeal distal myopathy type 2 is characterized by at least 31 (e.g., at least 32, 33, 34, 35, 40, 45, 50, or more) repeats of the RED codon CGG within the GIPC1 gene. In some embodiments, oculopharyngeal distal myopathy type 2 is characterized by at least 60 (e.g., at least 65, 70, 75, 100, or more) repeats of the RED codon CGG within the GIPC1 gene.

[0327] In some embodiments, RED is pseudoachondroplasia (PSACH). PSACH is an autosomal dominant inherited bone growth disorder. Symptoms of PSACH include gait disturbance, lower limb deformities, and mild to severe short stature. In some embodiments, PSACH is characterized by repeat elongation in the COMP gene. In some embodiments, the repeat elongation includes a repeat of the RED codon GAC. In some embodiments, PSACH is characterized by at least 5 (e.g., at least 6, 7, 8, 9, 10, or more) repeats of the RED codon GAC in the COMP gene.

[0328] In some embodiments, RED is multiple epiphyseal dysplasia (MED). MED is an autosomal dominant inherited skeletal disorder. Symptoms include joint pain and fatigue after exercise, small, irregular centers of ossification, and gait instability. In some embodiments, MED is characterized by repeat elongation within the COMP gene. In some embodiments, the repeat elongation includes a repeat of the RED codon GAC. In some embodiments, MED is characterized by at least 5 (e.g., at least 6, 7, 8, 9, 10, or more) repeats of the RED codon GAC within the COMP gene.

[0329] In some embodiments, RED is Jacobsen syndrome, a congenital disorder resulting in symptoms such as intellectual disability, malformations, developmental delay, and cardiac defects, as well as secondary symptoms such as eye disorders, ear and sinus infections, hearing impairment, bone deformities, growth hormone deficiency, gastrointestinal disorders, and renal failure. In some embodiments, Jacobsen syndrome is characterized by repeat elongation within the CBL2 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CCG. In some embodiments, Jacobsen syndrome is characterized by at least three (e.g., at least four, five, ten, fifteen, twenty, or more) repeats of the RED codon CCG within the CBL2 gene.

[0330] In some embodiments, RED is an intellectual disability associated with the fragile site FRA2A. Symptoms may include cognitive impairment, communication and behavioral impairments, and lack of concentration. In some embodiments, the intellectual disability associated with the fragile site FRA2A is characterized by repeat elongation within the AFF3 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CGG. In some embodiments, the intellectual disability associated with the fragile site FRA2A is characterized by at least 10 (e.g., at least 15, 20, 25, 50, or more) repeats of the RED codon CGG within the AFF3 gene.

[0331] In some embodiments, RED is oculopharyngeal myopathy with leukoencephalopathy (OPML). Symptoms of OPML include ptosis, ophthalmoplegia, dysphagia, dysarthria, and lower limb weakness. In some embodiments, OPML is characterized by repeat elongation within the LOC642361 gene. In some embodiments, this repeat elongation includes a repeat sequence of the RED codon CGG. In some embodiments, OPML is characterized by at least three (e.g., at least four, five, ten, fifteen, twenty, twenty-five, fifty, or more) repeats of the RED codon within the LOC642361 gene. In some embodiments, OPML is characterized by repeat elongation within the NUTM2B-AS1 gene. In some embodiments, the repeat elongation includes a repeat of the RED codon CCG. In some embodiments, OPML is characterized by at least three (e.g., at least four, five, ten, fifteen, twenty, twenty-five, fifty, or more) repeats of the RED codon within the NUTM2B-AS1 gene.

[0332] In some embodiments, RED is Huntington's disease type 2 (HDL2). HDL2 typically develops in middle age and is accompanied by a continuous, progressive triad of motor, emotional, and cognitive impairments, leading to death within 10–20 years. In some embodiments, HDL2 is characterized by repeat elongation within the JPH3 gene. In some embodiments, the repeat elongation includes repeats of the RED codon CTG. In some embodiments, HDL2 is characterized by at least 29 (e.g., at least 30, 35, 40, 45, 50, or more) repeats of the RED codon CTG within the JPH3 gene. In some embodiments, HDL2 is characterized by approximately 40–59 (e.g., approximately 45–58, 50–57, or 55–56) repeats of the RED codon CTG within the JPH3 gene.

[0333] In some embodiments, the condition is amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease that is the most common form of motor neuron disease. Symptoms of ALS include muscle weakness, muscle atrophy, and muscle spasms. In some embodiments, ALS is characterized by repeat elongation within the C9ORF72 gene. In some embodiments, the repeat elongation is a hexanucleotide repeat elongation (HRE). In some embodiments, the HRE includes repeats of the hexanucleotide sequence GGGGCC, GGCCGG, GGGCCG, CCCCGG, or CCGGCC. In some embodiments, ALS is characterized by at least three (e.g., at least four, five, 10, 15, 20, 25, 50, 100, 200, or more) repeats of a hexanucleotide sequence selected from GGGGCC, GGCCGG, GGGCCG, CCCCGG, and CCGGCC.

[0334] Treatment methods for RED In one embodiment, the present disclosure concerns a method for treating a disease or disorder in which the method involves administering a TREM (e.g., the TREMs of Figure 1, e.g., a TREM having the sequence provided by any one of SEQ ID NOs. 622-693) to a target. In one embodiment, the disease or disorder is a RED, e.g., a RED selected from Table 9.

[0335] In some embodiments, the method comprises inserting a missense mutation into the ORF of a gene, where the missense mutation results in the substitution of a RED codon by a substitution codon, and the method comprises contacting the ORF with a TREM as described herein. In some embodiments, the substitution codon corresponds to an amino acid selected from alanine (Ala), leucine (Leu), and serine (Ser). In some embodiments, the amino acid is Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the amino acid is Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the amino acid is Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0336] For example, in some embodiments, the present disclosure concerns methods for treating RED (e.g., Huntington's disease, SCA1, SCA2, SCA3, SCA7, SCA8, SCA17, DRPLA, glutaminase deficiency, and SBMA) having repeat extensions including a repeat motif (e.g., RED codon) CAG. In some embodiments, the RED codon is CAG, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is CAG, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is CAG, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is CAG, the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0337] In some embodiments, this disclosure relates to methods for treating RED (e.g., DM1, HDL2, and SCA8) having repeat extensions including a repeat motif (e.g., RED codon) CTG. In some embodiments, the RED codon is CTG, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is CTG, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is CTG, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is CTG, and the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0338] In some embodiments, this disclosure concerns methods for treating RED (e.g., FRAXA, FXPOI, FXTAS, intellectual disability associated with the fragile site FRA2A, distal oculopharyngeal myopathy type 2, and OPML) having repeat extensions including a repeat motif (e.g., RED codon) CGG. In some embodiments, the RED codon is CGG, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is CGG, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is CGG, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is CGG, and the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0339] In some embodiments, this disclosure concerns methods for treating RED (e.g., Jacobsen syndrome and OPML) having repeat extensions including a repeat motif (e.g., RED codon) CCG. In some embodiments, the RED codon is CCG, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is CCG, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is CCG, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is CCG, and the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0340] In some embodiments, this disclosure concerns methods for treating RED (e.g., MED and PSACH) having repeat extensions including a repeat motif (e.g., RED codon) GAC. In some embodiments, the RED codon is GAC, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is GAC, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is GAC, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is GAC, and the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0341] In some embodiments, the present disclosure concerns a method for treating RED (e.g., BPES, CCD, CHS, HPE, SPD1, X-linked hypopituitarism, and X-linked intellectual disability) having a repeat extension including a repeat motif (e.g., RED codon) GCN, where N is A, C, T, or G. In some embodiments, the RED codon is GCN, and the substitution codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the RED codon is GCN, and the substitution codon corresponds to Ala, and the substitution codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the RED codon is GCN, and the substitution codon corresponds to Leu, and the substitution codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the RED codon is GCN, and the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0342] In another embodiment, the method comprises inserting a missense mutation into an open reading frame (ORF) of a gene, wherein the missense mutation causes a substitution of a first or second trinucleotide sequence within a hexanucleotide repeat by a substitutional codon, and the method comprises contacting the ORF with a TREM described herein (e.g., the TREM in Figure 1, e.g., a TREM having a sequence provided by any of sequences 622-693). In one embodiment, the disease or disorder is a RED, e.g., selected from Table 9. In some embodiments, the RED is ALS, and the repeat extension sequence comprises a hexanucleotide sequence selected from GGGGCC, GGCCGG, GGGCCG, CCCCGG, and CCGGCC, wherein the first trinucleotide sequence comprises the first three nucleotides in the sequence, and the second trinucleotide sequence comprises the next three nucleotides in the sequence. For example, in some embodiments, (a) the hexanucleotide sequence is GGGGCC, the first trinucleotide sequence is GGG, and the second trinucleotide sequence is GCC; and (b) the substituted codon substitutes the first trinucleotide sequence (e.g., GGG). In some embodiments, (a) the hexanucleotide sequence is GGGGCC, the first trinucleotide sequence is GGG, and the second trinucleotide sequence is GCC; and (b) the substituted codon substitutes the second trinucleotide sequence (e.g., GCC). In some embodiments, the substituted codon corresponds to an amino acid selected from Ala, Leu, and Ser. In some embodiments, the substituted codon corresponds to Ala, and the substituted codon is selected from GCT, GCC, GCA, and GCG. In some embodiments, the substituted codon corresponds to Leu, and the substituted codon is selected from TTA, TTG, CTT, CTC, CTA, and CTG. In some embodiments, the substitution codon corresponds to Ser, and the substitution codon is selected from TCT, TCC, TCA, and TCG.

[0343] In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation (e.g., RED codon, e.g., HTT, SCA1, SCA2, SCA3, SCA7, SCA8, SCA17, DRPLA, glutaminase deficiency, and SBMA-related proteins) by administering a missense TREM to a sample (e.g., cells) or subject. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 1-fold (e.g., at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more). For example, in some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 2-fold. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 3-fold. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 4-fold. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 5-fold. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 10 times. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by 10 times or more.

[0344] In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 1% (e.g., at least 5%, 10%, 25%, 50%, 75%, or more). For example, in some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by 5%. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 10%. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 25%. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 50%. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by at least 75%. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation by more than 75%.

[0345] In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 2 hours (e.g., 3, 4, 5, 6, 10, 12, 24, 48, 72, 96 hours, or longer). For example, in some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 3 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 4 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 5 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 6 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 10 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 12 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 24 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 48 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 72 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation within 96 hours. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 96 hours.

[0346] In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 1 day (for example, 2, 3, 4, 5, 6, 7, 14, 21, or more days). For example, in some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 2 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 3 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 4 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 5 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 6 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 7 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 14 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after 21 days. In some embodiments, the method includes reducing the aggregation of proteins associated with repeat elongation after more than 21 days. In some embodiments, reducing the aggregation of proteins associated with repeat elongation includes administering one or more Leu-coded missense TREMs.

[0347] In some embodiments, reducing the aggregation of proteins associated with repeat elongation involves administering one or more Ser-coded missense TREMs.

[0348] In some embodiments, reducing the aggregation of proteins associated with repeat elongation involves administering one or more Ala-coded missense TREMs.

[0349] TREM, TREM core fragment, and method for producing TREM fragment In vitro methods for synthesizing oligonucleotides are known in the art and can be used to prepare the TREMs, TREM core fragments, or TREM fragments disclosed herein. For example, TREMs, TREM core fragments, or TREM fragments can be synthesized using solid-phase synthesis or liquid-phase synthesis.

[0350] In some embodiments, TREM, TREM core fragments, or TREM fragments prepared according to the in vitro synthesis methods disclosed herein have different modification profiles compared to TREM expressed and isolated from cells, or compared to native tRNA.

[0351] An exemplary method for preparing modified TREMs is provided in Example 1. The method provided in Example 1 can also be used to prepare synthetic TREM core fragments or synthetic TREM fragments. Further synthetic methods are disclosed in Hartsel SA et al., (2005) Oligonucleotide Synthesis, 033-050 (the entire contents of which are incorporated herein by reference).

[0352] TREM composition In some embodiments, the TREM composition, for example, the TREM pharmaceutical composition, comprises pharmaceutically acceptable excipients. Examples of excipients are provided in the FDA Inactive Ingredient Database (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.Cfm).

[0353] In one embodiment, the TREM composition, for example, the TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 grams of TREM, TREM core fragments, or TREM fragments. In one embodiment, the TREM composition, for example, the TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, or 100 milligrams of TREM, TREM core fragments, or TREM fragments.

[0354] In one embodiment, the TREM composition, for example, the TREM pharmaceutical composition, is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% by dry weight of TREM, TREM core fragments, or TREM fragments.

[0355] In one embodiment, the TREM composition is at least 1 × 10 6 A number of TREM molecules, at least 1 × 10⁶ 7 A number of TREM molecules, at least 1 × 10⁶ 8 individual TREM molecules or at least 1 × 10⁶ molecules 9 Contains individual TREM molecules.

[0356] In one embodiment, the TREM composition is at least 1 × 10 6 A number of TREM core fragment molecules, at least 1 × 10⁶ 7 A number of TREM core fragment molecules, at least 1 × 10⁶ 8 individual TREM core fragment molecules or at least 1 × 10⁶ 9 Contains individual TREM core fragment molecules.

[0357] In one embodiment, the TREM composition is at least 1 × 10 6 A number of TREM fragment molecules, at least 1 × 10⁶ 7 A number of TREM fragment molecules, at least 1 × 10⁶ 8 individual TREM fragment molecules or at least 1 × 10⁶ 9 Contains individual TREM fragment molecules.

[0358] In one embodiment, the TREM composition produced by any of the production methods disclosed herein may be loaded with amino acids using an in vitro loading reaction known in the art.

[0359] In some embodiments, the TREM composition comprises one or more species of TREM, TREM core fragments, or TREM fragments. In some embodiments, the TREM composition comprises a single species of TREM, TREM core fragment, or TREM fragment. In some embodiments, the TREM composition comprises a first species of TREM, TREM core fragment, or TREM fragment and a second species of TREM, TREM core fragment, or TREM fragment. In some embodiments, the TREM composition comprises X species of TREM, TREM core fragment, or TREM fragment, where X = 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0360] In one embodiment, the TREM, TREM core fragment, or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or 100%, identity with the nucleic acid-encoded sequence in Table 1.

[0361] In one embodiment, TREM includes a consensus sequence provided herein.

[0362] TREM compositions can be formulated as liquid compositions, lyophilized compositions, or frozen compositions.

[0363] In some embodiments, the TREM composition may be formulated to be suitable for pharmaceutical use, for example, as a pharmaceutical TREM composition. In some embodiments, the pharmaceutical TREM composition is substantially free of TREM, TREM core fragments, or materials and / or reagents used to separate and / or purify TREM fragments.

[0364] In some embodiments, the TREM composition may be formulated with water for injection. In some embodiments, the TREM composition formulated with water for injection is suitable for pharmaceutical use and includes, for example, pharmaceutical TREM compositions.

[0365] TREM Characteristic Evaluation TREM, TREM core fragments, or TREM fragments or TREM compositions, such as pharmaceutical TREM compositions, produced by any of the methods disclosed herein, may be evaluated for properties related to TREM, TREM core fragments, or TREM fragments or TREM compositions, such as purity, sterility, concentration, structure, or mechanical activity of TREM, TREM core fragments, or TREM fragments. Any of the above properties may be evaluated, for example, by evaluating or testing intermediates in the production of TREM, TREM core fragments, or TREM fragments or TREM compositions, by providing a value for the property. The value may also be compared to a standard or reference value. Depending on the evaluation, the TREM composition may be classified, for example, as ready for market, meeting production criteria for human clinical trials, conforming to ISO standards, cGMP standards, or other pharmaceutical standards. Depending on the evaluation, the TREM composition may be subjected to further processing, for example, it may be divided into fixed quantities, for example, single or multiple doses, placed in a container, for example, a vial to be ultimately used, packaged, transported, or marketed. In embodiments, depending on the evaluation, one or more features may be adjusted, processed, or reprocessed to optimize the TREM composition. For example, the TREM composition may be adjusted, processed, or reprocessed to (i) increase the purity of the TREM composition; (ii) decrease the amount of fragments in the composition; (iii) decrease the amount of endotoxin in the composition; (iv) increase the in vitro translational activity of the composition; (v) increase the TREM concentration of the composition; or (vi) inactivate or remove any viral contaminants present in the composition (for example, by lowering the pH of the composition or by filtration).

[0366] In one embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., a TREM composition or an intermediate in the production of a TREM composition) has a purity of at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by mass.

[0367] In one embodiment, the TREM (e.g., a TREM composition or an intermediate in the production of a TREM composition) has less than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, and 25% of the total TREM.

[0368] In some embodiments, TREM, TREM core fragments, or TREM fragments (e.g., TREM compositions or intermediates in the production of TREM compositions) have low levels or absence of endotoxins, resulting in a negative result, for example, as measured by a Limulus amebosite lysate (LAL) test.

[0369] In one embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., a TREM composition or an intermediate in the production of a TREM composition) has in vitro translational activity.

[0370] In one embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., a TREM composition or an intermediate in the production of a TREM composition) has a TREM concentration of at least 0.1 ng / mL, 0.5 ng / mL, 1 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL, 0.1 ug / mL, 0.5 ug / mL, 1 ug / mL, 2 ug / mL, 5 ug / mL, 10 ug / mL, 20 ug / mL, 30 ug / mL, 40 ug / mL, 50 ug / mL, 60 ug / mL, 70 ug / mL, 80 ug / mL, 100 ug / mL, 200 ug / mL, 300 ug / mL, 500 ug / mL, 1000 ug / mL, 5000 ug / mL, 10,000 ug / mL, or 100,000 ug / mL.

[0371] In one embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., a TREM composition or an intermediate in the production of a TREM composition) is sterile, and for example, the composition or preparation supports the growth of fewer than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation is USP <71> The composition or preparation meets the standards of the USP <85> It meets the standards.

[0372] In some embodiments, the TREM, TREM core fragment, or TREM fragment (e.g., a TREM composition or an intermediate in the production of a TREM composition) has undetectable levels of viral contamination, or, for example, is free of viral contamination. In some embodiments, any viral contamination present in the composition, such as residual viruses, is inactivated or removed. In some embodiments, any viral contamination, such as residual viruses, is inactivated, for example, by lowering the pH of the composition. In some embodiments, any viral contamination, such as residual viruses, is removed, for example, by filtration or other methods known in the art.

[0373] TREM administration Any TREM composition or pharmaceutical composition described herein may be administered to cells, tissues or subjects, for example, by direct administration in vitro, ex vivo, or in vivo to cells, tissues and / or organs. In vivo administration may be by local, systemic and / or parenteral routes, such as intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, ocular, nasal, urogenital, intradermal, transdermal, enteral, intravitreous, intracerebral, intrathecal, or epidural.

[0374] Vector and NT In some embodiments, the TREM, TREM core fragment, TREM fragment, or TREM composition described herein is delivered to cells, such as mammalian or human cells, using a vector. The vector may be, for example, a plasmid or a virus. In some embodiments, delivery is in vivo, in vitro, ex vivo, or in situ. In some embodiments, the virus is an adeno-associated virus (AAV), lentivirus, or adenovirus. In some embodiments, the system or components of the system are delivered to cells by virus-like particles or viromosomes. In some embodiments, delivery uses two or more viruses, virus-like particles, or viromosomes.

[0375] Carrier The TREMs, TREM compositions, or pharmaceutical TREM compositions described herein may include a carrier, be formulated together with a carrier, or be delivered within a carrier.

[0376] Viral vector The carrier may be a viral vector (e.g., a viral vector containing TREM, a TREM core fragment, or a sequence encoding a TREM fragment). The viral vector may be administered to cells or subjects (e.g., human subjects or animal models) to deliver TREM, a TREM core fragment, a TREM fragment, a TREM composition, or a pharmaceutical TREM composition.

[0377] Viral vectors can be administered systemically or locally (e.g., by injection). Viral genomes provide a rich source of vectors that can be used for the efficient delivery of foreign genes into mammalian cells. Viral genomes are known in the art as useful vectors for delivery because the polynucleotides contained within such genomes are typically incorporated into the nuclear genome of mammalian cells by universal or specific transduction. These processes occur as part of the natural viral replication cycle and do not require additional proteins or reagents to induce gene integration. Examples of viral vectors include negative-strand RNA viruses such as retroviruses (e.g., retroviridae family virus vectors), adenoviruses (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvoviruses (e.g., adeno-associated viruses), coronaviruses, and orthomyxoviruses (e.g., influenza virus), positive-strand RNA viruses such as rhabdoviruses (e.g., rabies and vesicular stomatitis viruses), paramyxoviruses (e.g., measles and Sendai virus), picornaviruses, and alphaviruses, and double-strand DNA viruses including adenoviruses, herpesviruses (e.g., herpes simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus, and replication-deficient herpesviruses), and poxviruses (e.g., vaccinia, modified vaccinia ankara (MVA), fowlpox, and canarypox). Other viruses include, for example, Norwalk virus, Togavirus, Flavivirus, Reovirus, Papovavirus, Hepadnavirus, Human papillomavirus, Human foamy virus, and Hepatitis viruses. Examples of retroviruses include avian leukemia sarcoma, avian type C virus, mammalian type C, B, and D viruses, onchoretrovirus, HTLV-BLV group, lentivirus, alpha-retrovirus, gamma-retrovirus, and spumavirus (Coffin, JM, Retroviridae: The viruses and their replication, Virology (Third Edition), Lippincott-Raven, Philadelphia, 1996).Other examples include mouse leukemia virus, mouse sarcoma virus, mouse mammalian oncovirus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, gibbon leukemia virus, Mason-Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus,...

Claims

1. A method for inserting a missense mutation into an open reading frame (ORF) of a gene, wherein the missense mutation results in the substitution of a repeat extension disorder (RED) codon by a substitute codon. The above method is given by formula (A): [L1]x - [AST Domain 1] - [L2]x - [DH Domain] - [L3]x - [ACH Domain] - [VL Domain] - [TH Domain] - [L4]x - [AST Domain 2] - [L5]x (A) (In the formula: Independently, [L1] and [VL domain] are arbitrary, and x = 0 or 1. This involves contacting a tRNA effector molecule (TREM) containing the sequence with the ORF, This provides a method for inserting the missense mutation into the ORF of the gene.

2. The method according to claim 1, wherein the RED codon includes CAG, CTG, CGG, GAC, CCG, or CTG.

3. The method according to claim 1, wherein the RED codon is selected from CAG, CTG, CGG, GAC, CCG, and CTG.

4. The method according to any one of claims 1 to 3, wherein the RED codon is CAG.

5. The method according to any one of claims 1 to 4, wherein the ORF includes at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more copies (e.g., consecutive copies) of the RED codon.

6. The method according to any one of claims 1 to 5, wherein the ORF comprises at least 10 copies (e.g., consecutive copies) of the RED codon.

7. The method according to any one of claims 1 to 6, wherein the gene is selected from HTT, ATXN1, ATXN3, DMPK, GIPC1, ARX, ATN1, AR, ATXN7, TBP, COMP, RUNX2, HOXD13, ATXN2, GLS, CBL2, AFF3, FMR1, ATXN8OS, ATXN8b, LOC642361, NUTM2b-AS1, JPH3, FOXL2, PHOX2B, ZIC2, SOX3, and C9orf72.

8. The method according to any one of claims 1 to 7, wherein the gene is selected from HTT, ATXN1, ATXN3, ATN1, AR, ATXN7, TBP, ATXN2, and GLS.

9. The method according to any one of claims 1 to 8, wherein the gene is HTT.

10. The method according to any one of claims 1 to 9, wherein the substituted codon is a codon encoding leucine, alanine, or serine.

11. The method according to any one of claims 1 to 10, wherein the substitution codon is selected from TTA, TTG, TCT, TCC, TCA, TCG, CTT, CTC, CTA, CTG, AGT, AGC, GCT, GCC, GCA, and GCG.

12. The method according to any one of claims 1 to 11, wherein the TREM includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the nucleotide sequence of the TREM shown in Figure 1.

13. The method according to any one of claims 1 to 12, wherein the TREM includes a nucleotide sequence that differs by only 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides from the nucleotide sequence of the TREM shown in Figure 1.

14. The method according to any one of claims 1 to 13, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 10, 15, 20, 25, 30, 35, or 40 nucleotides.

15. The method according to any one of claims 1 to 14, wherein the TREM includes a nucleotide sequence that is more than 5 nucleotides different from the nucleotide sequence of the TREM shown in Figure 1.

16. The method according to any one of claims 1 to 15, wherein the TREM includes a nucleotide sequence that is more than 10 nucleotides different from the nucleotide sequence of the TREM shown in Figure 1.

17. The method according to any one of claims 1 to 16, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

18. The method according to any one of claims 1 to 17, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 10, 15, 20, 25, 30, 35, or 40 nucleotides.

19. The method according to any one of claims 1 to 18, wherein the TREM includes a nucleotide sequence that differs by only one nucleotide from the nucleotide sequence of the TREM shown in Figure 1.

20. The method according to any one of claims 1 to 19, wherein the TREM includes a nucleotide sequence that differs by only 5 nucleotides from the nucleotide sequence of the TREM shown in Figure 1.

21. The method according to any one of claims 1 to 20, wherein the TREM includes a nucleotide sequence that differs by only 10 nucleotides from the nucleotide sequence of the TREM shown in Figure 1.

22. The method according to any one of claims 1 to 21, wherein the substitution of a RED codon with a substitution codon results in the alleviation of symptoms of a disease, disorder, or condition.

23. The method according to claim 22, wherein the disease, disorder, or condition is, for example, a repeat extension disease from one of the diseases listed in Table 9.

24. The method according to claim 23, wherein the repeat elongation disease is selected from Huntington's disease, spinocerebellar degeneration type 1, spinocerebellar degeneration type 2, spinocerebellar degeneration type 3, and myotonic dystrophy type 1.

25. The method according to claim 23 or 24, wherein the repeat extension disease is Huntington's disease.

26. The method according to any one of claims 1 to 25, wherein the TREM can insert a RED codon into the ORF of a gene with an efficiency of, for example, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 99.9% compared to a reference TREM.

27. The method according to any one of claims 1 to 26, wherein the TREM can adjust its functional parameters.

28. The method according to claim 27, wherein the adjustment includes improvement of a functional parameter.

29. The method according to claim 28, wherein the improvement includes, for example, an improvement of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to a reference standard.

30. The method according to claim 29, wherein the adjustment includes a reduction in a functional parameter.

31. The method according to claim 30, wherein the reduction includes, for example, a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to a reference standard.

32. The method according to any one of claims 27 to 31, wherein the functional parameter is an expression parameter or a signal transduction parameter.

33. The expression parameters are as follows: (a) Protein translation; (b) Expression level (e.g., of polypeptides or proteins, or of mRNAs); (c) Post-translational modification of polypeptides or proteins; (d) Folding (e.g., of polypeptides or proteins, or mRNA), (e) Structure (e.g., polypeptide or protein, or mRNA), (f) Transduction (e.g., of polypeptides or proteins), (g) Computation (e.g., of polypeptides or proteins, or mRNA), (h) Incorporation into supramolecular structures (e.g., polypeptides or proteins or mRNA), e.g., incorporation into membranes, proteasomes or ribosomes, (i) Incorporation into a polymer polypeptide, e.g., a homodimer or heterodimer, and / or (j) Stability The method according to claim 32, selected from the above.

34. The aforementioned signal transduction parameters are as follows: (1) Regulation of signaling pathways, such as cellular signaling pathways, downstream or upstream of the protein encoded by an endogenous ORF having a first sequence; (2) Regulation of cell fate; (3) Regulation of ribosome occupation; (4) Regulation of protein translation; (5) mRNA stability regulation; (6) Protein folding and structural regulation; (7) Protein transduction or compartmentalization control; and / or (8) Regulation of protein stability The method according to claim 32, selected from the above.

35. The method according to any one of claims 1 to 34, wherein the TREM includes non-natural modifications.

36. The method according to claim 35, wherein the unnatural modification is located at the 2' position of the nucleotide sugar or within the internucleotide region (for example, a skeletal modification).

37. The method according to claim 35 or 36, wherein the non-natural modification is selected from 2'-O-methyl (2'-OMe), 2'-halo (e.g., 2'-F or 2'-Cl), 2'-O-methoxyethyl (2'-MOE), or 2'-deoxy modification.

38. The method according to any one of claims 35 to 37, wherein the unnatural modification is a phosphorothioate modification.

39. The method according to any one of claims 35 to 38, wherein the TREM includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more unnatural modifications.

40. The method according to any one of claims 22 to 26, wherein the TREM comprises 5, 10, 15, 20, 25, 30, 35, 40, 45 or more unnatural modifiers.

41. The method according to any one of claims 1 to 40, wherein the TREM has an array selected from the arrays shown in Figure 1.

42. The method according to any one of claims 1 to 41, wherein the TREM includes a sequence selected from: TREM number 3 (sequence number 627), TREM number 4 (sequence number 628), TREM number 5 (sequence number 629), TREM number 6 (sequence number 630), TREM number 7 (sequence number 631), TREM number 9 (sequence number 633), and TREM number 11 (sequence number 635).

43. The method according to any one of claims 1 to 42, wherein the non-natural modification is located at a nucleotide position corresponding to one or more of nucleotide positions 1 to 76 according to CtNS.

44. A TREM having the nucleotide sequence shown in Figure 1 (for example, a TREM having one of sequence numbers 625 to 693).

45. The TREM according to claim 44, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides.

46. The TREM according to claim 44 or 45, wherein the TREM includes a nucleotide sequence that differs from the TREM shown in Figure 1 by only 10, 15, 20, 25, 30, 35, or 40 nucleotides.

47. The TREM according to any one of claims 44 to 46, wherein the TREM includes a nucleotide sequence that is more than 5 nucleotides different from the nucleotide sequence of the TREM shown in Figure 1.

48. The TREM according to any one of claims 44 to 47, wherein the TREM includes a nucleotide sequence that is more than 10 nucleotides different from the nucleotide sequence of the TREM shown in Figure 1.

49. The TREM according to any one of claims 44 to 48, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

50. The TREM according to any one of claims 44 to 49, wherein the TREM includes a nucleotide sequence that differs from the nucleotide sequence of the TREM shown in Figure 1 by only 10, 15, 20, 25, 30, 35, or 40 nucleotides.

51. The TREM according to any one of claims 44 to 50, wherein the TREM includes a nucleotide sequence that differs by only one nucleotide from the nucleotide sequence of the TREM shown in Figure 1.

52. The TREM according to any one of claims 44 to 51, wherein the TREM includes a nucleotide sequence that differs by only 5 nucleotides from the nucleotide sequence of the TREM shown in Figure 1.

53. The TREM according to any one of claims 44 to 52, wherein the TREM includes a nucleotide sequence that differs by only 10 nucleotides from the nucleotide sequence of the TREM shown in Figure 1.

54. The TREM according to any one of claims 44 to 53, wherein the TREM can insert a missense mutation into the open reading frame (ORF) of a gene, and the missense mutation results in the substitution of a repeat extension disorder (RED) codon by a substituted codon.

55. The TREM according to claim 54, wherein the RED codon includes CAG, CTG, CGG, GAC, CCG, or CTG.

56. The TREM according to claim 54 or 55, wherein the RED codon is selected from CAG, CTG, CGG, GAC, CCG, and CTG.

57. The TREM according to any one of claims 54 to 56, wherein the RED codon is CAG.

58. The TREM according to any one of claims 54 to 57, wherein the ORF includes at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more copies (e.g., consecutive copies) of the RED codon.

59. The TREM according to any one of claims 54 to 58, wherein the ORF includes at least 10 copies (e.g., consecutive copies) of the RED codon.

60. The TREM according to any one of claims 54 to 59, wherein the gene is selected from the following: HTT, ATXN1, ATXN3, DMPK, GIPC1, ARX, ATN1, AR, ATXN7, TBP, COMP, RUNX2, HOXD13, ATXN2, GLS, CBL2, AFF3, FMR1, ATXN8OS, ATXN8b, LOC642361, NUTM2b-AS1, JPH3, FOXL2, PHOX2B, ZIC2, SOX3, and C9orf72.

61. The TREM according to any one of claims 54 to 60, wherein the gene is selected from HTT, ATXN1, ATXN3, ATN1, AR, ATXN7, TBP, ATXN2, and GLS.

62. The TREM according to any one of claims 54 to 61, wherein the gene is HTT.

63. The TREM according to any one of claims 54 to 62, wherein the substituted codon is a codon encoding leucine, alanine, or serine.

64. The TREM according to any one of claims 54 to 63, wherein the substitution codon is selected from TTA, TTG, TCT, TCC, TCA, TCG, CTT, CTC, CTA, CTG, AGT, AGC, GCT, GCC, GCA, and GCG.

65. A pharmaceutical composition comprising TREM as described in any one of claims 44 to 64.

66. The pharmaceutical composition according to claim 65, further comprising pharmaceutically acceptable components, for example, excipients.

67. A lipid nanoparticle formulation comprising TREM according to any one of claims 44 to 64.

68. A lipid nanoparticle formulation comprising the pharmaceutical composition according to claim 67.

69. A method for treating a subject having a repeat extension disorder, comprising administering to the subject a TREM, a TREM core fragment, or a TREM fragment (for example, the TREM described in any one of claims 44 to 64) as described herein, thereby treating the subject having a repeat extension disorder.

70. The method according to claim 69, wherein the repeat elongation disease is selected from the diseases listed in Table 9.

71. The method according to claim 69, wherein the repeat elongation disease is selected from Huntington's disease, spinocerebellar degeneration type 1, spinocerebellar degeneration type 2, spinocerebellar degeneration type 3, and myotonic dystrophy type 1.

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