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  • C12N15/09—Recombinant DNA-technology
  • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
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  • C12N2310/00—Structure or type of the nucleic acid
  • C12N2310/10—Type of nucleic acid
  • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]

Definitions

• TnpB protein comprises any one of SEQ ID NOs: 1-49670, 53610-53844, 53898- 53921, 53996-57559, 57560-61736, 61767-61781, or 61815-228194, a TnpB protein sequence in any one of Tables 10-12, 14-23, or 25-31, or a TnpB protein sequence coded by a sequence in Table 4.
• a length of the scaffold is from 50 to 200 nucleotides, or 50 to 150 nucleotides.
• the donor polynucleotide introduces one or more mutations to the target polynucleotide; corrects a premature stop codon in the target polynucleotide; disrupts a splicing site; restores a splicing site; or a combination thereof.
• the one or more mutations introduced by the donor polynucleotide comprises substitutions, deletions, insertions, or a combination thereof.
• the one or more mutations causes a shift in an open reading frame on the target polynucleotide.
• the guide molecule is capable of sequence-specific binding the target polynucleotide in a prokaryotic cell, eukaryotic cell, a virus, or a combination thereof.
• the TnpB protein comprises any one of SEQ ID NOs: 1-49670, 53610-53844, 53898-53921, 53996-57559, 57560-61736, 61767-61781, or 61815-228194, a TnpB protein sequence in any one of Tables 10-12, 14-23, or 25-31, or a TnpB protein sequence coded by a sequence in Table 4.
• the guide molecule comprises any one of SEQ ID NOs: 49671-53376, 53922- 53995, or 61782-61814, or a scaffold sequence in Tables 4, 13, 24, or 32.
• the full nucleic acid sequences (TnpB ORF and scaffold) of the examples in Table 3A include SEQ ID NOs: 61737-61751.
• the nucleic acid sequences of the TnpBs in Table 3A include SEQ ID NOs: 61752-61766.
• the sequences of the TnpBs in Table 3A are SEQ ID NOs: 61767-
• the hADAR2- D has a sequence comprising amino acid 299-701 of hADAR2, e.g., amino acid 299-701 of the sequence under Accession No. AF525422.1.
• the system comprises a mutated form of an adenosine deaminase fused with a dead TnpB or TnpB nickase.
• the mutated form of the adenosine deaminase may have both adenosine deaminase and cytidine deaminase activities.
• the adenosine deaminase may comprise one or more of the mutations: E488Q based on amino acid sequence positions of hADAR2, and mutations in a homologous ADAR protein corresponding to the above. In some embodiments, the adenosine deaminase may comprise one or more of the mutations: E488Q, V351G, based on amino acid sequence positions of hADAR2, and mutations in a homologous ADAR protein corresponding to the above.
• the adenosine deaminase may comprise one or more of the mutations: E488Q, V351G, S486A, T375S, S370C, P462A, N597T, L332T, 1398V, K350I, M383L, D619G, S582T, V440I based on amino acid sequence positions of hADAR2, and mutations in a homologous ADAR protein corresponding to the above.
• a mutated adenosine deaminase e.g., an adenosine deaminase comprising E488Q and Q696L based on amino acid sequence positions of hADAR2, and mutations in a homologous ADAR protein corresponding to the above, fused with a dead -TnpB protein or a TnpB nickase.
• the adenosine deaminase may comprise one or more of the mutations: A 106V, D108N, D147Y, E155V, L84F, H123Y, I156F, H36L, R51L, S146C, K157N, P48S, W23R, P48A, based on amino acid sequence positions of E. coli TadA, and mutations in a homologous deaminase protein corresponding to the above.
• transposases examples include those described in Barabas, O., Ronning, D.R., Guynet, C., Hickman, A.B., TonHoang, B., Chandler, M. and Dyda, F. (2008) Mechanism of IS200/ IS605 family DNA transposases: activation and transposon-directed target site selection. Cell, 132, 208-220; in Sadler et al., Genes 2020, 11, 484, doi: 10.3390/genesl 1050484, and in He et al., (2013) NAR, 41:5, 3302-3313.
• the transposase is a single stranded DNA transposase.
• the single stranded DNA transposase is TnpA or a functional fragment thereof.
• the systems and compositions herein may comprise a TnpB-guide system, and one or more components of a recombinase or integrase.
• the TnpB is naturally catalytically inactive and utilized with one or more nucleic acid components to provide site-specific targetings, and the one or more components of the recombinase to introduce a modification.
• the TnpB protein may be catalytically inactivated via mutation of one or more residues of a catalytic domain (e.g. RuvC) or via truncation, and utilized with one or more nucleic acid components to provide site-specific targeting, and the one or more components of the recombinase introduce a modification.
• a naturally inactive TnpB is provided with a recombinase, e.g. an integrase, and optionally a reverse transcriptase.
• the systems and compositions herein may comprise a TnpB protein, one or more nucleic acid components, and one or more components of an integrase.
• the TnpB protein is a nickase, and utilized with one or more nucleic acid components to provide site-specific targeting, with the one or more components of the integrase introduce a modification.
• the systems and compositions may be used to insert a donor polynucleotide to a target polynucleotide.
• the systems and compositions may further comprise a donor polynucleotide.
• a mutant Vaccinia topoisomerase which is mutated in the amino terminal domain (e.g., at amino acid residues 70 and 72) may display identical properties as the full length topoisomerase.
• Mutation analysis of Vaccinia type IB topoisomerase reveals a large number of amino acid residues that can be mutated without affecting the activity of the topoisomerase, and has identified several amino acids that are required for activity.
• Nucleic acid molecules such as those comprising a cDNA library, or restriction fragments, or sheared genomic DNA sequences that are to be cloned into such a vector are treated, for example, with a phosphatase to produce 5' hydroxyl termini, then are added to the linearized vector under conditions that allow the topoisomerase to ligate the nucleic acid molecules at the 5' terminus containing the hydroxyl group and the 3' terminus containing the covalently bound topoisomerase.
• the protein component of the non-LTR retrotransposon may be connected to or otherwise engineered to form a complex with a site-specific nuclease, e.g. TnpB protein.
• the retrotransposon RNA may be engineered to encode a donor polynucleotide sequence.
• the TnpB protein via formation of a TnpB protein complex with a nucleic acid component molecule sequence, directs the retrotransposon complex (e.g.
• the reverse transcriptase domain is a retron RT domain.
• the RNA template encodes a retron RNA template that is recognized and reverse transcribed by the retron reverse transcriptase domain. conserveed across many bacterial species, retrons are highly efficient reverse transcription systems of relatively unknown function.
• the retron system consists of the retron RT protein, as well as the msr and msd transcripts, which function as the primer and template sequences, respectively.
• the one or more functional domains may be one or more topoisomerase domains.
• an engineered system for modifying a target polynucleotide comprising: a TnpB protein; a topoisomerase domain; and a nucleic acid template comprising or encoding a donor polynucleotide to be inserted to a target sequence of the target polynucleotide.
• two or more of: the TnpB protein; topoisomerase domain; and nucleic acid template may form a complex.
• two or more of: the TnpB protein; topoisomerase domain may be comprised in a fusion protein.
• PBCV-1 DNA Ligase or Chlorella virus DNA Ligase Thermostable 5' AppDNA/RNA Ligase, T4 RNA Ligase, T4 RNA Ligase 2, T4 RNA Ligase 2 Truncated, T4 RNA Ligase 2 Truncated K227Q, T4 RNA Ligase 2, Truncated KQ, RtcB Ligase (joins single stranded RNA with a 3 "-phosphate or 2', 3 '-cyclic phosphate to another RNA), CircLigase II, CircLigase ssDNA Ligase, CircLigase RNA Ligase, or Ampligase® Thermostable DNA Ligas, NAD-dependent ligases including Taq DNA ligase, Thermus filiformis DNA ligase, Escherichia coliDNA ligase, Tth DNA ligase, Thermus scotoductus DNA ligase (I and II), thermos
• the TnpB polypeptides, compositions, systems or complexes as defined herein provides an effective means for modifying multiple target polynucleotides.
• the TnpB protein, system or complex as defined herein has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) one or more target polynucleotides in a multiplicity of cell types.
• modifying e.g., deleting, inserting, translocating, inactivating, activating
• the TnpB protein, system or complex as defined herein of the invention has a broad spectrum of applications in, e.g., gene therapy, drug screening, disease diagnosis, and prognosis, including targeting multiple gene loci within a single system.
• the guide molecule comprises non-naturally occurring nucleic acids and/or non-naturally occurring nucleotides and/or nucleotide analogs, and/or chemically modifications.
• these non-naturally occurring nucleic acids and non-naturally occurring nucleotides are located outside the guide sequence.
• Non-naturally occurring nucleic acids can include, for example, mixtures of naturally and non-naturally occurring nucleotides.
• Non-naturally occurring nucleotides and/or nucleotide analogs may be modified at the ribose, phosphate, and/or base moiety.
• the guide molecule may comprise portions that are chemically linked or conjugated via a non- phosphodiester bond.
• the guide comprises, in non-limiting examples, direct repeat sequence portion and a targeting sequence portion that are chemically linked or conjugated via a non-nucleotide loop.
• the portions are joined via a non-phosphodi ester covalent linker.
• suitable spacers include, but are not limited to, polyethers (e.g., polyethylene glycols, polyalcohols, polypropylene glycol or mixtures of efhylene and propylene glycols), polyamines group (e.g., spennine, spermidine and polymeric derivatives thereof), polyesters (e.g., poly(ethyl acrylate)), polyphosphodi esters, alkylenes, and combinations thereof.
• Suitable attachments include any moiety that can be added to the linker to add additional properties to the polynucleotide linker, such as but not limited to, fluorescent labels.
• a naturally occurring nucleotide is replaced by a nucleotide analog.
• Another way to modulate stem-loop formation or change the equilibrium between stem-loop and intermolecular duplex is to modify the loop of the stem-loop of a guide molecule.
• the loop can be viewed as an intervening sequence flanked by two sequences that are complementary to each other. When that intervening sequence is not self-complementary, its effect will be to destabilize intermolecular duplex formation.
• guides are multiplexed: while the targeting sequences may differ, it may be advantageous to modify the stemloop region in the guide molecules of the different guides.
• three to five nucleotides at the 5’ and/or the 3’ end of the guide are chemically modified with 2’- O-methyl (M), 2’-O-methyl-3’-phosphorothioate (MS), S- constrained ethyl(cEt), or 2’-O-methyl- 3 ’-thioPACE (MSP).
• M 2’- O-methyl
• MS 2’-O-methyl-3’-phosphorothioate
• cEt S- constrained ethyl
• MSP 2’-O-methyl- 3 ’-thioPACE
• PS phosphorothioates
• the guide RNA is designed such that the SNP is located on position 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, or 30 of the spacer sequence (starting at the 5’ end). In certain embodiments, the guide RNA is designed such that the SNP is located on position 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the spacer sequence (starting at the 5’ end). In certain embodiments, the guide RNA is designed such that the SNP is located on position 2, 3, 4, 5, 6, or 7of the spacer sequence (starting at the 5’ end).
• the invention contemplates energy sources such as electromagnetic radiation, sound energy or thermal energy to induce the guide.
• the electromagnetic radiation is a component of visible light.
• the light is a blue light with a wavelength of about 450 to about 495 nm.
• the wavelength is about 488 nm.
• the light stimulation is via pulses.
• the light power may range from about 0-9 mW/cm2.
• a stimulation paradigm of as low as 0.25 sec every 15 sec should result in maximal activation.
• a method for designing highly active guide molecules, e.g., guide RNAs, for use in the detection systems may comprise the steps of designing putative guide RNAs tiled across a target molecule of interest; creating a training model based on results of incubating guide RNAs with a TnpB protein and the target molecule; predicting highly active guide RNAs for the target molecule, wherein the predicting comprises optimizing the nucleotide at each base position in the guide RNA based on the training model; and validating the predicted highly active guide RNAs by incubating the guide RNAs with the TnpB protein and the target molecule.
• the method can be as described in U.S. Provisional Application Nos. 62/818,702 and 62/890,555 incorporated by reference in their entireties.
• Guide RNAs generate by the design methods can be used with the systems for detecting coronavirus as described elsewhere herein.
• Unsupervised learning concepts may include; Expectation-maximization algorithm; Vector Quantization; Generative topographic map; Information bottleneck method; Artificial neural network, such as Self-organizing map; Association rule learning, such as, Apriori algorithm, Eclat algorithm, and FP-growth algorithm; Hierarchical clustering, such as Single-linkage clustering and Conceptual clustering; Cluster analysis, such as, K-means algorithm, Fuzzy clustering, DBSCAN, and OPTICS algorithm; and Outlier Detection, such as Local Outlier Factor.
• Semi-supervised learning concepts may include; Generative models; Low-density separation; Graph-based methods; and Co-training.
• Reinforcement learning concepts may include; Temporal difference learning; Q-learning; Learning Automata; and S ARSA.
• Deep learning concepts may include; Deep belief networks; Deep Boltzmann machines; Deep Convolutional neural networks; Deep Recurrent neural networks; and Hierarchical temporal memory.
• the amount of gene product expressed may be greater than or less than the amount of gene product from a cell that does not have altered expression or edited genome.
• the gene product may be altered in comparison with the gene product from a cell that does not have altered expression or edited genome.
• the first guide RNA can target any target sequence of interest within a genome, as described elsewhere herein.
• the second guide RNA targets a sequence within the vector which encodes the TnpB, and thereby inactivates the enzyme’s expression from that vector.
• the target sequence in the vector must be capable of inactivating expression.
• promoters include one or more pol III promoter (e.g., 1, 2, 3, 4, 5, or more pol III promoters), one or more pol II promoters (e.g., 1, 2, 3, 4, 5, or more pol II promoters), one or more pol I promoters (e.g., 1, 2, 3, 4, 5, or more pol I promoters), or combinations thereof.
• pol III promoters include, but are not limited to, U6 and Hl promoters.
• NHEJ is a mutagenic process, it may also be used to delete small sequence motifs as long as the generation of a specific final sequence is not required. If a double-strand break is targeted near to a short target sequence, the deletion mutations caused by the NHEJ repair often span, and therefore remove, the unwanted nucleotides. For the deletion of larger DNA segments, introducing two double-strand breaks, one on each side of the sequence, can result in NHEJ between the ends with removal of the entire intervening sequence. Both of these approaches can be used to delete specific DNA sequences; however, the error-prone nature of NHEJ may still produce indel mutations at the site of repair.
• the systems herein may introduce one or more indels via NHEJ pathway and insert sequence from a combination template via HDR.
• a method of treating a subject comprising inducing transcriptional activation or repression of multiple target gene loci by transforming the subject with the polynucleotides or vectors described herein, wherein said polynucleotide or vector encodes or comprises one or more components of composition, system, complex or component thereof comprising multiple TnpB proteins.
• a subject e.g., a subject in need thereof, comprising inducing transcriptional activation or repression of multiple target gene loci by transforming the subject with the polynucleotides or vectors described herein, wherein said polynucleotide or vector encodes or comprises one or more components of composition, system, complex or component thereof comprising multiple TnpB proteins.
• a eukaryotic or prokaryotic cell or component thereof e.g. a mitochondria
• the modification can include the introduction, deletion, or substitution of one or more nucleotides at a target sequence of a polynucleotide of one or more cell(s).
• the modification can occur in vitro, ex vivo, in situ, or in vivo.
• early coding region of a gene of interest includes sequence immediately following a transcription start site, within a first exon of the coding sequence, or within 500 bp of the transcription start site (e.g., less than 500, 450, 400, 350, 300, 250, 200, 150, 100 or 50 bp).
• a guide RNA and TnpB protein may be configured to position one double-strand break in close proximity to a nucleotide of the target position.
• Exemplary cells that are capable of differentiating into a hair cell include, but are not limited to stem cells (e.g., inner ear stem cells, adult stem cells, bone marrow derived stem cells, embryonic stem cells, mesenchymal stem cells, skin stem cells, iPS cells, and fat derived stem cells), progenitor cells (e.g., inner ear progenitor cells), support cells (e.g., Deiters' cells, pillar cells, inner phalangeal cells, tectal cells and Hensen's cells), and/or germ cells.
• stem cells e.g., inner ear stem cells, adult stem cells, bone marrow derived stem cells, embryonic stem cells, mesenchymal stem cells, skin stem cells, iPS cells, and fat derived stem cells
• progenitor cells e.g., inner ear progenitor cells
• support cells e.g., Deiters' cells, pillar cells, inner phalangeal cells, tectal cells and Hen
• the system set forth in Mukherjea et al. can be adapted for transtympanic administration of the composition, system, or component thereof to the ear.
• the system set forth in [Jung et al. can be adapted for vestibular epithelial delivery of the composition, system, or component thereof to the ear. Treating Diseases in Non-Dividing Cells
• the sd-rxRNA® system of RXi Pharmaceuticals may be used/and or adapted for delivering composition, system, to the eye.
• a single intravitreal administration of 3 pg of sd-rxRNA results in sequence-specific reduction of PPIB mRNA levels for 14 days.
• the sd-rxRNA® system may be applied to the nucleic acid-targeting system, contemplating a dose of about 3 to 20 mg of TnpB-guide administered to a human.
• the high levels of expression seen from the albumin promoter/enhancer allows for useful levels of correct or transgene production (from the inserted recombination template) to be achieved even if only a small fraction of hepatocytes are edited. See sites identified by Wechsler et al. (reported at the 57th Annual Meeting and Exposition of the American Society of Hematology - abstract available online at ash. confex.com/ash/2015/webprogram/Paper86495.html and presented on 6th December 2015) which can be adapted for use with the compositions, systems, herein.
• the transmembrane domain of a CAR may be derived either from a natural or from a synthetic source. Where the source is natural, the domain may be derived from any membrane bound or transmembrane protein. Transmembrane regions of particular use in this disclosure may be derived from CD8, CD28, CD3, CD45, CD4, CD5, CDS, CD9, CD 16, CD22, CD33, CD37, CD64, CD80, CD86, CD 134, CD137, CD 154, TCR. Alternatively, the transmembrane domain may be synthetic, in which case it will comprise predominantly hydrophobic residues such as leucine and valine.
• a CAR comprising (a) a zeta chain portion comprising the intracellular domain of human CD3 ⁇ chain, (b) a costimulatory signaling region, and (c) an antigen-binding element (or portion or domain), wherein the costimulatory signaling region comprises the amino acid sequence encoded by SEQ ID NO: 6 of US 7,446,190.
• chimeric antigen receptor that recognizes the CD70 antigen is described in W02012058460A2 (see also, Park et al., CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma, Oral Oncol. 2018 Mar;78: 145-150; and Jin et al., CD70, a novel target of CAR T-cell therapy for gliomas, Neuro Oncol. 2018 Jan 10;20(l):55-65).
• CD70 is expressed by diffuse large B-cell and follicular lymphoma and also by the malignant cells of Hodgkin’s lymphoma, Waldenstrom's macroglobulinemia and multiple myeloma, and by HTLV-1- and EBV-associated malignancies.
• CD70 is expressed by non-hematological malignancies such as renal cell carcinoma and glioblastoma.
• non-hematological malignancies such as renal cell carcinoma and glioblastoma.
• Physiologically, CD70 expression is transient and restricted to a subset of highly activated T, B, and dendritic cells.
• ACT includes co-transferring CD4+ Thl cells and CD8+ CTLs to induce a synergistic antitumor response (see, e.g., Li et al., Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumor, leading to generation of endogenous memory responses to non-targeted tumor epitopes. Clin Transl Immunology. 2017 Oct; 6(10): el 60).
• the treatment can be administered after lymphodepleting pretreatment in the form of chemotherapy (typically a combination of cyclophosphamide and fludarabine) or radiation therapy.
• chemotherapy typically a combination of cyclophosphamide and fludarabine
• ACT cyclophosphamide and fludarabine
• transgenes in particular CAR or exogenous TCR transgenes
• loci comprising genes coding for constituents of endogenous T-cell receptor, such as T-cell receptor alpha locus (TRA) or T-cell receptor beta locus (TRB), for example T-cell receptor alpha constant (TRAC) locus, T-cell receptor beta constant 1 (TRBC1) locus or T-cell receptor beta constant 2 (TRBC1) locus.
• TRA T-cell receptor alpha locus
• TRB T-cell receptor beta locus
• TRBC1 locus T-cell receptor beta constant 1 locus
• TRBC1 locus T-cell receptor beta constant 2 locus
• editing of cells may be performed to knock-out or knock-down expression of an endogenous TCR in a cell.
• NHEJ-based or HDR-based gene editing approaches can be employed to disrupt the endogenous TCR alpha and/or beta chain genes.
• gene editing system or systems can be designed to target a sequence found within the TCR beta chain conserved between the beta 1 and beta 2 constant region genes (TRBC1 and TRBC2) and/or to target the constant region of the TCR alpha chain (TRAC) gene.

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