Phase separation-based drug depots

Abstract

The invention relates to a drug depot using liquid-liquid phase separation (LLPS) by a macromolecule or macromolecular complex comprising an intrinsically disordered region (IDR) and at least one therapeutically active substance.

Description

[0001] Phase-separated drug depots

[0002] Description

[0003] Field of invention

[0004] The invention relates to a drug depot based on phase separation, as well as a macromolecule or macromolecule complex for forming such a drug depot.

[0005] Liquid-liquid phase separation (LLPS) is a phenomenon that occurs in living cells in which a macromolecule, upon reaching its solubility limit, splits into two distinct liquid phases. A condensate phase forms, consisting of droplets with a high concentration of the macromolecule, and a dilute phase, also called the soluble phase, forms, in which the concentration of the macromolecule is equal to its solubility limit. Riback JA, Brangwynne CP. Can phase separation buffer cellular noise? Science (80-). 2020; 367(6476): 364-365. doi: 10.1126 / sci-ence.aba0446; Shin Y, Brangwynne CP. Liquid phase condensation in cell physiology and disease. Science (80-).

[0006] 2017; 357 ( 6357 ): eaaf 4382. doi: 10. 1126 / science. aaf 4382 ). One of the proposed functions of such condensates in cells is the buffering of biomolecule concentrations. Since the phase separation of a biomolecule occurs above its solubility limit, a further increase in concentration beyond this point leads to an increase in droplet size and / or number, while the concentration in the dilute phase remains constant (Riback JA, Brangwynne CP. Can phase separation buffer cellular noise? Science (80-). 2020; 367 (6476): 364-365. doi: 10.1126 / science.aba0446; Klosin A, Oltsch F, Harmon T, et al. Phase separation provides a mechanism to reduce noise in cells. Science (80-). 2020; 367 (6476): 464-468. doi: 10.1126 / science.aav6691). Certain biomacromolecules, such as... For example, some proteins and nucleic acids tend to undergo LLPS.For example, it has been shown that proteins with intrinsically disordered regions (IDRs) exhibit a high tendency for phase separation (Schuster BS, Dignon G, Jahnke C, Good MC, Hammer DA, Mittal J. Sequence Determinants of Protein Phase Separation of the Intrinsically Disordered RGG Domain from LAF-1. Biophys J.

[0007] 2019; 116 (3): 453a-454a. doi: 10. 1016 / j. bp j. 2018. 11. 2447; Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP. Spatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets. Cell. 2017; 168 (1-2): 159-171. el4. doi: 10. 1016 / j. cell. 2016. 11. 054 ).

[0008] At the same time, there is the problem that therapeutically active substances must be administered in a specific quantity over a longer period. This often requires frequent injections, also to avoid exceeding the maximum dose. Alternatively, depots can be created using carrier systems, such as lipid shells. However, this requires additional degradation of these carrier systems in the body and can lead to further side effects.

[0009] The task is seen as providing a depot for at least one therapeutically active substance, which allows the release of at least one substance over a longer period of time.

[0010] This problem is solved by the inventions with the features of the independent claims. Advantageous embodiments of the inventions are characterized in the dependent claims. The wording of all claims is hereby incorporated by reference into the content of this description. The inventions also include all meaningful and, in particular, all mentioned combinations of independent and / or dependent claims.

[0011] "Identity" or "percent identity" refers to the degree of similarity between two nucleic acid or protein sequences. In sequence comparison, one sequence typically serves as a reference sequence against which the test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, partial sequence coordinates are optionally specified, and program parameters for the sequence algorithm are defined. The sequence comparison algorithm then calculates the percentage sequence identity for the test sequence(s) relative to the reference sequence based on the specified program parameters.The term "essentially identical" in the context of two nucleic acids or two amino acid sequences refers to two or more sequences or subsequences that exhibit at least approximately 50% nucleotide or amino acid residue identity when compared and aligned for maximum similarity, as measured by one of the following sequence comparison algorithms or by visual inspection. In certain implementations, essentially identical sequences exhibit at least approximately 60%, or at least approximately 70%, or at least approximately 80%, or at least approximately 85%, or even at least approximately 90% or 95% nucleotide or amino acid residue identity. In certain implementations, substantial identity exists over a region of the sequences that is at least approximately 50 residues long, or over a region of at least approximately 100 residues, or the sequences are essentially identical over at least approximately 150 residues.In other implementation forms, the sequences are essentially identical if they are identical over the entire length of the coding regions.

[0012] Optimal alignment of the sequences to be compared can be achieved, for example, using the local homology algorithm by Smith & Waterman, Adv. Appl. Math. 2: 482 (1981), the homology alignment algorithm by Needleman & Wunsch, J. Mol. Biol. 48: 443 (1970), the similarity search method by Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85: 2444 (1988), computer-aided implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by visual inspection.

[0013] An example of an algorithm suitable for determining percentage sequence identity and sequence similarity is the BLAST algorithm, mentioned in Altschul et al., J. Mol. Biol. 215: 403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm first identifies high-scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence that either match a word of the same length in a database sequence or satisfy a positively scored threshold T when aligned with that word. T is referred to as the neighborhood word score threshold (Altschul et al., 1990). These initial neighborhood word matches serve as a starting point for searching for longer HSPs containing these words.Word matches are then extended in both directions along each sequence as far as the cumulative alignment score can be increased. For nucleotide sequences, the cumulative results are calculated using the parameters M (reward value for a matching residue pair; always > 0) and N (penalty value for mismatched residues; always < 0). For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. The extension of word matches in either direction stops when the cumulative alignment score deviates by the amount X from its maximum achieved value, the cumulative score falls to zero or below due to the accumulation of one or more negatively scored residue alignments, or the end of either sequence is reached. The parameters W, T, and X of the BLAST algorithm determine the sensitivity and speed of the alignment.The BLASTN program (for nucleotide sequences) uses as its default values ​​a word length (W) of 11, an expectation (E) of 10, a cutoff of 100, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses by default a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 evaluation matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89: 10915 (1989)).

[0014] In addition to calculating the percentage sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Natl. Acad. Sci. USA 90: 5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which indicates the probability that a match between two nucleotide or amino acid sequences would occur by chance. For example, a test nucleic acid sequence is considered similar to a reference sequence if the smallest sum probability when comparing the test nucleic acid sequence with the reference nucleic acid sequence is less than about 0.1, preferably less than about 0.01, and most preferably less than about 0.001.

[0015] Another indication that two nucleic acids are essentially identical is the fact that the two molecules hybridize to each other under strict conditions. The term "specifically hybridize with" refers to the binding, duplex formation, or hybridization of a molecule with only a specific nucleotide sequence under strict conditions when that sequence is present in a complex mixture (e.g., all of cellular) DNA or RNA. "Binding(s) essentially" refers to the complementary hybridization between a probe nucleic acid and a target nucleic acid and includes minor mismatches that can be compensated for by reducing the stringency of the hybridization media to achieve the desired detection of the target nucleic acid sequence.

[0016] "Strict hybridization conditions" and "strict hybridization wash conditions" associated with nucleic acid hybridization experiments such as Southern and Northern hybridizations are sequence-dependent and differ in various environmental parameters. Longer sequences hybridize specifically at higher temperatures. A comprehensive guide to nucleic acid hybridization can be found in Tij ssen (1993) Laboratory Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Acid Probes, Part I, Chapter 2, "Overview of principles of hybridization and the strategy of nucleic acid probe assays," Elsevier, New York. Generally, very strict hybridization and wash conditions are chosen, which are approximately 5°C below the thermal melting point (Tm) for the specific sequence at a given ionic strength and pH.Typically, under "strict conditions", a probe hybridizes with its target subsequence, but not with other sequences.

[0017] The Tm value is the temperature (at a defined ionic strength and pH) at which 50% of the target sequence hybridizes with a perfectly matched probe. Very stringent conditions are chosen to correspond to the Tm value for a specific probe. An example of stringent hybridization conditions for hybridizing complementary nucleic acids with more than 100 complementary residues on a filter in a Southern or Northern blot is 50% formamide with 1 mg heparin at 42 °C, with the hybridization carried out overnight. An example of very stringent wash conditions is 0.15 M NaCl at 72 °C for approximately 15 minutes. An example of stringent washing conditions is a 0.2x SSC wash run at 65°C for 15 minutes (see J. Sambrook, et al., Molecular Cloning: A Laboratory Manual, 3rd Ed., Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press (2001), for a description of the SSC buffer).A high-stringency wash is often preceded by a low-stringency wash to remove the background probe signal. An example of a medium-stringency wash for a duplex of, say, more than 100 nucleotides is 1x SSC at 45°C for 15 minutes. An example of a low-stringency wash for a duplex of, say, more than 100 nucleotides is 4–6x SSC at 40°C for 15 minutes. For short probes (e.g., about 10 to 50 nucleotides), stringent conditions typically involve salt concentrations of less than about 1.0 M Na ions, typically about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3, and a temperature of typically at least about 30°C. Stringent conditions can also be achieved by adding destabilizing agents such as formamide.In general, a signal-to-noise ratio of 2x (or higher) compared to an unrelated probe in the respective hybridization assay indicates the detection of specific hybridization. Nucleic acids that do not hybridize with each other under strict conditions are nevertheless substantially identical if the proteins they encode are substantially identical. This is the case, for example, when a copy of a nucleic acid is created using the maximum codon degeneration permitted by the genetic code. Examples of hybridization / washing conditions that can be used to clone homologous nucleotide sequences that are substantially identical to the reference nucleotide sequences of the present invention are given below: A reference nucleotide sequence preferably hybridizes with the reference nucleotide sequence in 7% sodium dodecyl sulfate (SDS), 0.5 M NaPO4, 1 mM EDTA at 50°C with washing in 2X SSC, 0.1% SDS at 50°C, preferably in 7% sodium dodecyl sulfate (SDS). 0.5 M NaPO4, 1 mM EDTA at 50°C with washing in IX SSC, 0.1% SDS at 50°C, particularly in 7% sodium dodecyl sulfate (SDS). 0.5 M NaPO4, 1 mM EDTA at 50°C with washing in 0.5X SSC, 0.1% SDS at 50°C, preferably in 7% sodium dodecyl sulfate (SDS). 0.5 M NaPO4, 1 mM EDTA at 50°C with washing in 0.1X SSC, 0.1% SDS at 50°C, even more preferably in 7% sodium dodecyl sulfate. (SDS), 0.5 M NaPO4, 1 mM EDTA at 50°C with washing in 0.1% SSC, 0.1% SDS at 65°C.

[0018] Another indication that two nucleic acids or proteins are essentially identical is that the protein encoded by the first nucleic acid is immunologically cross-reactive with, or specifically binds to, the protein encoded by the second nucleic acid. Thus, a protein is typically essentially identical to another protein if the two proteins differ only by conservative substitutions.

[0019] A nucleic acid sequence is "isocoding" with a reference nucleic acid sequence if the nucleic acid sequence codes for a polypeptide that has the same amino acid sequence as the polypeptide coded by the reference nucleic acid sequence. The term "codon-optimized" sequence refers to the nucleotide sequence of a recombinant, transgenic, or synthetic polynucleotide in which the codons are chosen to reflect the particular codon bias that a host cell may have. This is done in such a way that the amino acid sequence of the polypeptide encoded by the codon-optimized polynucleotide is preserved. In certain formulations, the nucleotide sequence of the recombinant DNA construct contains a sequence that has been codon-optimized for the cell (e.g., an animal, plant, or fungal cell) in which the construct is to be expressed.

[0020] Nucleotides are denoted by their bases using the following standard abbreviations: adenine (A), cytosine (C), thymine (T), and guanine (G). Amino acids are also denoted using the following standard abbreviations: alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine ​​(Cys; C), glutamine (Gin; Q), glutamic acid (Glu; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0021] An intrinsically disordered region (IDR) is a sequence that does not have a stable three-dimensional structure. These sequences are therefore flexible and can interact with other molecules.

[0022] For the purposes of this application, an intrinsically disordered region is understood to be a sequence in which at least 30%, 40%, 50%, 60%, 70%, 80%, or 85% of the amino acids of the sequence in IUPred2 (Zsuzsanna Dosztänyi, Protein Sei. 2018) are intrinsically disordered.

[0023] Jan; 27 (1): 331-340. doi: 10. 1002 / pro. 3334; Bälint Meszäros, Gabor Erdds, Zsuzsanna Dosztänyi, IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding, Nucleic Acids Research, Volume 46, Issue W1, 2 July 2018, Pages W329-W337, https: / / doi. org / 10.1093 / nar / gky384; https: / / iupred2a. elte.hu / ) have an IUPred2 score (type long) of greater than 0.5.

[0024] The task is solved by a macromolecule or a macromolecule complex comprising at least one intrinsically disordered region (IDR) and at least one therapeutically active substance.

[0025] Such a macromolecule or macromolecular complex is capable of achieving phase separation in the chosen environment, resulting in the formation of a condensate phase of the macromolecule or macromolecular complex, while the concentration of the active ingredient in the surrounding phase remains low. If the active ingredient is degraded or eliminated in the surrounding phase, equilibrium is re-established as new active ingredient passes from the condensate phase into the surrounding phase. The condensate phase therefore serves as the reservoir for at least one therapeutically active substance of the macromolecule or macromolecular complex.

[0026] In a preferred embodiment, the intrinsically disordered region (IDR) of the macromolecule or macromolecule complex can be completely degraded in the body. The at least one IDR is preferably a peptide. The sequence of the IDR can be homologous or heterologous with respect to Homo sapiens.

[0027] The presence of the IDR enables the macromolecule or macromolecule complex according to the invention to undergo LLPS at sufficient concentration and for the aforementioned phases to form.

[0028] The type and duration of the IDR (Integrated Residual Dry Rate) can be used to control the concentration at which low-level plasma storage (LLPS) occurs. This also depends on environmental conditions such as ionic strength, buffer concentration, viscosity, pH value, etc.

[0029] In a preferred embodiment, the ratio of IDR to the at least one therapeutic substance is at least 0.8:1, preferably greater than 1:1, particularly greater than 1.1:1, and especially greater than 1.5:1, each based on the molar mass. Any connecting regions, such as linkers or connecting sequences, are included in the IDR. The ratio may vary depending on the type of IDR.

[0030] An intrinsically disordered region is understood to be a polymer structure that does not have a fixed tertiary structure.

[0031] Preferably, this is a peptide. Generally, these are regions with a high proportion of polar and electrically charged amino acids, such as alanine, arginine, glycine, glutamine, serine, proline, glutamic acid, and lysine, especially glycine and glutamine. Preferably, these regions also include a high proportion of aromatic amino acids, such as tyrosine or phenylalanine.

[0032] The sequence of the IDR can be selected according to the application. In a preferred embodiment, the IDR comprises at least one sequence that is at least partially repeated. Since an IDR does not form a structure, the size of the IDR required for the chosen purpose can be selected. Short connecting sequences of 0 to 10 amino acids can be placed between the repetitions. These are also included in the IDR when calculating its length or composition. Preferably, the amino acids of these connecting sequences are also selected from alanine, arginine, glycine, glutamine, serine, proline, glutamic acid, and lysine, preferably glycine and glutamine.

[0033] In a preferred embodiment of the invention, at least 30%, 40%, 50%, 60%, 70%, 80%, or 85% of the amino acids of the IDR in IUPred2 have an IUPred2 score (type long) of greater than 0.5, particularly preferably at least 50%, 60%, 70%, 80%, or 85%.

[0034] In a preferred embodiment of the invention, the IDR additionally comprises at least 20 consecutive amino acids which have an IUPred2 score (type long) of greater than 0.5.

[0035] In a further preferred embodiment of the invention, the IDR sequence exhibits at least 80%, at least 90%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with a sequence which, in the D2P2 database (https: / / d2p2.pro / , Matt E. Oates, et al. Nucleic Acids Research, Volume 41, Issue D1, 1 January 2013, Pages D508-D516, https: / / doi.org / 10.1093 / nar / gksl226), is classified as disordered for at least 50%, at least 60%, at least 70%, at least 80%, or at least 85% of the sequence, with at least 75% agreement with the disorder prediction models.

[0036] In a preferred embodiment, the IDR comprises at least one sequence selected from QQQ, GGG, RGG, YSP, FSP, VPG, FG, QQ, or GG. Preferably, it contains at least two, three, four, five, six, or seven sequences selected from QQQ, GGG, RGG, YSP, FSP, VPG, FG, QQ, or GG. The IDR also preferably comprises at least one aromatic amino acid, preferably tyrosine or phenylalanine.

[0037] In a preferred embodiment of the invention, the content of Q and G of the IDR (sum of the number of Q and the number of G) relative to the number of amino acids of the IDR is at least 15%, preferably at least 18%.

[0038] In a preferred embodiment of the invention, the Q and G content of the IDR, based on the number of amino acids of the IDR, is at least 25%, preferably at least 30%, particularly preferably at least 35%, and particularly preferably at least 40%.

[0039] In a preferred embodiment of the invention, the F and Y content of the IDR, based on the number of amino acids in the IDR, is at least 4%, preferably at least 6%, particularly preferably at least 7%, and most preferably at least 10%.

[0040] In a preferred embodiment of the invention, the content of Q and G of the IDR, based on the number of amino acids of the IDR, is at least 15%, preferably at least 18%, and the content of F and Y of the IDR, based on the number of amino acids of the IDR, is at least 4%, preferably at least 6%, particularly preferably at least 7%, and most preferably at least 10%.

[0041] In a preferred embodiment of the invention, the Q and G content of the IDR, based on the number of amino acids in the IDR, is at least 15%, and the F and Y content of the IDR, based on the number of amino acids in the IDR, is at least 6%.

[0042] In a preferred embodiment of the invention, the Q and G content of the IDR, based on the number of amino acids in the IDR, is at least 25%, and the F and Y content of the IDR, based on the number of amino acids in the IDR, is at least 6%.

[0043] In a preferred embodiment of the invention, the Q and G content of the IDR, based on the number of amino acids in the IDR, is at least 30%, and the F and Y content of the IDR, based on the number of amino acids in the IDR, is at least 7%.

[0044] In a preferred embodiment of the invention, the Q and G content of the IDR, based on the number of amino acids in the IDR, is at least 35%, and the F and Y content of the IDR, based on the number of amino acids in the IDR, is at least 10%.

[0045] In a preferred embodiment of the invention, the content of Q and G of the IDR, based on the number of amino acids of the IDR, is 15% to 65%, and the content of F and Y of the IDR, based on the number of amino acids of the IDR, is 4% to 25%.

[0046] In a preferred embodiment of the invention, the content of Q and G of the IDR, based on the number of amino acids of the IDR, is 15% to 65%, and the content of F and Y of the IDR, based on the number of amino acids of the IDR, is 6% to 25%.

[0047] In a preferred embodiment of the invention, the content of Q and G of the IDR, based on the number of amino acids of the IDR, is 25% to 65%, and the content of F and Y of the IDR, based on the number of amino acids of the IDR, is 10% to 25%.

[0048] In a preferred embodiment, the IDR is at least 50 amino acids long, preferably at least 100 amino acids, and particularly preferably at least 120 amino acids. In a preferred embodiment, the IDR has a length of 50 to 1000 amino acids, preferably 100 to 700 amino acids.

[0049] In a preferred embodiment, the IDR comprises at least the sequence selected from a sequence that is substantially identical to a sequence selected from FUS. N (Seq ID #30, IUPred2 scores in Table 4 ), hnRNP C (Seq-Id No. 31) or Ddx4 N (Seq-Id No. 32), preferably this sequence has an identity of at least 90%, at least 91%, at least 92%, at least 93%.

[0050]

[0051] at least 94 at least 95

[0052]

[0053] at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the sequence selected from FUS N , hnRNP C or Ddx4 N (Referring to the protein sequences). The respective protein sequences and the encoding nucleic acids are given in Table 3.

[0054] In a particularly preferred embodiment, the IDR comprises at least the sequence selected from a sequence which is substantially identical to a sequence selected from FUS. N (Seq-Id No. 30) or hnRNP C (Seq-Id No. 31), preferably this sequence exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the sequence selected from FUS N or hnRNP C(Referring to the protein sequences). The respective protein sequences and the encoding nucleic acids are given in Table 3.

[0055] The sequence is preferably present at least once. If a longer IDR is necessary, the sequence is preferably repeated at least partially. This ensures that the disordered structure is preserved.

[0056] The at least one therapeutically active substance can be selected accordingly. In a preferred embodiment, the at least one pharmaceutically active substance is a peptide. This allows the macromolecule or macromolecule complex according to the invention to be produced directly by expression as a fusion protein. In a preferred embodiment, the peptide is at least 30 amino acids long, preferably 30 to 2500 amino acids, and particularly preferably 30 to 2000 amino acids.

[0057] The at least one therapeutically active substance is preferably covalently linked to at least one IDR. Several, even different, substances can also be part of the macromolecule or macromolecule complex.

[0058] The at least one therapeutically active substance is preferably covalently linked to one end of an IDR, preferably to the N-terminus or C-terminus. In a preferred embodiment, the substance is located at the C-terminus of the IDR.

[0059] The covalent bond can be any covalent compound, with or without a linker. It can be a single bond. Other possible linkers include short peptide sequences of 1 to 10 amino acids, modified peptide linkers, disulfide bridges, amide compounds, esters or ethers, and polyethylene glycols. The type of linker depends on the type of substance. The linker may be cleavable under certain conditions.

[0060] In a preferred embodiment, the macromolecule or macromolecular complex comprises at least one cleavable solubility domain. The solubility domain can be covalently or non-covalently bound to the macromolecule or macromolecular complex. This preferably ensures that the LLPS only occurs after cleavage of this domain.

[0061] This solubility domain is preferably a protein that increases the solubility of proteins and prevents aggregation. Such proteins are known from expression systems. An example of such a protein is maltodextrin-binding protein (MBP). Preferably, this solubility domain is located at the N-terminus of the IDR, preferably via a linker comprising 0 to 50 amino acids.

[0062] The solubility domain is preferably cleavable. This means that it can be cleaved from the macromolecule or macromolecular complex according to the invention by cleaving the covalent bond. This can be achieved by providing the linker between the solubility domain and the IDR with a protease cleavage site, which can be cleaved by a suitable protease. This allows the formation of the LLPS to be controlled by the cleavage of this solubility domain.

[0063] The macromolecule or macromolecule complex may have additional regions, such as binding domains for purification, such as affinity tags like His tags.

[0064] In another embodiment of the invention, a dimerization domain is arranged in addition to the IDR. This can promote aggregation and the formation of LLPS. An example of a dimerization domain is F. M(Seq-ID No. 33). The molecular weight of the dimerization domain is included in the weight ratio to the weight of the IDR.

[0065] The macromolecules or macromolecule complexes according to the invention allow them to undergo low-level plasma perfusion (LLPS) at a specific concentration, thereby ensuring that the at least one therapeutically active substance is present in the surrounding phase in an effective amount. The LLPS makes it possible to maintain this concentration over a longer period. An "effective concentration" refers to an amount that is sufficient to treat a disease, disorder, and / or condition, or to achieve a specified effect. For example, an effective amount may be an amount that reduces the progression or severity of the condition or symptoms being treated. Determining a therapeutically effective amount is entirely within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein.The term "effective amount" is intended to encompass an amount of a compound described herein, or an amount of a combination of compounds described herein, that is effective, for example, in treating or preventing a disease or disorder, or in treating the symptoms of a disease or disorder in a host. Thus, an "effective amount" generally means an amount that produces the desired effect.

[0066] A "therapeutically active substance," "therapeutic agent," "active ingredient," or "drug" is a molecule used to treat, cure, prevent, or diagnose a disease or other medical condition. Examples of therapeutic agents include FDA-approved drugs, experimental drugs, antibiotics, nucleic acids (e.g., siRNA, DNA), antibodies, and antibody fragments.

[0067] The macromolecule or macromolecule complex according to the invention can be in different forms. For example, it can be in lyophilized form. In a preferred embodiment of the invention, the at least one therapeutically active substance is a peptide.

[0068] In a preferred embodiment of the invention, the at least one IDR and the at least one therapeutically active substance are a peptide.

[0069] The invention further relates to a nucleic acid, in particular DNA or RNA, which encodes a fusion protein comprising at least one IDR and at least one therapeutically active substance, each of which is a peptide. The nucleic acid may be modified, for example, to slow down its degradation.

[0070] In a particularly preferred embodiment, the sequence of the IDR is selected from a nucleic acid sequence that encodes an IDR according to the preferred embodiments of the invention as described above, in particular the sequences selected according to IUPred2. Preferably, the sequence is selected from a sequence that is substantially identical to a sequence selected from the nucleic acid sequence for FUS. N (Seq-Id No. 3) or hnRNP C (Seq-Id No. 4), preferably this nucleic acid sequence exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the nucleic acid sequence selected from FUS N or hnRNP C on.

[0071] The invention further relates to a vector comprising a nucleic acid encoding the aforementioned fusion protein. The invention further relates to a pharmaceutical composition comprising the macromolecule or macromolecule complex according to the invention.

[0072] The composition may also include buffers, salts, or other pharmaceutical carriers.

[0073] The invention further relates to a kit comprising the macromolecule or macromolecule complex according to the invention. In addition to the macromolecule or macromolecule complex, the kit may also include buffers and, for example, agents for cleaving the solubility domain. This may, for example, be a protease.

[0074] The invention relates to the use of the macromolecule or macromolecule complex according to the invention as a drug.

[0075] The macromolecule or macromolecule complex according to the invention can be used to treat a wide variety of diseases, depending on the therapeutically active substance. Preferably, it consists of well-defined areas where only minimal fluid exchange with the rest of the organism takes place. These are preferably areas filled with fluid or gel, resulting in limited exchange.

[0076] This allows the therapeutically active substance to be released selectively at the target site. Diffusion of the particles is also restricted, enabling an equilibrium to develop within these areas. Examples of such areas include the vitreous humor, the ear (including the inner ear), joints, the spine, intervertebral discs, adipose tissue, the brain, and the spinal cord.

[0077] This allows the therapeutically active substance to act selectively in this area and to be released over a longer period of time.

[0078] In a preferred embodiment, the invention is used in ophthalmological diseases. The eye, and in particular the vitreous body, forms a defined compartment for the application of the invention.

[0079] Therapeutically preferred is a substance for the treatment of age-related macular degeneration, especially an anti-VEGF agent such as Abicipar. Particularly in macular degeneration, the release of the active ingredient over a longer period is important.

[0080] For application, the macromolecule or macromolecule complex according to the invention is exposed to conditions such that LLPS occurs and corresponding compartments are formed. This can be achieved in particular by its concentration.

[0081] In one embodiment of the invention, it may be necessary to separate the solubility domain beforehand.

[0082] The invention therefore also relates to a method for providing a depot of the therapeutically active substance in vitro. For this purpose, the macromolecule or macromolecule complex according to the invention is provided under conditions such that low-level phase separation (LLPS) occurs. This can be influenced, for example, by selecting the buffer or the concentration. The process then continues until phase separation has occurred. This can take between 10 minutes and 4 hours. It may be necessary to cleave the solubility domain beforehand, if present. Subsequently, a composition with compartments is obtained, which form the depot of the therapeutically active substance. The compartments are formed by LLPS, i.e., by droplet formation of the macromolecule and macromolecule complex according to the invention.

[0083] Further details and features will become apparent from the following description of preferred embodiments in conjunction with the dependent claims. The respective features can be implemented individually or in combination with one another. The possibilities for solving the problem are not limited to the embodiments. For example, range specifications always include all intermediate values ​​not explicitly mentioned and all conceivable sub-intervals.

[0084] The exemplary embodiments are shown schematically in the figures. Identical reference numbers in the individual figures denote identical or functionally equivalent elements, or elements corresponding to each other in terms of their functions. Specifically, the figures show:

[0085] Fig. 1 Schematic representation of the liquid drug depots. The droplet suspension is injected into the patient's vitreous humor, where the drug is released to achieve a specific soluble-phase concentration in the vitreous. As the drug is eliminated, the liquid depots maintain a constant volumetric phase concentration until they are depleted (a: macula; b: vitreous humor; c: liquid drug depots; d: soluble phase; e: drug (pharmaceutical active substance); f: elimination / depletion of the drug).

[0086] Fig. 2 a) Design concept of the phase-separation-capable anti-VEGF constructs. An N-terminal maltose-binding protein (MBP) is followed by a 3C protease cleavage site (3CS), which enables cleavage of the solubility tag and the initiation of phase separation. Downstream of the 3CS, one or two intrinsically disordered regions (IDRs) are arranged sequentially to effect phase separation. Finally, the IDRs are fused with the abicipar DARPin, which exhibits anti-VEGF activity and is responsible for the therapeutic effect. A C-terminal hexahistidine tag enables affinity purification of the fusion proteins. b) Fusion proteins with the N-terminal IDR of FUS (FUS N ). c) Fusion proteins with the C-terminal IDR of hnRNP-Al (hnRNP C ) d) Fusion proteins containing the N-terminal IDR of Ddx4 (Ddx4 N ) e) Fusion protein forming a FUS N Repeat followed by two Fs MContains homodimerization domains. (Barrero JJ, Papanikou E, Casler JC, Day KJ, Glick BS. An improved reversibly dimerizing mutant of the FK506-binding protein FKBP. Cell Logist. 2016;6(3):8. doi:10.1080 / 21592799.2016.1204848); Fig. 3 Fluid behavior of FUS N -FUS N -DARPin-Drop en. a) Schematic representation of the construct with two FUS N - Domains in tandem selected for further experiments (above). Microscopic images of FUS N - FUS N -DARPin droplets obtained by cleavage of MBP (by incubation with 3CP for at least 2 h) at three different total protein concentrations: 25 µM, 50 µM, and 90 µM (below). b) FUSN-FUSN-DARPin droplets have a spherical morphology when in suspension; they wet the surface on which they settle and fuse together upon contact. Scale bar: 50 µm;

[0087] Fig. 4 Measurement of the soluble-phase concentration. a) Microscopic images of FUS N -FUS N -DARPin droplets after cleavage of MBP at 25 µM and 50 µM total protein concentrations. Scale bars: 50 µM. b) Procedure of the experiment to measure the volume phase concentration. A droplet suspension was obtained by incubation with 3C-Protease overnight to cleave the MBP tag. A sample of the droplet suspension was taken for SDS-PAGE, while the remaining sample was centrifuged at 100,000 g for 25 minutes to sediment the droplets. A sample of the supernatant (soluble phase) was taken for SDS-PAGE. An SDS-PAGE gel was prepared (Figure 7a), and the intensity of the bands was quantified using Fiji (I: soluble phase). c) Intensity of MBP and FUS N -FUS N- DARPin bands in the droplet suspension (total mixture) compared to the soluble phase at 25 µM and 50 µM total protein concentrations. The 25 µM sample was obtained by cleavage of the MBP tag at a concentration of 50 pM and dilution of the sample to 25 pM after droplet formation;

[0088] Fig. 5 Simulation of drug elimination and release. a) Procedure of an experiment simulating drug elimination by progressive dilution of liquid drug depots in DPBS. A droplet suspension was obtained by incubation with 3C protease to cleave the MBP tag at a total protein concentration of 80 pM. From each sample, 50% of the volume of the droplet suspension was taken, while the remaining sample was diluted 1:1 with DPBS and incubated for 1 h at room temperature. This procedure was repeated once more. At each step, a sample was taken from the droplet suspension for SDS-PAGE, while the remaining suspension was centrifuged at 100,000 g for 25 minutes to sediment the droplets. A sample was taken from the supernatant (soluble phase) for SDS-PAGE and for a VEGF assay.An SDS-PAGE gel was prepared (Figure 7b), and the intensity of the bands was quantified using Fiji (I: 50% volume removed; II: soluble phase; III: repeated at each measurement point). b) Microscopic images of the original droplet suspension (80 µM) and the two subsequent dilutions (40 µM and 20 µM). Scale bar: 50 µm. c) FUS intensity. N - FUS N DARPin bands in the droplet suspension (total mixture, I, left column in each case) compared to the soluble phase (II, right column in each case) at each step of the workflow in (a). For the total mixtures, the band intensity was multiplied by the dilution factor of the sample. (d) VEGF assay using samples of the soluble phase from the workflow in (a). Cells expressing a VEGF-dependent luciferase (KDR / NFAT-RE HEK293 cell line (Promega, Madison, WI)) were treated with a fixed VEGF concentration and with known concentrations of FUS. N -FUSN DARPin was incubated to obtain a standard curve (blue dots). A dose-response adjustment was performed to obtain a formula that correlates the luminescence signal with the FUS. N -FUS N The -DARPin concentration in the sample (bottom line, I) is related. Furthermore, the cells were incubated with several dilutions of the soluble-phase samples obtained as shown in (a). Using dose-response matching, the FUS was N -FUS N DARPin concentration was determined in the soluble-phase samples. The concentration ratios between the samples were calculated and compared with the original concentration ratios. Top straight line: luminescence signal of cells incubated with VEGF only. The fit parameters are shown in Figures 9b and 9c.

[0089] Fig. 6 Microscopic images of other abicipar constructs. a) Fusion proteins with multiple copies of the FUSN or hnRNP C IDRs after MBP cleavage. The proteins with 1 and 1,2 copies of FUS. N are shown at a concentration of 50 µM, the first to show some degree of phase separation, b) fusion of Abici-par-DARPin with a copy of FUS N IDR followed by two copies of the F M Homodimerization domain (Barrero JJ, Papanikou E, Casler JC, Day KJ, Glick BS. An improved reversibly dimerizing mutant of the FK506-binding protein FKBP. Cell Logist. 2016;6(3):8. doi:10.1080 / 21592799.2016.1204848) to achieve further multivalence. The protein undergoes phase separation at 25 µM after MBP cleavage, in contrast to the protein with only one FUS. N Copy. The structures formed by the condensate phase do not have the appearance of spherical droplets and do not fuse upon contact. Scale bar: 50 µm;

[0090] Fig. 7 SDS-PAGE gels. a) SDS-PAGE gel of the experiment shown in Figure 4, b) SDS-PAGE gel of the experiment shown in Figure 5.

[0091] Fig. 8 Dose-response adjustments of the VEGF assay. a) VEGF assay of VEGF-inducible luciferase-expressing cells incubated with increasing concentrations of mouse VEGF-164. The VEGF concentration used in subsequent assays was 17 ng / mL (0.9 nM), a concentration between EC80 and EC90 of VEGF. b) Formula for the dose-response curve of the VEGF assay shown in Figure 5d. y = luminescence [RLU], x = Ln (conc [nM] ). c) Fit parameters of the VEGF assay shown in Figure 5d.

[0092] Fig. 9 Liquid anti-VEGF deposits in the human vitreous humor.

[0093] FUS N -FUS NDARPin droplets were generated by cleavage of the MBP tag through incubation with 3CP for 1 h at a high protein concentration (380 µM) in DPBS. The droplet suspension was then diluted 1:5, 1:10, and 1:20 in human vitreous samples. *For the 1:5 dilutions, sample t2 was taken a few seconds after sample ti to demonstrate droplet fusion upon contact. For comparison, a 1:1 dilution of the droplet suspension in DPBS and a vitreous sample without droplet suspension are shown.

[0094] Age-related macular degeneration (AMD) is one of the most common causes of vision loss and blindness in industrialized countries (Bourne RRA, Steinmetz JD, Saylan M, et al. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: The Right to Sight: An analysis for the Global Burden of Disease Study. Lancet Glob Heal. 2021; 9 (2 ): e144-e160. doi:10.1016 / S2214-109X(20)30489-7) and affects 196 million people worldwide (Allyn MM, Luo RH, Hellwarth EB, Swindle-Reilly KE. Considerations for Polymers Used in Ocular Drug Delivery. Front Med. 2022; 8).

[0095] doi:10.3389 / fmed.2021.787644). In its late stages, AMD often develops into neovascular or wet AMD, characterized by abnormal growth of blood vessels in the macula that invade the retina. Because vascular endothelial growth factor (VEGF) plays a central role in neovascularization, current treatment for wet AMD involves injecting anti-VEGF drugs into the vitreous humor (Fleckenstein M, Keenan TDL, Guymer RH, et al. Age-related macular degeneration. Nat Rev Dis Prim. 2021; 7(1): 31. doi:10.1038 / s41572-021-00265-2). To date, various anti-VEGF agents are on the market, ranging from antibodies or antibody fragments to chimeras of anti-VEGF receptors and antibodies (Nguyen QD, Das A, Do D V., et al. Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration. Ophthalmology.

[0096] 2020; 127 (7 ): 963-976. doi: 10. 1016 / j. ophtha. 2019. 12. 031; Panos GD, Lakshmanan A, Dadoukis P, Ripa M, Motta L, Amoaku WM.

[0097] Faricimab: Transforming the Future of Macular Diseases Treat-ment-A Comprehensive Review of Clinical Studies. Drug Des Devel Ther. 2023; 17: 2861-2873. doi: 10. 2147 / DDDT. S427416).

[0098] Despite the enormous improvement in AMD treatment through anti-VEGF therapy, drug injections must be repeated every 4-8 weeks (Fabre M, Mateo L, Lamaa D, et al. Recent Advances in Age-Related Macular Degeneration Therapies. Molecules. 2022; 27(16): 5089. doi: 10.3390 / molecules27165089), which carries a higher risk of intraocular inflammation and places a burden on patients and the healthcare system (Ehlken C, Ziemssen F, Eter N, et al. Systematic review: non-adherence and non-persistence in intravitreal treatment. Graefe's Arch Clin Exp Ophthalmol. 2020; 258(10): 2077-2090. doi: 10. 1007 / s00417-020-04798-2; Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature. Eye.

[0099] 2013; 27 (7 ): 787-794. doi: 10. 1038 / eye. 2013. 107; Anderson WJ, da Cruz NFS, Lima LH, Emerson GG, Rodrigues EB, Melo GB. Mechanisms of sterile inflammation after intravitreal inj ection of antiangiogenic drugs: a narrative review. Int J Retin Vitr. 2021; 7(1). doi: 10. 1186 / s40942-021-00307-7 ). Außerdem kann die Anti-VEGF-Therapie den Verlust des Sehvermögens langfristig nicht verhindern (Jaffe GJ, Ying GS, Toth CA, et al. Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials. Ophthalmology. 2019; 126 (2 ): 252-260. doi: 10. 1016 / j. ophtha. 2018. 08. 035; Ro-fagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP). Ophthalmology.

[0100] 2013; 120 (11): 2292-2299. doi: 10. 1016 / j. ophtha. 2013. 03. 046). For this reason, there is a great need for therapeutic alternatives that allow for a longer injection frequency (Seah I, Zhao X, Lin Q, et al. Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases. Eye. 2020; 34 ( 8 ): 1341-1356. doi: 10. 1038 / s41433-020-0770-y; Moisseiev E, Loewenstein A. Abicipar pegol— a novel anti-VEGF therapy with a long duration of action. Eye. 2020; 34 (4 ): 605-606. doi: 10. 1038 / s41433-019-0584-y).

[0101] Since a high concentration of the drug in the vitreous humor also correlates with a higher elimination rate (Xu L, Lu T, Tu-omi L, et al. Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: A population approach. Investig Ophthalmol Vis Sci. 2013; 54 (3): 1616-1624. doi: 10.1167 / iovs.12-10260), the injection frequency cannot be effectively reduced by injecting higher drug concentrations. An ideal solution would therefore be a depot injection that can regulate the drug concentration in the vitreous humor by releasing the drug over time as it is excreted, thus extending the time the drug concentration is maintained within the therapeutic window.

[0102] To meet this need, various approaches for the sustained release of anti-VEGF have been investigated. These include polymer-based nano- and microparticles, hydrogels, and liposomes (Seah I, Zhao X, Lin Q, et al. Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases. Eye. 2020; 34(8): 1341–1356. doi: 10.1038 / s41433-020-0770-y; Huang X, Zhang L, Fu Y, Zhang M, Yang Q, Peng J. Rethinking the potential and necessity of drug delivery systems in neovascular age-related macular degeneration therapy. Front Bioeng Biotechnol.

[0103] 2023; 11: 1199922. doi: 10.3389 / fbioe.2023.1199922). Another approach involves using adeno-associated viruses to transduce cells in the eye so that they can release VEGF inhibitors (Fabre M, Mateo L, Lamaa D, et al. Recent Advances in Age-Related Macular Degeneration Therapies. Molecules. 2022; 27(16): 5089. doi: 10.3390 / molecules27165089). Finally, non-degradable implants, so-called port delivery systems, have been clinically tested and have proven to be very effective, as they only need to be refilled approximately every six months. Port delivery systems were the only approach approved by the FDA based on their efficacy and safety (Eichenbaum DA, Ahmed A, Hiya F. Ranibizu-mab port delivery system: a clinical perspective. BMJ Open Ophthalmol. 2022; 7 ( 1 ): e001104. doi: 10. 1136 / bmj ophth-2022-001104 ).In Europe, the step towards clinical implementation has not been completed due to a high risk of adverse effects, as a surgical procedure is required to place the implant into the vitreous humor (Sharma A, Khanani AM, Parachuri N, Kumar N, Bandello F, Kuppermann BD. Port delivery system with ranibizumab (Susvimo) recall- What does it mean to the retina specialists. Int J Retin Vitr. 2023; 9(1):6).

[0104] doi: 10. 1186 / s40942- 023- 00446- z).

[0105] This paper presents a drug depot concept inspired by liquid-liquid phase separation (LLPS). By fusing an anti-VEGF protein with an inductively coupled membrane reagent (IDR) that promotes phase separation, LLPS has been shown to be used to create phase-separated liquid compartments that act as drug depots. These compartments release the drug as it is consumed from the diluted phase and maintain a constant concentration at the intended site of action over an extended period. This strategy not only reduces the injection frequency but also ensures that the depots are completely degraded upon drug depletion, as they contain no additional components. Furthermore, the depots can be injected in the same manner as the anti-VEGF drugs already used clinically, without the need for surgery.To facilitate the production and handling of proteins, the anti-VEGF agent Abicipar (Moisseiev E, Loewenstein A. Abicipar pegol— a novel anti-VEGF therapy with a long duration of action. Eye. 2020; 34 ( 4 ): 605- 606) was developed.

[0106] doi: 10. 1038 / s41433-019-0584-y; Luu KT, Seal JR, Attar M. A mechanistic and translational pharmacokinetic-pharmacodynamic model of abicipar pegol and vascular endothelial growth factor inhibition. J Pharmacol Exp Ther. 2020; 373 (2): 184-192.

[0107] doi: 10.1124 / jpet.119.263178) is used to demonstrate this principle. Abicipar is a designed ankyrin repeat protein (DARPin) (Stumpp MT, Binz HK, Amstutz P. DARPins: A new generation of protein therapeutics. Drug Discov Today.

[0108] 2008; 13 ( 15-16): 695-701. doi: 10. 1016 / j. drudis. 2008. 04. 013 ) which can bind VEGF with high affinity. The drug abicipar-pegol was developed by Molecular Partners AG (Zurich, Switzerland) and consists of the 14 kDa abicipar-DARPin, which is coupled to a 20 kDa polyethylene glycol (PEG) chain at the C-terminus to improve the half-life (Alshaikh RA, Waeber C, Ryan KB. Polymer based sustained drug delivery to the ocular posterior segment: barriers and future opportunities for the treatment of neovascular pathologies. Adv Drug Deliv Rev. ).

[0109] 2022; 187: 114342. doi: 10.1016 / .addr.2022.114342). Although the drug has proven effective in clinical trials, it has not been approved for clinical use because it is associated with a higher risk of eye inflammation (Kunimoto D, Yoon YH, Wykoff CG, et al. Efficacy and Safety of Abicipar in Neovascular Age-Related Macular Degeneration: 52-Week Results of Phase 3 Randomized Controlled Study. In: Ophthalmology. Vol 127. Elsevier Inc.; 2020: 1331-1344).

[0110] doi: 10.1016 / j.ophtha.2020.03.035). However, the concept presented here would also be compatible with other anti-VEGF agents.

[0111] In this study, an anti-VEGF drug capable of phase separation was developed, and it was demonstrated that the liquid depots are able to maintain a constant mass-phase concentration of the drug in a commonly used laboratory buffer. Furthermore, the drug's ability to inhibit the binding of VEGF to its receptor was tested.

[0112] 1. Materials and methods

[0113] 1.1. CONSTRUCTION OF EXPRESSION SECTORS

[0114] The amino acid sequence of Abicipar was extracted from the KEGG Drug Database (entry D11517). A suitable DNA sequence, omitting the codon encoding the C-terminal cysteine, was obtained by codon optimization using the GeneArt tool (Thermo Fisher Scientific, Waltham, MA). The sequence was then ordered as a G-block from Integrated DNA Technologies (Coralville, IA) with flanking Nhei and HindIII restriction sites. After digestion with both restriction enzymes, the sequence was inserted into the pH JW288 plasmid, which was then expanded between the FUS using the same enzymes. N -sequences and His tag were digested, resulting in an MBP-3CS-FUS NThe -Abicipar-His6 construct was created (pCJL313; 3CS: HRV-3C protease interface). To obtain a construct without an IDR, the pCJL314 plasmid was generated via Gibson assembly, removing the MBP, 3CP interface, and FUS sequences. To obtain constructs with additional FUSN repeats, sections between 0, 2, and 1 of the FUS were removed. N The sequence (starting from the N-terminus) is amplified from pCJL313 by PCR and inserted into the pCJL313 plasmid upstream of the previous FUS sequence N by Gibson assembly (plasmids pCJL326, pCJL327, pCJL328, pCJL329, pCJL320). Details of these vectors are given in Table 1.

[0115] To construct the structures with the hnRNP CTo obtain IDR, the hnRNPC sequence, originally from pNS027 (Schneider N, Wieland FG, Kong D, et al. Liquid-liquid phase separation of light-inducible transcription factors increases transcription activation in mammalian cells and mice. Sci Adv. 2021; 7 ( 1 ): eabd3568. doi: 10. 1126 / sciadv. abd3568 ), was amplified by PCR and one or two copies were inserted into pCJL313 by Gibson assembly, with the sequence FUS N The original plasmid was replaced, resulting in pCJL321 and pCJL322. Subsequently, segments between 0.2 and 0.8 of the hnRNP were extracted. C -Sequence (starting from the C-terminus) amplified by PCR and inserted into the pC JL321 plasmid downstream of the original hnRNP C -sequence inserted, resulting in the plasmids pCJL600, pCJL601, pCJL602, and pCJL603. Details of these vectors are given in Table 1. The constructs with the N-terminal IDR of Ddx4 were created by amplification of the IDR sequence of Ddx4 (Ddx4 N) originally from pNS025 (Schneider N, Wieland FG, Kong D, et al. Liquid-liquid phase separation of light-inducible transcription factors increases transcription activation in mammalian cells and mice. Sci Adv. 2021; 7 ( 1 ): eabd3568. doi: 10. 1126 / sciadv. abd3568 ) amplified by PCR and one or two copies in pCJL313 by Gibson assembly instead of FUS N (Plasmids pCJL323 and pCJL324) were inserted. The constructs with other Ddx4N lengths were created by amplification of Ddx4. N -sequence segments in the range of 0.2 to 0.8 (starting from the N-terminus) and their insertion into the pC JL323 plasmid, downstream of the original Ddx4 N -sequence (plasmids pCJL604, pCJL605, pCJL606 and pCJL607). Details of these vectors are given in Table 1.

[0116] To construct this with a FUS N -Repetition and two F M-domains in tandem (Barrero JJ, Papanikou E, Casler JC, Day KJ, Glick BS. An improved reversibly dimerizing mutant of the FK506-binding protein FKBP. Cell Logist. 2016; 6 (3): 8. doi: 10. 1080 / 21592799. 2016. 1204848 ), pCJL315, the sequence F M amplified by PCR from the pMK6 plasmid and two copies were assembled by Gibson assembly into pCJL313 downstream of the FUS N -Sequence inserted. See Table 1 for details on this vector.

[0117] 1.2. 3C-PROTEASE PRODUCTION AND CLEANING

[0118] E. coli BL21 (DE3)-pLysS cells (Thermo Fisher Scientific, Cat. No. C602003) were transformed with the plasmid pHJW257 (Jerez-Longres C, Gómez-Matos M, Becker J, et al. Engineering a material-genetic interface as safety switch for embedded therapeutic cells. Biomater Adv. 2023; 150 (January). doi: 10.1016 / j.bioadv.2023.213422), which encodes Strep-tagged HRV-3C protease (3CP), and selected by growth in Luria / Miller broth (LB) supplemented with ampicillin (100 pg / mL) and chloramphenicol (36 pg / mL). The bacteria were incubated in LB medium in flasks at 37 °C with shaking until an OD was reached. 600The bacteria were cultured from 0.9 before induction with 1 mM isopropyl-β-Dl-thiogalactopyranoside (IPTG; Carl Roth, Karlsruhe, Cat. No. 2316.5) and protein production for 5 h at 37 °C. Subsequently, the bacteria were harvested by centrifugation and the cells were resuspended in column buffer (100 mM Tris / HCl, 150 mM NaCl, pH 8, 0.35 mL per 1 L of initial culture), shock-frozen in liquid nitrogen, and stored at -80 °C until purification.

[0119] For affinity chromatographic purification, the resuspended pellets were lysed using ultrasound (Sonoplus HD, Bandelin, Berlin, Germany). The lysates were clarified by centrifugation at 30,000 g for 30 minutes, and the supernatant was loaded onto a gravity flow column containing StrepTactin XT 4Flow resin (IBA Lifesciences, Göttingen, Germany, Cat. No. 2-5030-002; 1.5 ml StrepTactin beads per 1 L bacterial culture), which had been previously equilibrated with column buffer. The 1.5 mL column was washed with 15 mL of column buffer, after which the protein was eluted in 7 fractions of 1 mL each with elution buffer (100 mM Tris / HCl, 150 mM NaCl, 50 mM biotin, pH 8.0). The fractions with the highest absorbance at 280 nm were pooled, and β-mercaptoethanol was added to a final concentration of 10 mM. The eluate was concentrated using a Vivaspin Turbo 5k molecular weight cut-off (MWCO) centrifugal concentrator (Sartorius AG, Göttingen, Germany, Cat. No.VS15T12) was concentrated, and the final concentration was determined by Bradford assay. Finally, 10% (v / v) glycerol was added, and the protein was shock-frozen in disposable aliquots in liquid nitrogen and stored at -80 °C. The protease is also commercially available (Sigma Aldrich, HRV-3C-Protease, SAE0045).

[0120] 1.3. PRODUCTION AND PURIFICATION OF ABICI PAR- FUSION PROTEIN

[0121] E. coli BL21 (DE3)-pLysS cells were transformed with the Abicipar constructs and selected by growth in Luria / Miller broth (LB) supplemented with ampicillin (100 pg / mL) and chloramphenicol (36 pg / mL). The bacteria were incubated in LB medium in flasks at 37 °C with shaking until an OD was reached. 600The bacteria were cultured from 0.9 before induction with 1 mM IPTG and protein production for 6 hours at 30 °C. The bacteria were harvested by centrifugation and resuspended in lysis buffer (50 mM NaH2PO4, pH 8, 0.300 mM NaCl, 10 mM imidazole, 35 mL per 1 L of starting culture), shock-frozen in liquid nitrogen, and stored at -80 °C until purification.

[0122] For affinity chromatographic purification, the resuspended pellets were pressed on a French press (for the large-scale production of MBP-3CS-FUS). N -FUS N-Abicipar-Hise) or by ultrasound (for the small-scale production of all other fusion proteins). The lysates were clarified by centrifugation at 30,000 g for 30 minutes, and the supernatant was loaded onto a gravity flow column containing nickel nitrilotriacetic acid (Ni-NTA) superf low agarose resin (Qiagen, Hilden, Germany, Cat. No. 30410; 2 ml resin per 3 L culture), which had been previously equilibrated with lysis buffer. Each 3 mL column was washed twice with 10 mL of wash buffer (50 mM NaH₂PO₄, pH 8, 0, 300 mM NaCl, 20 mM imidazole), and the protein was eluted in 9 fractions of 1 mL each with elution buffer (50 mM NaH₂PO₄, pH 8, 0, 300 mM NaCl, 250 mM imidazole). The fractions with the highest absorbance at 280 nm were pooled. The buffer was concentrated and diluted by repeated concentration and dilution using a Vivaspin 1 Ok-MWCO spin concentrator (Sartorius AG, Cat. No.

[0123] VS04T11) was exchanged for DPBS (8.03 mM Na2HPO4, 1.47 mM KH2PO4, 137.00 mM NaCl, 2.68 mM KCl, pH 7.2) and the protein was finally concentrated to approximately 100 pM. Finally, 10% (v / v) glycerol was added and the protein was shock-frozen in disposable aliquots in liquid nitrogen and stored at -80 °C.

[0124] 1.4. Induction of Phase Division and Microscopy

[0125] 3CP was added at a concentration of 0.1 mg / ml, and the mixtures were incubated at room temperature for 2 hours unless otherwise specified. Microscopic images were obtained using a digital inverted EVOS XL microscope (Thermo Fisher Scientific) with phase contrast.

[0126] 1.5. Concentration measurements in the soluble phase

[0127] For the experiment shown in Figure 4, the protein MBP-3CS-FUS was used. N -FUS NDARPin-His6 in PBS was brought to the concentrations shown in the figure, and phase separation was initiated as described above. Samples were prepared in duplicate. The resulting protein droplets were imaged as described above, and samples were taken from the droplet suspensions for SDS-polyacrylamide gel electrophoresis (PAGE). Subsequently, the mixtures were ultracentrifuged at 100,000 g and 4 °C for 25 min. The supernatants, consisting of the main phase without the droplets, were transferred to new tubes, examined under a microscope to confirm the absence of droplets, and samples were taken for SDS-PAGE.

[0128] For the progressive dilution experiments (Figure 5), the protein MBP-3CS-FUS was used. N -FUS NDARPin-His6 was thawed and diluted with the appropriate buffer to the initial concentration shown in each figure. The mixtures were incubated with 3CP (0.1 mg / mL) as described above. The resulting droplets were imaged, an SDS-PAGE sample was taken, and a volume of the sample (as shown in each figure) was taken for 25-minute ultracentrifugation at 100,000 g and 4 °C, after which an SDS-PAGE sample of the supernatant was taken. The remaining supernatant was stored at 4 °C until needed for a VEGF assay (see below). The remaining mixtures were made up to the initial volume with the appropriate buffer to obtain the second dilution. This procedure was repeated as shown in the figure. In all cases, the total mixture and the supernatant samples were loaded onto a polyacrylamide gel, which was then stained with Coomassie Brilliant Blue R250 (Carl Roth, Cat. No. 3862.2).

[0129] 1. 6. VEGF TEST

[0130] To assess the ability of the abicipar fusions to inhibit VEGF receptor activation, the VEGF-inducible, luciferase-expressing KDR / NFAT-RE HEK293 cell line (Promega, Madison, WI) was used. Recombinant mouse VEGF-164 was acquired from BioLegend (San Diego, CA, Cat. No. 583104). For VEGF inhibition assays, the cells were stimulated with a VEGF concentration between EC80 and EC90. A stimulation assay was performed to determine these concentrations, and a VEGF concentration of 50 ng / ml was chosen for subsequent experiments (Figure 8). Dilutions of the abicipar fusions were prepared in 100 µL at concentrations ranging from 6 nM to 0.15 nM. 100 µL of VEGF at a concentration of 50 ng / mL were added to the Abicipar solutions. One vial (containing ~10 7Cells containing luciferase reporter cells were thawed and washed once in Dulbecco's modified Eagle's complete medium (DMEM; Pan Biotech, Aidenbach, Germany, Cat. No. P04-03550), supplemented with 10% (v / v) fetal bovine serum (FBS; PAN Biotech, Cat. No. P30-3602). The cells were then resuspended in 5 mL of DMEM and seeded at 25 µL per well of a tissue culture-treated 96-well plate (Corning, Corning, NY, Cat. No. 3599). Finally, 50 µL of Abicipar-VEGF mixture per well was added, and the cells were incubated for 6 hours at 37 °C and 5% CO2. Each sample was prepared in triplicate. To analyze luciferase expression, the culture medium was removed from the cells and 100 µL of luciferase lysis buffer (25 mM Tris-HCl pH=7, 8, 15 mM MgSO4, 4 mM ethylene glycol bis(β-aminoethyl ether) tetraacetic acid (EGTA), 1% Triton X 100) with 1 mM DTT per well was added, followed by a 10-minute incubation at RT.Subsequently, 80 µL of each sample were transferred to a white 96-well plate (Corning, Cat. No. 3912), 20 µL of luciferase substrate (20 mM tricinate, 2.67 mM MgSO4, 0.1 mM Na2EDTA, 33.3 mM DTT, 524 µM ATP, 218 µg / mL acetyl-CoA, 131 µg / mL luciferin, 5 mM NaOH, pH 8.0) were added, and the luminescence was measured using a Synergy 4 microplate reader (Biotek, Winooski, VT). 1.7. Preparation of deposits in the human glass body.

[0131] The MBP-FUS-FUS-Abicipar protein was thawed and concentrated to 380 µM using a Corning 10k MWCO 500 µL spin concentrator (Cat. No. 431478). The MBP tag was then cleaved by incubation with 3CP for 1 hour at room temperature. The resulting phase-separated droplets were mixed with human vitreous samples in ratios of 1:5, 1:10, and 1:20. For comparison, some dilutions were also prepared in DPBS. The mixtures were observed under an Axio Observer Z1 / 7 microscope (Zeiss, Oberkochen, Germany).

[0132] 1.8. SOFTWARE

[0133] The band intensities of SDS-PAGE gels were quantified using the gel analysis tool in Fiji (Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: An open-source platform for biological-image analysis. Nat Methods. 2012; 9(7): 676-682. doi: 10.1038 / nmeth.2019). Dose-response curve fitting was performed in Origin. Figures 1, 2, 3a, 4b, 5a, and 6 were generated using Biorender.com.

[0134] 2. Results and Discussion

[0135] 2.1. FUSION OF IDRS AND DIMERIZATION DOMAS TO FORM AN ANTI-VEGF DARPIN TO PROVIDE A PHASE-SEPARING DRUG.

[0136] A sequence encoding the abicipar polypeptide without the C-terminal cysteine ​​was fused with one of three different intrinsically disordered regions (IDRs): the N-terminal IDR of Fused in Sarcoma (FUS). N ), the C-terminal IDR of the heteronuclear ribonucleoprotein Al (hnRNP) C) and the N-terminal IDR of the DEAD-Box helicase 4 (Ddx4) N ) (Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP. Spatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets. Cell. 2017; 168 ( 1-2 ): 159-171. el4.

[0137] doi: 10.1016 / j.cell.2016.11.054). To enable the production of fusion proteins in bacteria in soluble form and to facilitate handling prior to the induction of phase separation, a maltose-binding protein (MBP) solubility tag was added to the N-terminus of each construct, followed by an HRV-3C protease (3CP) interface, which allows for the removal of the MBP tag and the induction of phase separation (Schuster BS, Reed EH, Parthasarathy R, et al. Controllable protein phase separation and modular recruitment to form responsive membraneless organelles. Nat Commun. 2018; 9(1):2985).

[0138] doi: 10. 1038 / s41467-018-05403-1; Burke KA, Janke AM, Rhine CL, Fawzi NL. Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II. Mol Cell.

[0139] 2015; 60 (2): 231-241. doi:10.1016 / j.molcel.2015.09.006) (Figure 2).

[0140] The proteins were produced in bacteria, concentrated to different levels, and incubated with 3CP for at least 2 hours to cleave the MBP tag and induce phase separation. The resulting liquid droplets were then observed under a microscope. The final construct was selected based on its ability to phase separate at physiologically relevant concentrations and the behavior of the droplets as a liquid phase—spherical shape, wetting of surfaces, and fusion upon contact (Shin Y, Brangwynne CP. Liquid phase condensation in cell physiology and disease. Science (80-). 2017; 357 (6357):eaaf 4382).

[0141] doi: 10.1126 / science.aaf4382). In clinical studies, 1 mg of abicipar pegol was injected per eye, corresponding to an initial vitreous concentration of approximately 13 pM. Therefore, the construct of choice had to be capable of phase separation at similar concentrations. Based on these properties, the construct MBP-3CS-FUS was selected for further work. N -FUS N -DARPin was selected. Microscopic images of the protein droplets at different total protein concentrations are shown in Figure 3. Microscopic images of droplets formed from other constructs are shown in Figure 6. As expected, higher protein concentrations result in larger and more numerous droplets. Concentrations are given in pM to allow comparison of the concentrations of the different abicipar fusion proteins. The molecular weights of all proteins used are listed in Table 2.

[0142] 2.2. Concentration of the soluble phase at different starting concentrations of ions

[0143] 2.2.1. Measurement of the concentration of the soluble phase

[0144] An essential prerequisite for the liquid droplets to serve as reservoirs releasing the DARPin drug over time is that the protein concentration in the diluted phase (soluble phase) remains constant. Therefore, a test was developed to measure the DARPin concentration in the soluble phase after removal of the MBP tag and formation of the droplets.

[0145] First, it was confirmed that the DARPin concentration in the soluble phase after droplet formation is the same regardless of the initial total protein concentration. For this purpose, the MBP-3CS-FUS assay was first performed. N -FUS NDARPin protein in DPBS was diluted to two different concentrations at which phase separation took place – 25 pM and 50 pM. Additionally, a 50 pM sample was prepared and diluted after droplet formation.

[0146] Then 3CP was added and the mixtures were incubated overnight at room temperature to allow MBP cleavage and droplet formation. The additional 50 pM sample was diluted to 25 pM and incubated for another hour. Subsequently, the droplets were observed under a microscope (Figure 4a) and samples of the entire mixture were taken for SDS-PAGE. The remaining sample volume was centrifuged to separate the droplets and obtain a soluble phase sample for SDS-PAGE (Figure 4b). SDS-PAGE was performed and the bands showing MBP and FUS were determined. N -FUS N-DARPin bands were identified based on their molecular weight (Figure 7a). The intensity of each band was determined using Fiji (Schindelin J, Arganda-Carreras I, Frise E, et al.).

[0147] Fiji: An open-source platform for biological-image analysis. Nat Methods. 2012; 9 ( 7 ): 676-682. doi: 10.1038 / nmeth.2019) quantified and shown in Figure 4c. In the overall mixtures, the intensity of the band FUS was N -FUS N -DARPin was twice as high in the 50 pM sample as in the 25 pM sample. The 50 pM sample, diluted after droplet formation, had the same band intensity as the 25 pM sample, suggesting that the FUS N -FUS N DARPin protein was released from the droplets to maintain a constant concentration in the soluble phase. In the soluble-phase samples, the intensity of FUS was N -FUS NThe DARPin band in the 50 pM sample was only 1.3 times higher than in the 25 pM sample. This was not the case for the MBP band, whose intensity was twice as high in the 50 pM sample as in the 25 pM sample, since MBP does not form droplets. These results suggest that the soluble-phase concentration of the phase-separating protein is not proportional to the original protein concentration, but remains constant regardless of the total concentration.

[0148] 2.2.2. Simulation of drug excretion and release

[0149] Next, the elimination of the drug from the vitreous humor was simulated, and it was verified that the concentration in the soluble phase remained constant. For this purpose, a progressive dilution experiment was performed, starting with an initial protein concentration in DPBS, inducing droplet formation, and then carrying out two successive dilution steps in which a portion of the droplet suspension was removed and the tube was refilled with the same volume of DPBS. A schematic representation of the procedure is shown in Figure 5a. At each step, samples were taken from the droplet suspension and the soluble phase after centrifugation and subjected to SDS-PAGE (Figure 7b). The intensity of the bands was quantified, as was the FUS. N -FUS N-DARPin correspond to Fiji (Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: An open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676-682. doi:10.1038 / nmeth.2019) and the result is shown in Figure 5c. The results show that the concentration of FUS N -FUS NDARPin in the soluble phase remains constant after each dilution and incubation time, while the total protein concentration decreases with each step, as expected. Microscopic images of the droplet suspension were also taken at each step. The size and number of droplets decrease with the total protein concentration, as observed in previous experiments and expected by the principles of LLPS (Figure 5b). To further confirm these results with a quantitative approach, a VEGF inhibition assay was performed on each soluble-phase sample. For this purpose, a cell line with VEGF-induced luciferase expression was used. The cells are incubated with VEGF (to induce luciferase expression) and with the anti-VEGF agent. Depending on the concentration of the latter, luciferase expression is reduced accordingly. For this study, mouse VEGF-164 was used for induction.This isoform was chosen because it is the most common in mouse eyes for testing the retinal depots in AMD mouse models. A standard curve with known FUS was used. N -FUS N DARPin concentrations were generated that were fitted to a dose-response curve (Figure 5d, Figure 8b, c). Additionally, the cells were incubated with the soluble-phase samples and their signal was compared with the fitted curve to determine the FUS. N -FUS NDARPin concentration values ​​were obtained for each soluble-phase sample. Finally, the ratios of the calculated protein concentrations in the soluble phase between samples with different total protein concentrations were calculated. In all three cases, the concentration ratios between the samples were lower than the ratios of the total protein concentrations (Figure 5d). The results show that the liquid droplets are able to maintain a constant DARPin concentration in the soluble phase during protein elimination under these reaction conditions.

[0150] 2.3. LIQUID ANTI-VEGF DEPOSITS IN THE HUMAN GLASS BODY

[0151] In parallel with the experiments described above, attempts were made to dilute the liquid deposits obtained by cleaving the MBP tag at very high initial protein concentrations (380 pM) in human vitreous samples and to image the resulting droplet suspensions (Figure 9). Due to its spherical shape and ability to fuse upon contact, the FUS appears to be N -FUS NDARPin remained liquid at these high protein concentrations. Even when the original suspension was diluted 1:5 and 1:10 with human vitreous, the droplets appeared to retain this behavior, merging within seconds of contact. Interestingly, the highest protein concentrations resulted in droplets containing other droplets in their center. It is unclear whether this represents three phases or whether droplets from the diluted phase were trapped within the more protein-concentrated condensate phase. This behavior was not observed with more diluted samples.

[0152] 3. CONCLUSION AND OUTLOOK It has been shown that the anti-VEGF DARPin Abicipar can be fused to an LLPS-promoting protein domain and placed in a separate phase. A test was developed to measure the soluble-phase concentration at various total protein concentrations under laboratory conditions. A constant soluble-phase concentration was successfully achieved in a commonly used laboratory buffer. For their intended use as drug depots for the treatment of AMD, it is of utmost importance that the liquid depots are able to maintain a constant concentration of the drug in their environment.

[0153] Comparing the strategy presented here with other currently investigated drug delivery methods, LLPS-based depots likely offer some advantages, but also some limitations. For example, LLPS-based depots consist solely of the anti-VEGF protein. Therefore, unlike polymer-based nanoparticles, liposomes, or nanogels, once the depots and the soluble drug are depleted, no other components remain that could interact with the surrounding tissue (Seah I, Zhao X, Lin Q, et al. Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases. Eye. 2020; 34 ( 8 ): 1341-1356. doi: 10. 1038 / s41433-020-0770-y).

[0154] To increase the likelihood of circumventing the problems associated with phase separation, other LLPS-promoting sequences should be tested in parallel. Since LLPS is present in living cells, it is likely that a combination exists capable of maintaining a constant concentration of the soluble phase in the vitreous humor. Ultimately, the principle could be extended to anti-VEGF drugs, which, unlike Abicipar, are approved for clinical use. Where genetic fusions are not feasible, LLPS-promoting sequences could be used in combination with antibody-binding proteins to introduce antibody- or antibody-fragment-based anti-VEGF agents into phase separation. (Cited literature)

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[0209] Name Description Sequence

[0210] bung

[0211] pCJL3 MBP-3CS DNA sequence (Seq ID #9):

[0212] 13 1XFUS N- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abi cipar - TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGCAGCAGTCCTC CTACCCTGGCTATGCCAGCCAGCCAGCCGCCGCCGCCTC GTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCCAGAGTGGGAGCTACAGC CAACAGCCTAGCTATGGTGGAGCAGCAATCTTACGGTCAACAACAGAGCTA TAATCCCCCTCAGGGCTATGGACAGCAGAACCAGTACAACAGCAGCAGTGGTG GTGGAGGTGGAGGTGGAGGTGGAGGTAACTATGGCCAAGATCAATCCTCCATG AGTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCAATCAAGACCAGAGTGGTGG AGGTGGCAGCGGTGGCTATGGACAGCAGGACCGTGGAAGCGGCTCTGGCTCTG GC"C"GC"AGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGC ACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATC CGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGAT TTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAAT CGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTG GTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAA ATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCA TCATCATTGA

[0213] Proteinsequenz ( Seq-ID Nr. 36): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA Name Beschrei- Sequenz

[0214] bung

[0215] GINAAS PNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR T AVI NAAS GRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLBVLFQGPASIIDYTQQATQSYGAYPTQPGQG SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSYS QQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGNYGQDQSSM SSGGGSGGGYGNQDQSGGGGSGGYGQQDRGS GS GS GSAS GSDLDKKLLEAARA GQDDEVRILMANGADVNARDSTGWTPLHLAAPWGHPEIVEVLLKNGADVNAAD FQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLAE ILQKAAGGGSGGGSHHHHHH

[0216] pCJL3 MBP-3CS-DNA-Sequenz (Seq-ID Nr. 10):

[0217] 26 1. 2XFUS N- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abi cipar - TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCGGTGGCGGTGCCTCAAACGATTATACCCAACAAGCAACCCAAAGCTATG GGGCCTACCCCACCCAGCCCGGGCAGGGCTATTCCCAGCAGAGCAGTCAGCCC TACGGACAGCAGAGTTACAGTGGTTATAGCCAGTCCACGGACACTTCAGGCTA TGGCCAGAGCAGCTATTCTTCTTATGGCCAGAGCCAGAACACAGGCTATGGAA CTCAGTCAACTCCCCAGGGATATGGCTCGACTGGCGGCTATGGCAGTAGCCAG AGCTCCCAATCGTCTTACGGGCAGCAGTCCTCCTACCCTGGCTATGGCCAGCA GCCAGCTCCCAGCAGCACCTCGGGAAGTTACGGTAGCAGTTCTCAGAGCAGCA GCTATGGGCAGCCCCAGAGTGGGAGCTACAGCCAACAGCCTAGCTATGGTGGA CAGCAGCAATCTTACGGTCAACAACAGAGCTATAATCCCCCTCAGGGCTATGG ACAGCAGAACCAGTACAACAGCAGCAGTGGTGGTGGAGGTGGAGGTGGAGGTG GAGGTAACTATGGCCAAGATCAATCCTCCATGAGTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCAATCAAGACCAGAGTGGTGGAGGTGGCAGCGGTGGCTATGG ACAGCAGGACCGTGGAAGCGGCTCTGGCTCTGGCTCTGCTAGCGGTAGCGATC TGGATAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGT ATTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGAC ACCGCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGC TGAAAAACGGTGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTG CACTTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATA Name Beschrei- Sequenz

[0218] bung

[0219] TGGCGCAGATGTGAACGCACAGGATAAATTTGGTAAAACCGCCTTTGATATCA GCATCGATAATGGCAATGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGT GGTGGTTCAGGTGGTGGTAGC CATCATCACCATCATCATT GA

[0220] Proteinsequenz ( Seq-ID No. 37 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGPSQPSQVLSCAVGAGNA PNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AÄ TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPASNDYTQQATQSYGAYPTQGQGGY SQQSSQPYGQQSYSGYSQSGGASNDYTQQATQSYGAYPTQPGQGYSQQSSQP YGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGSTGGYGSSQ SSQSSYGQQSSYPGYGQPAPSSTSGSYGSSSQSSYGQPQSGSYSQQPSYGG QQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGQDQSSMSSGGGSGGGGYGNQDQSGGGGQGGGSGGSGGSGGGGGGGGG GSASGSDLDKKLLEAARAGQDDEVR I LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPL HLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLAEILQKAAG GGSGGGSHHHHHH

[0221] pCJL3 MBP-3CS-27 1. 4XFUS N- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abicipar- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGCGGCTATGGCAGTAGCCAGAGCGGTGGCGGTGCCTCAAACGATTATACCCA ACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTATT CCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCAG TCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCTTATGGCCAGAG CCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACTG GCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGGCAGCAGTCCTCC Name Beschrei- Sequenz

[0222] bung

[0223] TACCCTGGCTATGGCCAGCAGCCAGCTCCCAGCAGCACCTCGGGAAGTTACGG TAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCAGAGTGGGAGCTACAGCC AACAGCCTAGCTATGGTGGACAGCAGCAATCTTACGGTCAACAACAGAGCTAT AATCCCCCTCAGGGCTATGGACAGCAGAACCAGTACAACAGCAGCAGTGGTGG TGGAGGTGGAGGTGGAGGTGGAGGTAACTATGGCCAAGATCAATCCTCCATGA GTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCAATCAAGACCAGAGTGGTGGA GGTGGCAGCGGTGGCTATGGACAGCAGGACCGTGGAAGCGGCTCTGGCTCTGG CT CT GCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGCAG GTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGCA CGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATCC GGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGATT TTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAATC GTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTGG TAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAAA TCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCAT CATCATTGA

[0224] Proteinsequenz ( Seq-ID Nr. 38 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPASNdYTQQATQSYGAYPTQPGQG SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSGGGASNDYTQQATQSYGAYPTQPGQGYSQQSSQPYGQQSYSGYSQ STDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGSTGGYGSSQSSQSSYGQQSS YPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSYSQQPSYGGQQQSYGQQQSY NPPQGYGQQNQYNSSSGGGGGGGGGGNYGQDQSSMSSGGGSGGGYGNQDQSGG GGSGGYGQQDRGS GS GS G S AS GSDLDKKLLEAARAGQDDEVRI LMANGADVNA RD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLE I VEVLLKYGADVNAQDKFGKTAFD I S IDNGNEDLAE I LQKAAGGGS GGGS HHHH HH

[0225] pCJL3 MBP- 3CS- DNA-Sequenz ( Seq-ID Nr. 12 ):

[0226] 28 1. 6XFUS N- ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA Abi cipar- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG - TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA Name Description Sequence

[0227] good

[0228] GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGGCAGCAGTCCTC CTACCCTGGCTATGGCCAGCAGCCAGCTCCCAGCAGCACCTCGGGAAGTTACG GTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCAGAGTGGGAGCGGTGGC GGTGCCTCAAACGATTATACCCAACAAGCAACCCAAAGCTATGGGGCCTACCC CACCCAGCCCGGGCAGGGCTATTCCCAGCAGAGCAGTCAGCCCTACGGACAGC AGAGTTACAGTGGTTATAGCCAGTCCACGGACACTTCAGGCTATGGCCAGAGC AGCTATTCTTCTTATGGCCAGAGCCAGAACACAGGCTATGGAACTCAGTCAAC TCCCCAGGGATATGGCTCGACTGGCGGCTATGGCAGTAGCCAGAGCTCCCAAT CGTCTTACGGGCAGCAGTCCTCCTACCCTGGCTATGGCCAGCAGCCAGCTCCC AGCAGCACCTCGGGAAGTTACGGTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCAGAGTGGGAGCTACAGCCAACAGCCTAGCTATGGTGGACAGCAGCAAT CTTACGGTCAACAACAGAGCTATAATCCCCCTCAGGGCTATGGACAGCAGAAC CAGTACAACAGCAGCAGTGGTGGTGGAGGTGGAGGTGGAGGTGGAGGTAACTA TGGCCAAGATCAATCCTCCATGAGTAGTGGTGGTGGCAGTGGTGGCGGTTATG GCAATCAAGACCAGAGTGGTGGAGGTGGCAGCGGTGGCTATGGACAGCAGGAC CGTGGAAGCGGCTCTGGCTCTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAA ACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGG CAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACCGCTGCAT CTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGG TGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAG CAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGAT GTGAACGCACAGGATAAATTTGGTAAAACCGCCTTTGATATCAGCATCGATAA TGGCAATGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAG GTGGTGGTAGC CATCATCACCATCATCATT GA

[0229] Proteinsequenz ( Seq-ID Nr. 39 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPASNDYTQQATQSYGAYPTQPGQGY SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSGG GASNDYTQQATQSYGAYPTQPGQGYSQQSSQPYGQQSYSGYSQSTDTSGYGQS SYSSYGQSQNTGYGTQSTPQGYGSTGGYGSSQSSQSSYGQQSSYPGYGQQPAP SSTSGSYGSSSQSSSYGQPQSGSYSQQPSYGGQQQSYGQQQSYNPPQGYGQQN QYNSSSGGGGGGGGGGNYGQDQSSMSSGGGSGGGYGNQDQSGGGGSGGYGQQD RGSGSGSGSAS GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLH LAAPWGHPEIVEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGAD VNAQDKFGKTAFD I S IDNGNEDLAE I LQKAAGGGS GGGS HHHHHH

[0230] pCJL3 MBP- 3CS- DNA-Sequence ( Seq-ID No. 13 ):

[0231] 29 1. 8XFUS N - ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA Abi cipar- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG - TCACCGTTGAGCATCCAGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA Name Sequence Bequez

[0232] chapter

[0233] ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCGAACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGGCAGCAGTCCTC CTACCCTGGCTATGGCCAGCAGCCAGCTCCCAGCAGCACCTCGGGAAGTTACG GTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCAGAGTGGGAGCTACAGC CAACAGCCTAGCTATGGTGGACAGCAGCAATCTTACGGTCAACAACAGAGCTA TAATCCCCCTCAGGGCTATGGACAGCAGAACCAGTACAACAGCAGCAGTGGTG GTGGAGGTGGAGGTGGAGGTGGCGGTGCCTCAAACGATTATACCCAACAAGCA ACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTATTCCCAGCA GAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCAGTCCACGG ACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCTTATGGCCAGAGCCAGAAC ACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACTGGCGGCTA TGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGGCAGCAGTCCTCCTACCCTG GCTATGGCCAGCAGCCAGCTCCCAGCAGCACCTCGGGAAGTTACGGTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCAGAGTGGGAGCTACAGCCAACAGCC TAGCTATGGTGGACAGCAGCAATCTTACGGTCAACAGAGCTATAATCCCC CTCAGGGCTATGGACAGCAGAACCAGTACAACAGCAGTGGTGGTGGAGGT GGAGGTGGAGGTGGAGGTAACTATGGCCAAGATCAATCCTCCATGAGTAGTGG TGGTGGCAGTGGTGGCGGTTATGGCAATCAAGACCAGAGTGGTGGAGGTGGCA GCGGTGGCTATGGACAGCAGGACCGTGGAAGCGGCTCTGGCTCTGGCTCTGCT AGCGGTAGCGGATCTGGATAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGA TGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATA GCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATT GTTGAAGTTCTGGAAATTGGATTGATTGATTGATTGGATT TTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAG TGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAATTTGGTAAAACC GCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAAATCCTGCA GAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCATCATCATT GA

[0234] Proteinsequenz ( Seq-ID Nr. 40 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA Name Beschrenz- Sequenz

[0235] chapter

[0236] YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR T AVI NAAS GRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLBVLFQGPASIIDYTQQATQSYGAYPTQPGQG SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSYS QQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGASNDYTQQA TQSYGAYPTQPGQGYSQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQN TGYGTQSTPQGYGSTGGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSS SQSSSYGQPQSGSYSQQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGG GGGGGGNYGQDQSSMSSGGGSGGGYGNQDQSGGGGSGGYGQQDRGSGSGSGSA S GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKT AFD ISI DNGNED LAE I LQKAAGGGS GGGS HHHHHH

[0237] pCJL3 MBP-3CS-DNA-Sequenz (Seq-ID Nr. 14):

[0238] 20 2XFUS N- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abi cipar - TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGTGTCGTCAGACTGTCGATGAAGCCCTGAAAGAGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAAACCTCGGGATCGAGGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGAGATGAAGATTGG AACAAGCAACCCAAAGCTATGGGGCCTACCACCCAGCCCGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGACAGCTATTCTTCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGGCAGGCAGTCCTC CTACCCTGGCTATGCCAGCAGCCAGCTCCCAGCAGCACCTGGGAAGTTACG GTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCCCAGAGTGGGAGCTACAGC CAACAGCCTAGCTATGGTGGACACAGCCAATCTTACGGTCAACAACAGAGCTA TAATCCCCCTCAGGGCCTATGGACAGCAAGCAACCAGTACAACAGCAGCAGTGGTG GTGGAGGTGGAGGTGGAGGTGAGGTGGAGGTAACTATGGCCAAGATCAATCCTCATG AGTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCAATCAAGACCAGTGTG AGGTGGCAGCGGTGGCCTATGGACAGCAGCGACCGTGGGAGGTGGGCGGTGCCTCAA ACGATTATACCCAACAACCCAAAGCTATGGGCCCTACCCCACCACCCAGCCCGGGCAGGGCTATTCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAG Name Beschrei- Sequenz

[0239] bung

[0240] TGGTTATAGCCAGTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTT CTTATGGCCAGAGCCAGAACAGGCTATGGAACTCAGTCAACTCCCCAGGGA TATGGCTCGACTGGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGG GCAGCAGTCCTCCTACCCTGGCTATGGCCAGCAGCCAGCTCCCAGCAGCACCT CGGGAAGTTACGGTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCAGAGT GGGAGCTACAGCCAACAGCCTAGCTATGGTGGACAGCAGCAATCTTACGGTCA ACAACAGAGCTATAATCCCCCTCAGGGCTATGGACAGCAGAACCAGTACAACA GCAGCAGTGGTGGTGGAGGTGGAGGTGGAGGTGGAGGTAACTATGGCCAAGAT CAATCCCTCCATGAGTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCAATCAAGA CCAGAGTGGTGGAGGTGGCAGCGGTGGCTATGGACAGCAGGACCGTGGAAGCG GCTCTGGCTCTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAA GCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGC AGATGTTAATGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCAC CGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTG AATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGG CCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCAC AGGATAATTTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAA GATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAG C CATCATCACCATCATCATCATT GA

[0241] Proteinsequenz ( Seq-ID Nr. 41 ) MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPASNDYTQQATQSYGAYPTQPGQGY SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSYS QQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGNYGQDQSSM SSGGGSGGGYGNQDQSGGGGSGGYGQQDRGGGGASNDYTQQATQSYGAYPTQP GQGYSQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQG YGSTGGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQS GSYSQQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGNYGQD QSSMSSGGGSGGGYGNQDQSGGGGSGGYGQQDRGSGSGSGSASGSDLDKKLLE AARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGCTAFDISIDNGNE DLAE I LQKAAGGGS GGGS HHHHHH

[0242] pCJL3 MBP-3CS- DNA-Sequence ( Seq-ID No. 15 ):

[0243] 21 IxhnRNPc- ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA Abi cipar- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG - TCACCGTTGAGCATCCGGATAACTGGAAGAGAAATTCCCGATTGCGAGCAGATTAGGAAAG ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTCCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACCACGATTACTCC ATCGCAGAAGCTGCCTTTAATAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC Name Description- Sequence

[0244] dude

[0245] TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGG TTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAA AACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCT GGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCA GCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGA TGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAG TTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAAC GCACAGGATAAATTTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAA TGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTG GTAGC CATCATCACCATCATCATT GA

[0246] Proteinsequenz ( Seq-ID Nr. 42 ) ) MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMASASSSQRGRSGSGNFGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG S GRRFG S AS GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLA APWGHPEIVEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVN AQDKFGKTAFD I S IDNGNEDLAE I LQKAAGGGS GGGS HHHHHH-pCJL6 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 16):

[0247] 00 1. 2xhnRNP A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA c TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG

[0248] TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA

[0249]

[0250] His6ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC Name Beschrei- Sequenz

[0251] bung

[0252] TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGG TTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAA AACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGTGGCGGTCAATACTTTGCAAAACCACGAAACCAAGG TGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGCAGTGGCAGAAGATTTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGCA GGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGC ACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATC CGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGAT TTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAAT CGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTG GTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAA ATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCA TCATCATTGA

[0253] Proteinsequenz ( Seq-ID Nr. 43 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMASASSSQRGRSGSGNFGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG SGRRFGGGQ YFAKPRNQGGYGGS S S S SSYGSGRRFGSASGSDLDKKLLEAARA GQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAAD FQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLAE

[0254] _ I LQKAAGGGS GGGSHHHHHH- _

[0255] pCJL6 MBP- 3CS- DNA-Sequenz ( Seq-ID Nr. 17 ):

[0256] 01 1. 4xhnRNP ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA c TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA E - ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA 136 CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT Name Beschrei- Sequenz

[0257] bung

[0258] TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGG TTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAAAACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGTGGCGGTAACAATCAGTCTTCAAATTTTGGACCCAT GAAGGGAGGAAATTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCC AATACTTTGCAAAACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGC AGTAGCTATGGCAGTGGCAGAAGATTTGGCTCTGCTAGCGGTAGCGATCTGGA TAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTC TGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACCG CTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAA AAACGGTGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACT TAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGC GCAGATGTGAACGCACAGGATAAATTTGGTAAAACCGCCTTTGATATCAGCAT CGATAATGGCAATGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTG GTTCAGGTGGTGGTAGC CATCATCACCATCATCATT GA

[0259] Proteinsequenz ( Seq-ID Nr. 44 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMASASSSQRGRSGSGNFGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG SGRRFGGGNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S SSYGSGRRFGSASGSDLDKKLLEAARAGQDDEVRILMANGADVNARDSTGWTP LHLAAPWGHPEIVEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYG ADVNAQDKFGKTAFD I S IDNGNEDLAE I LQKAAGGGS GGGS HHHHHH-pCJL6 MBP- 3CS- DNA-Sequenz ( Seq-ID Nr. 18 ):

[0260] 02 1. 6xhnRNP ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA c TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA — His6ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC Name Beschrei- Sequenz

[0261] bung

[0262] GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGGTTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAA AACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGTGGCGGTAGTGGGGATGGCTATAATGGATTTGGTAA TGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGATTTTGGGAATTACA ACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAATTTTGGAGGCAGA AGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAAAACCACGAAACCA AGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGCAGTGGCAGAAGAT TTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGT GCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAA TGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTC ATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCA GATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGA AATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAAT TTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCA GAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCA CCATCATCATT GA

[0263] Proteinsequenz ( Seq-ID Nr. 45 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMASA. SSSQRGRSGSGNFGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG SGRRFGGGSGDGYNGFGNDGSNFGGGGSYNDFGNYNNQSSNFGPMKGGNFGGR S SGPYGGGGQYFAKPRNQGGYGGS S S S SSYGSGRRFGSASGSDLDKKLLEAAR AGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAA DFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLA E I LQKAAGGGS GGGS HHHHHH- Name Beschrei- Sequenz

[0264] bung

[0265] pCJL6 MBP- 3CS- DNA-Sequenz ( Seq-ID Nr. 19 ):

[0266] 03 1. 8xhnRNP ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA c TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA — His6ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGGGTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGG TTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAA AACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGTGGCGGTAATGACAACTTCGGTCGTGGAGGAAACTT TAGTGGTCGAGGCGGTTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTA GTGGGGATGGCTATAATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGT GGAAGCTACAATGATTTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACC CATGAAGGGAGGAAATTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAAAACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGC AGCAGTAGCTATGGCAGTGGCAGAAGATTTGGCTCTGCTAGCGGTAGCGATCT GGATAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTA TTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACA CCGCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCT GAAAAACGGTGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCCTCTGC ACTTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATAT GGCGCAGATGTGAACGCACAGGATAAATTTGGTAAAACCGCCTTTGATATCAG CATCGATAATGGCAATCTCTGGCAGAAATCCTGCAGAAAGCAGCCGGTG GTGGTTCAGGTGGTCAGCATCCATTCATTCATTGA

[0267] Proteinsequenz ( Seq-ID No. 46): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKQPSQPSKVLSKVLSKDVGVDNAGA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS Name Description- Sequenz

[0268] bung

[0269] NNNNNNNNNNLGIEGRGGGGSLEVLFQGEitASASSSQRGRSGSGNEGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG SGRRFGGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGG GSYNDFGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S SSSYGSGRRFGSASGSDLDKKLLEAARAGQDDEVRILMANGADVNARDSTGWT PLHLAAPWGHPEIVEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKY GADVNAQDKFGKTAFD I S IDNGNEDLAE I LQKAAGGGS GGGS HHHHHH-pCJL3 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 20 ):

[0270] 22 2xhnRNP C- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abi cipar - TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGCTAGTGCTTCATCCA GCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGT TTCGGTGGGAATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGG TTTCGGTGGGTCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATA ATGGATTTGGTAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGAT TTTGGGAATTACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAA TTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAA AACCACGAAACCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGTAGCTATGGC AGTGGCAGAAGATTTGGTGGCGGTATGGCTAGTGCTTCATCCAGCCAAAGAGG TCGAAGTGGTTCTGGAAACTTTGGTGGTGGTCGTGGAGGTGGTTTCGGTGGGA ATGACAACTTCGGTCGTGGAGGAAACTTTAGTGGTCGAGGCGGTTTCGGTGGG TCTCGTGGTGGCGGTGGATATGGAGGTAGTGGGGATGGCTATAATGGATTTGG TAATGATGGAAGCAATTTTGGAGGTGGTGGAAGCTACAATGATTTTGGGAATT ACAACAATCAGTCTTCAAATTTTGGACCCATGAAGGGAGGAAATTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGTGGAGGCCAATACTTTGCAAAACCACGAAA CCAAGGTGGCTATGGCGGTTCCAGCAGCAGCAGCTATGGCAGTGGCAGAA GATTTGGCTCTGCTAGCGGTAGCGATCTGGATAAAAACTGCTGGAAGCAGCA CGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGT TAATGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGG GTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCC GCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCT GGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATA AATTTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTG Name Description- Sequenz

[0271] chapter

[0272] GCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCA TCACCATCATCATT GA

[0273] Proteinsequenz ( Seq-ID Nr. 47 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMASA. SSSQRGRSGSGNFGGGRGGG FGGNDNFGRGGNFSGRGGFGGSRGGGGYGGSGDGYNGFGNDGSNFGGGGSYND FGNYNNQS SNFGPMKGGNFGGRS SGPYGGGGQYFAKPRNQGGYGGS S S S S S YG SGRRFGGGMASASSSQRGRSGSGNFGGGRGGGFGGNDNFGRGGNFSGRGGFGG SRGGGGYGGSGDGYNGFGNDGSNFGGGGSYNDFGNYNNQSSNFGPMKGGNFGG RS SGPYGGGGQYFAKPRNQGGYGGS S S S SSYGSGRRFGSASGSDLDKKLLEAA RAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNA ADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDL AE I LQKAAGGGS GGGS HHHHHH-pCJL3 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 21 ):

[0274] 23 1xDdx4 N- A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA Abi cipar - TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG His6TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGT CTAGTAATGACTGCGAAGATAATCCAACACGGAACAGAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAA ATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAG Name Beschrei- Sequenz

[0275] bung

[0276] AAGTGGCAGTGGAAGTGAACGAGGTGGTTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAGCAGAAGGAGGAGAAAGT GGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGC AGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATG CACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCAT CCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGA TTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAA TCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTT GGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGA AATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACC ATCATCATTGA

[0277] Proteinsequenz ( Seq-ID Nr. 48 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKd RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES G S AS GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGH PEIVEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKF GKTAFD I S I DNGNED LAE I LQKAAGGGS GGGS HHHHHH-pCJL6 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 22 ):

[0278] 04 1.2xDdx4 NA TGAAAA TCGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA TAACGCGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG

[0279] Abi cipar - TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA His6ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTCCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAAGCCAAGACCAACCAACCAACCAATC GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG Name Description Sequence

[0280] bung

[0281] CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGT CTAGTAATGACTGCGAAGATAATCCAACACGGAACAGAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAA ATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAG AAGTGGCAGTGGAAGTGAACGAGGTGGTTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAGCAGAAGGAGGAGAAAGT GGTGGCGGTATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTC TTCCTATGTTCCCATATTTGAGAAGGATAGGTATTCTGGAGAAAATGGAGACA ATTTTAACAGGACTCCAGCTTCATCATCAGAAATGGATGATGGAGGCT CT GCT AGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGA TGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATA GCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATT GTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGATTTTCAAGG TTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTGGTAAAACC GCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAAATCCTGCA GAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCATCATCATT GA

[0282] Proteinsequenz ( Seq-ID Nr. 49 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKd RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES GGGMGDEDWEAEINPHMSSYVPIFEKDRYSGENGDNFNRTPASSSEMDDGGSA S GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKT AFD I S I DNGNED LAE I LQKAAGGGS GGGS HHHHHH-pCJL6 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 23 ):

[0283] 05 1.4xDdx4 NATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG

[0284] Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA E - ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA HiSg

[0285] CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC Name Beschrei- Sequenz

[0286] bung

[0287] TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGT CTAGTAATGACTGCGAAGATAATCCAACACGGAACAGAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAAATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCAAAGCAG AAGTGGCAGTGGAAGTGAACGAGGTGGTTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAGCAGAAGGAGGAAAGT GGTGGCGGTATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTC TTCCTATGTTCCCATATTTGAGAAGGATAGGTATTCTGGAGAAAATGGAGACA ATTTTAACAGGACTCCAGCTTCATCATCAGAAATGGATGATGGACCTTTCGA AGAGATCATTTCATGAAAAGTGGATTTGCCTCTGGGCGGAATTTTGGAAACAG AGATGCTGGTGAGTGTAATAAGCGAGATAATACATCCAATGGGTGGTTTTG GAGTTGGAAAGAGTTTTGGAAACAGAGGCTCTGCTAGCCGGTAGCGATCTGGAT AAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGAAGTTCGTATTCT GATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACCGCGC TGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAA AACGGTGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTT AGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCG CAGATGTGAACTACCATGGATTGATTGATTGATTGATTGATT GATAATGGCAATGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGG TTCAGGTGGTGGTAGC CATCATCACCATCATCATT GA

[0288] Proteinsequenz ( Seq-ID Nr. 50 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKd RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES GGGMGDEDWEAEINPHMS S YVPI FEKDRYS GENGDNFNRTPAS S SEMDDGPSR RDHFMKS GFAS GRNFGNRDAGECNKRDNTS TMGGFGVGKS FGNRG SASGSDLD KKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLK NGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISI DNGNEDLAE I LQKAAGGGS GGGS HHHHHH- Name Beschrei- Sequenz

[0289] chapter

[0290] pCJL6 MBP-3CS- DNA-Sequence ( Seq-ID No. 24 ):

[0291] 06 1.6xDdx4 N A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG

[0292] Abi cipar - TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA His6ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTCCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAAGCCAAGACCAACCAACCAACCAATC GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGT CTAGTAATGACTGCGAAGATAATCCAACACGGAACAGAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAA ATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAG AAGTGGCAGTGGAAGTGAACGAGGTGGTTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAGCAGAAGGAGGAGAAAGT GGTGGCGGTATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTC TTCCTATGTTCCCATATTTGAGAAGGATAGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATCAGAAATGGATGATGGACCTTCTCGA AGAGATCATTTCATGAAAAGTGGATTTGCCTCTGGGCGGAATTTTGGAAACAG AGATGCTGGTGAGTGTAATAAGCGAGATAATACATCCACAATGGGTGGTTTTG GAGTTGGAAAGAGTTTTGGAAACAGAGGTTTTTCAAACAGCAGGTTTGAAGAT GGTGATAGCTCTGGTTTCTGGAGAGAGTCTAGTAATGACTGCGAAGATAATCC AACACGGAACAGAGGGTTTTCCAAGAGAGGCGGCTATCGAGATGGAAATAATT CAGAAGCTTCAGGGGGCTCTGCTAGCGGTAGCGATCTGGATAAAAAACTGCTG GAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGG TGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAG CACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGAT GTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGT TGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACG CACAGGATAAATTTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAAT GAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGG TAGC CATCATCACCATCATCATT GA Name Beschrei- Sequenz

[0293] bung

[0294] Proteinsequenz ( Seq-ID Nr. 51 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKd RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES GGGMGDEDWEAEINPHMS S YVPI FEKDRYS GENGDNFNRTPAS S SEMDDGPSR RDHFMKS GFAS GRNFGNRDAGECNKRDNTS TMGGFGVGKS FGNRGFSNSRFED GD S S GFWRE S SNDCEDNPTRNRGFSKRGGYRDGNNSEAS GG S AS GSDLDKKLL EAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGAD VNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGN ED LAE ILQKAAGGGS GGGS HHHHHH-pCJL6 MBP- 3CS- DNA-Sequenz ( Seq-ID No. 25 ):

[0295] 07 1.8xDdx4 N ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG

[0296] Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA — His6ACTGGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAGCGTTGACCAGGA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTCCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAAGCCAAGACCAACCAACCAACCAATC GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGT CTAGTAATGACTGCGAAGATAATCCAACACGGAACAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAA ATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAG Name Description Sequence

[0297] bung

[0298] AAGTGGCAGTGGAAGTGAACGAGGTGGTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAAGCAGAAGGAGAGAAAGT GGTGGCGGTATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTC TTCCTATGTTCCCATATTTGGAAGGAAGGATAGGTATTCTGGGAGAAAATGGAGACA ATTTTAACAGGACTCCAGCTTCATCATCAGAAATGGATGATGGACCTTCTCGA AGAGATCATTTCATGAAAAGTGGATTTGCCTCTGGGCGGAATTTTGGAAACAG AGATGCTGGTGAGTGAATAAGCGAGATAATACATCCACAATGGGTGGTTTTG GAGTTGGAAAGAGTTTTGGAAACAGAGGTTTTTCAAACAGCAGGTTTTGAAGAT GGTGATAGCTCTGGTTTCTGGAGAGAGATCGGAGAGTCTAGTAATGACTCGAAGATAATCC AAACGGAACAGAGGTTTTTCCAAGAGAGGCGGCTATCGAGATGGAAATAATT CAGAAGCTTCAGGGCCATACAGAAGAGGGTGGAAGAGGGTAGTTTCCGAGGTTGC CGTGGAGGATTTGGTCTAGGAAGTCCAAATAATGACTTAGACCCAGACGAATG TATGCAGCGCACTGGTGGCCTTTTTGGTTTCTAGAAGACCAGTATTAGGCTCTG CTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAG GATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTTAATGCACGTGA TAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGTTCATCCGGAAA TTGTTGAAGTTTCTGCTGAAAAAACGGTGCCGATGTGGAATGCCGCAGATTTTCAA GGTTGGACCCCCTTGCACTTAGCAGCAGCAGTTGGGCCATCTGGAAATCGTGAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTGGTAAAA CCGCCTTTGATATCAGCATCGATAATGGCAATGAAGATCTGGCAGAAATCCTG CAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCATCATCACCATCATCA TTGA

[0299] Proteinsequenz ( Seq-ID Nr. 52 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKd RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES GGGMGDEDWEAEINPHMS S YVPI FEKDRYS GENGDNFNRTPAS S SEMDDGPSR RDHFMKS GFAS GRNFGNRDAGECNKRDNTS TMGGFGVGKS FGNRGFSNSRFED GD S S GFWRE S SNDCEDNPTRNRGFSKRGGYRDGNNSEAS GPYRRGGRGS FRGC RGGFGLGSPNNDLDPDECMQRTGGLFGSRRPVLGSASGSDLDKKLLEAARAGQ DDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLAEIL QKAAGGGS GGGS HHHHHH-pCJL3 MBP- 3CS- DNA-Sequenz ( Seq-ID No. 26):

[0300] 24 2xDdx4 N - ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA Abi cipar- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG - TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTCCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT Name Description- Sequenz

[0301] chapter

[0302] TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGG AGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AAGCAGAAATCAACCCTCATATGTCTTCCTATGTTCCCATATTTGAGAAGGAT AGGTATTCTGGAGAAAATGGAGACAATTTTAACAGGACTCCAGCTTCATCATC AGAAATGGATGATGGACCTTCTCGAAGAGATCATTTCATGAAAAGTGGATTTG CCTCTGGGCGGAATTTTGGAAACAGAGATGCTGGTGAGTGTAATAAGCGAGAT AATACATCCACAATGGGTGGTTTTGGAGTTGGAAAGAGTTTTGGAAACAGAGG TTTTTCAAACAGCAGGTTTGAAGATGGTGATAGCTCTGGTTTCTGGAGAGAGTCTAGTAATGACTGCGAAGATAATCCAACACGGAACAGAGGGTTTTCCAAGAGA GGCGGCTATCGAGATGGAAATAATTCAGAAGCTTCAGGGCCATACAGAAGAGG TGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGATTTGGTCTAGGAAGTCCAA ATAATGACTTAGACCCAGACGAATGTATGCAGCGCACTGGTGGCCTTTTTGGT TCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAG AAGTGGCAGTGGAAGTGAACGAGGTGGTTACAAAGGTTTAAATGAAGAAGTAA TAACAGGCTCTGGAAAGAATTCTTGGAAGTCAGAAGCAGAAGGAGGAGAAAGT GGTGGCGGTATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTC TTCCTATGTTCCCATATTTGAGAAGGATAGGTATTCTGGAGAAAATGGAGACA ATTTTAACAGGACTCCAGCTTCATCATCAGAAATGGATGATGGACCTTCTCGA AGAGATCATTTCATGAAAAGTGGATTTGCCTCTGGGCGGAATTTTGGAAACAG AGATGCTGGTGAGTGTAATAAGCGAGATAATACATCCACAATGGGTGGTTTTG GAGTTGGAAAGAGTTTTGGAAACAGAGGTTTTTCAAACAGCAGGTTTGAAGAT GGTGATAGCTCTGGTTTCTGGAGAGAGTCTAGTAATGACTGCGAAGATAATCC AACACGGAACAGAGGGTTTTCCAAGAGAGGCGGCTATCGAGATGGAAATAATT CAGAAGCTTCAGGGCCATACAGAAGAGGTGGAAGAGGTAGTTTCCGAGGTTGC CGTGGAGGATTTGGTCTAGGAAGTCCAAATAATGACTTAGACCCAGACGAATG TATGCAGCGCACTGGTGGCCTTTTTGGTTCTAGAAGACCAGTATTAAGTGGCACAGGTAATGGTGATACTTCTCAAAGCAGAAGTGGCAGTGGAAGTGAACGAGGT GGTTACAAAGGTTTAAATGAAGAAGTAATAACAGGCTCTGGAAAGAATTCTTG GAAGTCAGAAGCAGAAGGAGGAGAAAGTGGCT CT GCTAGCGGTAGCGATCTGG ATAAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGATGAAGTTCGTATT CTGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCACCGGTTGGACACC GCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTTGAAGTTCTGCTGA AAAACGGTGCCGATGTGAATGCCGCAGATTTTCAAGGTTGGACCCCTCTGCAC TTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGTTACTGAAATATGG CGCAGATGTGAACGCACAGGATAAATTTGGTAAAACCGCCTTTGATATCAGCA TCGATAATGGCAATGAAGATCTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGT GGTTCAGGTGGTGGTAGC CATCATCACCATCATCATT GA

[0303] Proteinsequenz ( Seq-ID Nr. 53 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI Name Beschrei- Sequenz

[0304] bung

[0305] AA TMENAQKGEIMPNIPQMSAFWYAVR T AVI NAAS GRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPMGDEDWEAEINPHMSSYVPIFEKD RY S GENGDNFNRTPAS S SEMDDGPSRRDHFMKS GFAS GRNFGNRDAGECNKRD NTSTMGGFGVGKSFGNRGFSNSRFEDGDSSGFWRESSNDCEDNPTRNRGFSKR GGYRDGNNSEASGPYRRGGRGSFRGCRGGFGLGSPNNDLDPDECMQRTGGLFG SRRPVLSGTGNGDTSQSRSGSGSERGGYKGLNEEVITGSGKNSWKSEAEGGES GGGMGDEDWEAEINPHMS S YVPI FEKDRYSGENGDNFNRTPAS S SEMDDGPSR RDHFMKS GFAS GRNFGNRDAGECNKRDNTS TMGGFGVGKS FGNRGFSNSRFED GD S S GFWRE S SNDCEDNPTRNRGFSKRGGYRDGNNSEAS GPYRRGGRGS FRGC RGGFGLGSPNNDLDPDECMQRTGGLFGSRRPVLSGTGNGDTSQSRSGSGSERG GYKGLNEEVI TGS GKNSWKSEAEGGE S G SAS GSDLDKKLLEAARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLH LAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNEDLAEILQKAAGG GSGGGSHHHHHH-pCJL3 MBP-3CS- DNA-Sequenz ( Seq-ID Nr. 27 ):

[0306] 15 1xFUS N - ATGAAAATCGAAGAAGGTAAACTGGTAATCTGGATTAACGGCGATAAAGGCTA F M -F N- TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG Abi cipar- TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA — - E - ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA His6

[0307] CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATT GCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AACAACAACAACAATAACAATAACAACAACCTCGGGATCGAGGGAAGGGGTGGAGGCGGATCGCTGGAAGTTCTGTTCCAGGGGCCCATGGGAGATGAAGATTGGG AACAAGCAACCCAAAGCTATGGGGCCTACCCCACCCAGCCCGGGCAGGGCTAT TCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGAGTTACAGTGGTTATAGCCA GTCCACGGACACTTCAGGCTATGGCCAGAGCAGCTATTCTTCCTTATGGCCAGA GCCAGAACACAGGCTATGGAACTCAGTCAACTCCCCAGGGATATGGCTCGACT GGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGTCTTACGGCAGCAGTCCTC CTACCCTGGCTATGCCAGCCAGCCAGCCGCCGCCGCCTC GTAGCAGTTCTCAGAGCAGCAGCTATGGGCAGCCCCCAGAGTGGGAGCTACAGC CAACAGCCTAGCTATGGTGGAGCAGCAATCTTACGGTCAACAACAGAGCTA TAATCCCCCTCAGGGCTATGGACAGCAGAACCAGTACAACAGCAGCAGTGGTG GTGGAGGTGGAGGTGGAGGTGGAGGTAACTATGGCCAAGATCAATCCTCCATG AGTAGTGGTGGTGGCAGTGGTGGCGGTTATGCAATCAAGACCAGAGTGGTGG AGGTGGCAGCGGTGGCTATGGACAGCAGGACCGTGGAAGCGGCTCTGGCGGCGG TGCAGGTGGAAACCATTAGCCCGGGTGATGGCCGTACCTTTCCGAAACGTGGC CAGACCTGCGTGGTGCATTACCGGCATGCTGGAAGATGGCAAAAATGGA TAGCAGCCGTGATCGTAACAAACCGTTTAAATTCATGGGGCAAACAGGAAG TGATTCGCGGCTGGGAAGAGGGCGTGGCGCAGATGAGCGTTGGCCAGCGTGCG Name Description- Sequence

[0308] chapter

[0309] AAACTGACCATCAGCCCGGATTATGCCTATGGCGCGACCGGCCATCCGGGTAT TATTCCGCCGCATGCGACCCTGGTGTTTGATGTGGAACTGCTGAAACTGGAAG GCTCTGGCGTGCAGGTGGAAACCATTAGCCCGGGTGATGGCCGTACCTTTCCG AAACGTGGCCAGACCTGCGTGGTGCATTATACCGGCATGCTGGAAGATGGCAA AAAAATGGATAGCAGCCGTGATCGTAACAAACCGTTTAAATTCATGCTGGGCA AACAGGAAGTGATTCGCGGCTGGGAAGAGGGCGTGGCGCAGATGAGCGTTGGC CAGCGTGCGAAACTGACCATCAGCCCGGATTATGCCTATGGCGCGACCGGCCA TCCGGGTATTATTCCGCCGCATGCGACCCTGGTGTTTGATGTGGAACTGCTGA AACTGGAAGGCT CT GCTAGCGGTAGCGATCTGGATAAAAAACTGCTGGAAGCA GCACGTGCAGGTCAGGATGATGAAGTTCGTATTCTGATGGCAAATGGTGCAGA TGTTAATGCACGTGATAGCACCGGTTGGACACCGCTGCATCTGGCAGCACCGT GGGGTCATCCGGAAATTGTTGAAGTTCTGCTGAAAAACGGTGCCGATGTGAAT GCCGCAGATTTTCAAGGTTGGACCCCTCTGCACTTAGCAGCAGCAGTTGGCCA TCTGGAAATCGTGGAAGTGTTACTGAAATATGGCGCAGATGTGAACGCACAGG ATAAATTTGGTAAAACCGCCTTTGATATCAGCATCGATAATGGCAATGAAGAT CTGGCAGAAATCCTGCAGAAAGCAGCCGGTGGTGGTTCAGGTGGTGGTAGCCA TCATCACCATCATCATTGA

[0310] Proteinsequenz ( Seq-ID Nr. 54 ): MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSA GINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS NNNNNNNNNNLGIEGRGGGGSLEVLFQGPASNDYTQQATQSYGAYPTQPGQGY SQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQSQNTGYGTQSTPQGYGST GGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSSSYGQPQSGSYS QQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGNYGQDQSSM SSGGGSGGGYGNQDQSGGGGSGGYGQQDRGSGSGGVQVETISPGDGRTFPKRG QTCVVHYTGMLEDGKKMDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRA KLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEGSAGVQVETISPGDGRTFP KRGQTCVVHYTGMLEDGKKMDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVG QRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEGSASGSDLDKKLLEA ARAGQDDEVRI LMANGADVNARD S TGWTPLHLAAPWGHPE I VEVLLKNGADVNAADFQGWTPLHLAAAVGHLEIVEVLLKYGADVNAQDKFGKTAFDISIDNGNED LAE I LQKAAGGGS GGGS HHHHHH- Table 2. Molecular weights of the proteins used

[0311] Molecular name of the plasmid (including MBP) [kDa] pCJL313 MBP-3CS-1xFUS N -Abicipar-His680.5 pCJL326 MBP-3CS-1. 2xFUS N -Abicipar-His685.4 pCJL327 MBP-3CS-1. 4xFUS N -Abicipar-His689. 6 pCJL328 MBP-3CS-1. 6xFUS N -Abicipar-His693.8 pCJL329 MBP-3CS-1. 8xFUS N -Abicipar-His698.3 pCJL320 MBP-3CS-2xFUS N -Abicipar-His6102.1 pCJL321 MBP-3CS-lxhnRNP C -Abicipar-His671.8 pCJL600 MBP-3CS-1. 2xhnRNP C -Abicipar- 74.8

[0312] His6

[0313] pCJL601 MBP-3CS-1. 4xhnRNP C -Abicipar- 77.4

[0314] His6

[0315] pCJL602 MBP-3CS-1. 6xhnRNP C -Abicipar- 80.1

[0316] His6

[0317] pCJL603 MBP-3CS-1. 8xhnRNPC -Abicipar- 82. 6

[0318] His6

[0319] pCJL322 MBP-3CS-2xhnRNP C -Abicipar-His685.0 pCJL323 MBP-3CS-1xDdx4 N -Abicipar-His684.2 pCJL604 MBP-3CS-1. 2xQdx4 N -Abicipar-His689. 6 pCJL605 MBP-3CS-1. 4xQdx4 N -Abicipar-His694.7 pCJL606 MBP-3CS-1. 6xQdx4 N -Abicipar-His6100.1 pCJL607 MBP-3CS-1. 8xQdx4 N -Abicipar-His6105.1 pCJL324 MBP-3CS-2xDdx4 N -Abicipar-His6109.7 ★ Theoretical molecular weights were determined using the online tool Expasy ProtParam (https: / / web.expasy.org / protparam / ). Table 3 Sequences

[0320] Name Description Sequence

[0321] ung

[0322] MBP Soluble DNA Sequence (Seq ID No. 1):

[0323] keitsdomä A TGAAAA TCGAAGAAGGTAAACTGGTAA TCTGGATTAACGGCGA TAAAGGCTA ne TAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAAAGATACCGGAATTAAAG TCACCGTTGAGCATCCGGATAAACTGGAAGAGAAATTCCCACAGGTTGCGGCA ACTGGCGATGGCCCTGACATTATCTTCTGGGCACACGACCGCTTTGGTGGCTA CGCTCAATCTGGCCTGTTGGCTGAAATCACCCCGGACAAAGCGTTCCAGGACA AGCTGTATCCGTTTACCTGGGATGCCGTACGTTACAACGGCAAGCTGATTGCT TACCCGATCGCTGTTGAAGCGTTATCGCTGATTTATAACAAAGATCTGCTGCC GAACCCGCCAAAAACCTGGGAAGAGATCCCGGCGCTGGATAAAGAACTGAAAG CGAAAGGTAAGAGCGCGCTGATGTTCAACCTGCAAGAACCGTACTTCACCTGG CCGCTGATTGCTGCTGACGGGGGTTATGCGTTCAAGTATGAAAACGGCAAGTA CGACATTAAAGACGTGGGCGTGGATAACGCTGGCGCGAAAGCGGGTCTGACCT TCCTGGTTGACCTGATTAAAAACAAACACATGAATGCAGACACCGATTACTCC ATCGCAGAAGCTGCCTTTAATAAAGGCGAAACAGCGATGACCATCAACGGCCC GTGGGCATGGTCCAACATCGACACCAGCAAAGTGAATTATGGTGTAACGGTAC TGCCGACCTTCAAGGGTCAACCATCCAAACCGTTCGTTGGCGTGCTGAGCGCA GGTATTAACGCCGCCAGTCCGAACAAAGAGCTGGCAAAAGAGTTCCTCGAAAA CTATCTGCTGACTGATGAAGGTCTGGAAGCGGTTAATAAAGACAAACCGCTGG GTGCCGTAGCGCTGAAGTCTTACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACGCCCAGAAAGGTGAAATCATGCCGAACATCCCGCA GATGTCCGCTTTCTGGTATGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCG GTCGTCAGACTGTCGATGAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCG AA CAA CAA CAA CAA TAA CACTGA CGA CGA CGA CGA CGA GG

[0324] Proteinsequenz: ( Seq-ID No. 28 ) MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAA TGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIA YPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTW PLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYS IAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGPSQPSQVLSCAVGAGNA PNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEEELAKDPRI AA TMENAQKGEIMPNIPQMSAFWYAVR TAVINAASGRQTVDEALKDAQTNSSS

[0325] _ NNNNNNNNNNLGIEGR _

[0326] 3CS Schnittst DNA Sequence ( Seq-ID No. 2 ):

[0327] eile CTGGAAGTTCTGTTCCAGGGGCCC

[0328] Protein-Sequence ( Seq-ID No. 29 ):

[0329] _ LEVLFQGP _

[0330] FUS NIDR DNA-Sequence ( Seq-ID No. 3 ):

[0331] GCCTCAAACGATTATACCCAACAAGCAACCCAAAGCTATGGGGCCTACCCCAC CCAGCCCGGGCAGGGCTATTCCCAGCAGAGCAGTCAGCCCTACGGACAGCAGA GTTACAGTGGTTATAGCCAGTCCACGGACACTTCAGCTATGGCCAGAGCAGC TATTCTTCTTATGACCATGACCGACCATCAGCCGACCAACCAACCAACCAAGC CCAGGGATATGGCTCGACTGGCGGCTATGGCAGTAGCCAGAGCTCCCAATCGT CTTACGGGCAGCAGTCCTCCTACCCTGGCTATGGCCAGCAGCCAGCTCCCAGC AGCACCTCGGGAAGTTACGGTAGCAGTTCTCAGCAGCAGCTATGGGCAGCC CCAGAGTGGGAGCTACAGCCAACAGCCTAGCTATGGTGGACAGCAGCAATCTT ACGGTCAACAACAGAGCTATAATCCCCCTCAGGGCTATGGACAGCAGAACCAG TACAACAGCAGCAGT GGT GGAGGT GGAGGT GGAGGT GGAGGTAACTAT GG CCAAGATCAATCCTCCATGAGTAGTGGTGGTGGCAGTGGTGGCGGTTATGGCA ATCAAGACCAGAGTGGTGGAGGTGGCAGCGGTGGCTATGGACAGCAGGACCGT GGA Proteinsequenz ( Seq-ID No. 30 ):

[0332] ASNDYTQQATQSYGAYPTQPGQGYSQQSSQPYGQQSYSGYSQSTDTSGYGQSS YSSYGQSQNTGYGTQSTPQGYGSTGGYGSSQSSQSSYGQQSSYPGYGQQPAPS STSGSYGSSSQSSSYGQPQSGSYSQQPSYGGQQQSYGQQQSYNPPQGYGQQNQ YNSSSGGGGGGGGGGQDQSSMSSGGGGGGYGNQDQSGGGGGGQQQDR

[0333] G

[0334] hnRNP C IDR DNA-Sequence ( Seq-ID No. 4 ):

[0335] ATGGCTAGTGCTTCATCCAGCCAAAGAGGTCGAAGTGGTTCTGGAAACTTTGG TGGTGGTCGTGGAGGTGGTTTCGGTGGGAATGACAACTTCGGTCGTGGAGGAA ACTTTAGTGGTCGAGGCGGTTTCGGTGGGTCGTGGTGGCGGTGGGAATGGA GGTAGTGGGGATGGCTATAATGGATTTGGTAATGGAAGCAATTTGGAGG TGGTGGAAGCTACATGATTTTGGGAATTACAACAATCAGTCTTCAAATTTTG GACCCATGAAGGGAGGAAATTTTGGAGGCAGAAGCTCTGGCCCCTATGGCGGT GGAGGCCAATACTTTGCAAAACCACGAAACCAAGGTGGCTATGGCGGTTCCAG CAGCAGCAGTAGCTATGGCAGTGGCAGAAGATTT

[0336] Protein sequence ( Seq-ID No. 31 ): MASASSQRGRSGSGNFGGGRGGGGGNDNFGRGGNFSGRGGFGGGGGGGYG GSGDGYNGFGNDGSNFGGGGSYNDFGNYNNQSSNFGPMKGGNFGGRSSGPYGGGGQNQY

[0337] Ddx4 N IDR DNA-Sequence ( Seq-ID No. 5 ):

[0338] ATGGGAGATGAAGATTGGGAAGCAGAAATCAACCCTCATATGTCTTCCTATGT TCCCATATTTGAGAAGGATAGGTATTCTGGAAAATGGAGACAATTTTAACA GGACTCCAGCTTCATCATCAGAAATGGATGATGGACCTTCTCGAAGAGATCAT TTCATGAAAAGTGGATTTGCCTCTGGGCGGAATTTTGGAACAGAGATGCTGG TGAGTGTAATAAGCGAGATAATACATCCACAATGGGTGGTTTTGGAGTTGGAA AGAGTTTTGGAACAGAGGTTTTTCAAACAGCAGGTTGAAGATGGTGATAGC. TCTGGTTTCTGGAGAGAGTCTAGTAATGACTGCGAAGATAATCCAACACGGAA CAGAGGGTTTTCCAAGAGAGGCGGCTATCGAGATGGAAATAATTCAGAAGCTT CAGGGCCATACAGAAGAGGTGGAAGAGGTAGTTTCCGAGGTTGCCGTGGAGGA TTTGGTCTAGGAAGTCCAAATAATGACTTAGACCCAGACGAATGTATGCAGCG CACTGGTGGCCTTTTTGGTTCTAGAAAGACCAGTATTAAGTGGCACAGGTAATG GT GATACT CT CAAAGCAGAAGT GGCAGT GGAAGT GAACGAGGT GGTTACAAA GGTTTAAAT GAAGAAGTAATAACAGGCT CT GGAAAGAATT CTT GGAAGT CAGA AGCAGAAGGAGGGAAAGT

[0339] Protein-Sequence ( Seq-ID Nr. 32 ): MGDEDWEAEINPHMSSYVPIFEKDRYSGENGDNFNRTPASSSEMDDGPSRRDH FMKSGFASGRNFGNRDAGECNKRDNTSTMGGFGVGKSFGNRGFSNSRFEDGDS SGFWRESSNDCEDNPTRNRGFSKRGGYRDGNNSEASGPYRRGGRGSFRGCRGG FGLGSPNDLDPDECMQRTGGLFGSRRPVLSGTGNGDTSQSRSGSGSERGGYK GLNEEVITGSGKNSWKSEAEGGES Di - DNA Sequence ( Seq-ID No. 6 ):

[0340] meri si er- GGCGTGCAGGTGGAAACCATTAGCCCGGGTGATGGCCGTACCTTTCCGAAACG ungsdomän TGGCCAGACCTGCGTGGTGCATTATACCGGCATGCTGGAAGATGGCAAAAAAAA e TGGATAGCAGCCGTGATCGTAACAAACCGTTTAAATTCATGCTGGGCAAACAG GAAGTGATTCGCGGCTGGGAAGAGGGCGTGGCGCAGATGAGCGTTGGCCAGCG TGCGAAACTGACCATCAGCCCGGATTATGCCTATGGCGCGACCGGCCATCCGG GTATTATTCCGCCGCATGCGACCCTGGTGTTTGATGGGAACTGCTGAAACTG GAA

[0341] Protein sequence ( Seq-ID No. 33 ): GVQVETISPGDGRTFPKRGQTCWHYTGMLEDGKKMDSSRDRNKPFCFMLGKQ EVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKL E

[0342] Abici Wirkstoff DNA-Sequence ( Seq-ID No. 7 ):

[0343] pair GGTAGCGATCTGGATAAAAACTGCTGGAAGCAGCACGTGCAGGTCAGGATGA

[0344] TGAAGTTCGTATTCTGATGGCAAATGGTGCAGATGTTAATGCACGTGATAGCA CCGGTTGGACACCGCTGCATCTGGCAGCACCGTGGGGTCATCCGGAAATTGTT GAAGTTCTGCTGAAAAACGGTGCCGATGTGAATGCCGCAGATTCAAGGTTG GACCCCTCTGCACTTAGCAGCAGCAGTTGGCCATCTGGAAATCGTGGAAGTGT TACTGAAATATGGCGCAGATGTGAACGCACAGGATAAATTTGGTAAAACCGCC TTT GAT AT CAGCAT CGATAAT GGCAAT GAAGAT CT GGCAGAAAT CCT GCAGAA AGCAGGGTGGTGGGTGGGGGTA

[0345] Protein-Sequence ( Seq-ID Nr. 34 ): GSDLDKKLLEAARAGQDDEVRILMANGADVNARDSTGWTPLHLAAPWGHPEIV E VL L KN GADVNAAD FQ GWT P LH LAAAVGH LEI VE VL LK YGADVNAQ DK FGKT A FDISGIDGGGGGGGGGG

[0346] His 6 Tag DNA-Sequence ( Seq-ID No. 8 ):

[0347] CAT CAT C AC CAT CAT CAT

[0348] Protein-Sequence ( Seq-ID No. 35 ):

[0349] HHHHHH Table 4: IUPred2-Scores ( type length) for FUS ( Seq-ID No. 30 ):

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

Claims

Patent claims 1. Macromolecule or macromolecular complex comprising at least one intrinsically disordered region (IDR) and at least one therapeutically active substance.

2. Macromolecule or macromolecule complex according to claim 1, characterized in that at least one IDR is a peptide.

3. Macromolecule or macromolecular complex according to claim 1 or 2, characterized in that the at least one IDR is at least 50 amino acids long.

4. Macromolecule or macromolecule complex according to one of the preceding claims, characterized in that the at least one therapeutically active substance is arranged at the N-terminus or C-terminus of the IDR.

5. Macromolecule or macromolecule complex according to one of the preceding claims, characterized in that the at least one therapeutically active substance is arranged at the C-terminus of the IDR.

6. Macromolecule or macromolecular complex according to one of the preceding claims, characterized in that the macromolecule or macromolecular complex comprises at least one cleavable solubility domain.

7. Macromolecule or macromolecule complex according to any of the preceding claims, characterized in that the therapeutically active substance is a substance for the treatment of age-related macular degeneration.

8. Macromolecule or macromolecule complex according to any one of claims 1 to 7, characterized in that the at least one therapeutically active substance is a peptide.

9. Macromolecule or macromolecule complex according to any one of claims 1 to 7, characterized in that the at least one IDR and the at least one therapeutically active substance are a peptide.

10. Nucleic acid comprising a fusion protein encoding the at least one IDR and the at least one therapeutically active substance according to claim 9.

11. Use of the macromolecule or macromolecule complex according to any one of claims 1 to 9 as a drug.

12. Use of the macromolecule or macromolecule complex according to any one of claims 1 to 9 for the treatment of ophthalmic diseases.

13. Method for providing a depot of the therapeutically active substance in vitro comprising the following steps: a) Providing the macromolecule or macromolecule complex according to any one of claims 1 to 9 under conditions such that LLPS takes place; b) Waiting for phase separation; c) Obtaining a composition with compartments that form the depot of the therapeutically active substance.

14. Pharmaceutical composition comprising the macromolecule or macromolecule complex according to any one of claims 1 to 9.

15. Kit comprising the macromolecule or macromolecule complex according to any one of claims 1 to 9.

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