Inducible gene expression system

Abstract

The present disclosure relates to the field of molecular biology and nucleic acid technology. The disclosure also relates to therapies and prophylaxis of disease.

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) ™ (19) World Intellectual Property SS Organization LNA AMAA International Bureau — (10) International Publication Number (43) International Publication Date =— WO 2024 / 251925 Al 12 December 2024 (12.12.2024) WIPOIPCT (51) International Patent Classification: (74) Agent: BUSER, Andres; c / o F. Hoffmann-La Roche AG, CI2N 15 / 63 (2006.01) CI2N 15 / 1 (2006.01) Patent Department, Grenzacherstrasse 124, 4070 Basel CI2N 15 / 1173 (2010.01) CI2N 15 / 86 (2006.01) (CH). A6LK 48 / 00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available); AE, AG, AL, AM, PCT / EP2024 / 065689 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 22) Int ti 1 Filing Date: CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, (22) International Filing Date: 07 June 2024 (07.06.2024 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, une (07.06.2024) HN,HR, HU, ID, IL, IN, IO, IR, IS, IT, JM, JO, JP, KE, KG, (25) Filing Language: English KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, 6 lication L . Enelish MA, MD, MG, MK, MN, MU, MW, Mx, MY, MZ, NA, (26) Publication Language: nglis NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, (30) Priority Data: RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, 23178358.0 09 June 2023 (09.06.2023) EP TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, : . ZA, ZM, ZW. (71) Applicant (for all designated States except US): F. HOFF- MANN-LA ROCHE AG [CH / CH]; Grenzacherstrasse (84) Designated States (unless otherwise indicated, for every 124, 4070 Basel (CH). kind of regional protection available): ARIPO (BW, CV, . GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, (71) Applicant (for US only): HOFFMANN-LA ROCHE SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, — INC. [US / U SI; Overlook at Great Notch, 150 Clove Road, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, — 8th Floor, Suite8 - Legal Department, Little Falls, New Jer- DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, — sey 07424 (US). LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, == (72) Inventors: EBELING, Martin: c / o F. Hoffmann-La Roche SL SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, — AG, Grenzacherstrasse 124, 4070 Basel (CH). JAGASIA, GQ, GW, KM, ML, MR, NE, SN, TD, TG). = Ravi; c / o F. Hoffmann-La Roche AG, Grenzacherstrasse — 124, 4070 Basel (CH). MENDEL, Mateusz Piotr; c / o Published: — F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 — _ with international search report (Art. 21(3)) — Basel (CH). ROUDNICKY, Filip, c / o F. Hoffmann-La — i” black and white; the international application as filed — Roche AG, Grenzacherstrasse 124, 4070 Basel (CH). contained color or greyscale and is available for download — SCHUKUR, Lina; c / o F. Hoffmann-La Roche AG, Gren- from PATENTSCOPE — zacherstrasse 124, 4070 Basel (CH). me (54) Title: INDUCIBLE GENE EXPRESSION SYSTEM =— in-frame — ¥ —-Risdiplam +Risdiplam re _ Brent | Exon | Exons | col N in fa Figure 1 a NN 4 (57) Abstract: The present disclosure relates to the fields of molecular biology and nucleic acid technology. The present disclosure ° also relates to therapy and prophylaxis of disease. WO 2024 / 251925 PCT / EP2024 / 065689 Inducible Gene Expression System This application claims priority from EP23178358.0 filed 9 June 2023, the contents and elements of which are herein incorporated by reference for all purposes. Technical Field The present disclosure relates to the fields of molecular biology and nucleic acid technology. The present disclosure also relates to therapy and prophylaxis of disease. 5 Background Gene therapy as a modality aims at ameliorating disease-related phenotypes by using both viral and non- viral delivery systems. Significant efforts have been focusing on optimizing this therapy to be more efficient, non-immunogenic and less toxic while enabling a long-term expression of the gene of interest.One of the key challenges to achieve this goal is to regulate the expression of the transgene to meet the 10 required level and to be expressed upon demand. For certain targets, where constitutive and unlimited expression leads to adverse events, regulated gene expression is necessary to render gene therapy a viable option as a treatment modality. One example is Rett Syndrome (RTT), an X-linked neurological disorder associated with severe motor abnormalities and 15 reduced lifespan that occurs in 1 in 1,000 females. RTT is characterized by seemingly normal neurological and physical development during early postnatal period followed by a rapid regression with the loss of the purposeful motor skills and the onset of repetitive and autistic behaviors'*. During the rapid progression stage, the child loses purposeful hand skills and spoken language, experiences motor impairments, and develops breathing abnormalities and may also develop autistic-like features and 20 seizures. At laterstages, further motor deterioration begins, typified by severe physical disability, which leads many patients to become dependent on the use of wheelchairs. Current treatment options are limited to symptom control. Mutations in the MECP2 gene on the X chromosome, encoding for methyl- CpG-binding protein 2 account for 95% of RTT cases*. MeCP2 is highly expressed in neurons and functions as a ubiquitous transcriptional regulator by binding to methylated DNA and recruiting protein 25 partners and regulatory complexes to control transcriptional activity. MeCP2 regulates neuronal physiology and maintenance and landmark studies have demonstrated that restoring levels of the MeCP2 protein dramatically reverses symptoms in mice*?. Given that it is a monogenetic disorder driven by the lack of MeCP2, a protein with multiple functions, 30 gene therapy is one potential avenue to treat RTT. Studies in RTT mice have provided encouraging data showing attenuated neurological dysfunctions as well asextended lifespan by intravenous administration of an Adeno-associated virus serotype 9 (AAV9) expressing the wild-type (WT) MeCP2 gene>*. Despite the promising potential of gene replacement therapy, high doses of MeCP2 by overexpression systems — which rely on the use of ubiquitous promoters resulting in uncontrolled level of the transgene — can lead 35 to toxicity with phenotypes similar to those observed in duplication syndrome, a condition mainly affecting males, characterized by moderate to severe intellectual impairment, and caused by a duplication of the MeCP2 gene on the X-chromosome®"°. The requirement of keeping MeCP2 expression level within a window for normal function is one of the most challenging aspects that has yet to be solved. One solution 1 WO 2024 / 251925 PCT / EP2024 / 065689 would be to develop controlled transgene expression systems in order to overcome this limitation and make gene therapy a viable treatment option. Inducible gene expression systems allow forreversibility and flexibility and enable the production of 5 therapeutics upon demand, thereby circumventing overdose-associated side effects. Such regulation can be achieved using small molecules, with which transgene expression can be induced (generating ON- switches) or repressed (OFF-switch). Among the existing inducible transcriptional gene regulatory systems, the tetracycline (Tet)-regulable system is the most widely exploited tool and can be used as an ON- or an OFF-switch. Tet-inducible systems, however, are derived from bacteria and require the 10 expression of the regulator protein, e.g. the ON-switch components include the tetracycline-controlled transactivator (tTA), which consists of the bacterial tetR with a C-terminal domain of VP16 (virion protein 16), derived from the herpes simplex virus. The required co-expression of these components further increase the limitations in the size of the transgene for AAV packaging, and can cause both silencing and potentialimmunogenicity effects when introduced into human tissue, which has hampered further 15 translation into the clinics’7. Another class of genetic switches originating from bacteria are riboswitches, RNA elements that are able to control gene expression in response to ligand binding, have a small genomic footprint and do not depend on other proteins for activity, which renders these types of regulated gene expression an attractive alternative to protein-based expression control systems'°. However, riboswitches suffer from a poor dynamic range as well as high basal activity’. 20 A new class of small molecules that regulate splicing of SMN2 exon 7 was recently identified, via screening using a reporter system based on the SMN2 transcript (described e.g. in WO 2009 / 151546 A2). SMN2 reporter systems have since been proposed to be used as gene expression switches, where expression of a transgene is regulated through small molecule-controlled splicing of the expression 25 cassette (Monteys efal. Nature (2021) 596: 291-295). Known human SMN2 exon 6 to exon 8-derived transgene expression systems are described e.g. in Zhang, ef al., Gene Ther. (2001) 8: 1532-1538, WO 2022 / 204471 A1, Monteys ef a / . Nature (2021) 596: 291-295 and WO 2021 / 163556 A1. However, these known SMNZ2-based switch systems have very long nucleotide sequences, limiting the 30 __ size of the transgene that can be employed under the control of the system. That is, the size of an insert comprising the switch and the coding sequence for a therapeutic polypeptide to be delivered as gene therapy would very often be much larger than the packaging limit for vectors routinely employed in the delivery of gene therapies, e.g. adeno-associated viral (AAV) vectors. 35 Summary In a first aspect, the present disclosure provides a polynucleotide comprising in 5’ to 3’ order: (i) a first nucleotide sequence, comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ IDNO:222, wherein the first nucleotide sequence does not comprise SEQ ID NO:2; 40 (ii) a second nucleotide sequence, comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:7 at its 5’ end, and comprising a nucleotide sequence having at least 2 WO 2024 / 251925 PCT / EP2024 / 065689 80% sequence identity to a nucleotide sequence according to SEQ ID NO:378 at its 3’ end, and consisting of fewer than 1044 nucleotides; (iii) a third nucleotide sequence consisting of a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:226; 5 (iv) a fourth nucleotide sequence, comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:15 at its 5’ end, and comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:16 at its 3’ end; (v) a fifth nucleotide sequence: (a) consisting of the dinucleotide ‘GA’, ‘TG’ or ‘TT’, or (b) comprising a nucleotidesequence having at least 80% sequence identity to a nucleotide sequence 10 according to SEQ ID NO:19, wherein the nucleotide sequence comprises ‘GA’, ‘TG’ or ‘TT’ at the positions corresponding to positions 1 and 2 of SEQ ID NO:19, or (c) encoding a polypeptide of interest, and comprising ‘GA’, ‘TG’ or ‘TT’ at positions 1 and 2; and (vi) where the fifth nucleotide sequence is a nucleotide sequence according to (v)(a) or (v)(b), a sixth nucleotide sequence encoding a polypeptide of interest; 15 wherein the polynucleotide comprises a start codon 35’ to the nucleotide sequence encoding a polypeptide of interest. In a second aspect, the present disclosure provides a polynucleotide comprising in 5’ to 3’ order: (i) a first nucleotide sequence, comprising a nucleotide sequence having at least 80% sequence 20 identity to a nucleotide sequence according to SEQ ID NO:1, wherein the first nucleotide sequence does not comprise SEQ ID NO:2; (ii) a second nucleotide sequence, comprising anucleotide sequence having at least 80% sequence identity to SEQ ID NO:7 at its 5’ end, and comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 at its 3’ end, and consisting of fewer than 1044 nucleotides; 25 (iii) a third nucleotide sequence consisting of a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:26, wherein the third nucleotide sequence comprises ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; (iv) a fourth nucleotide sequence, comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:15 at its 5’ end, and comprising a nucleotide sequence having at least 30 80% sequence identity to SEQ ID NO:16 at its 3’ end; (v) a fifth nucleotide sequence: (a) consisting of the trinucleotide ‘GAG’ or (b) encoding a polypeptide of interest, and comprising ‘GAG’ at positions 1 to 3; and (vi) where the fifth nucleotide sequence is a nucleotide sequenceaccording to (v)(a), a sixth nucleotide sequence encoding a polypeptide of interest; 35 wherein the polynucleotide comprises a start codon 5’ to the nucleotide sequence encoding a polypeptide of interest. In some embodiments in accordance with the various aspects of the present disclosure, when the polynucleotide is a polyribonucleotide, splicing of the polyribonucleotide in the absence of a splicing 40 modifier that promotes SMNV2 exon 7 inclusion yields polyribonucleotides substantially lacking the third nucleotide sequence. 3 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the first nucleotide sequence comprises a nucleotide sequence according to SEQ ID NO:222. In some embodiments, the first nucleotide sequence comprises, or consists of, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:106, SEQ ID NO:219 or SEQ ID NO:220. In some embodiments, the first nucleotide sequence comprises, or consists of, SEQ ID NO:3. 5 In some embodiments, the second nucleotide sequence comprisesSEQ ID NO:7 at its 5’ end, and comprises SEQ ID NO:8 or SEQ ID NO:377 at its 3’ end. In some embodiments, the second nucleotide sequence consists of fewer than 500 nucleotides. In some embodiments, the second nucleotide sequence comprises, or consists of, SEQ ID NO:9, SEQ ID NO:10 or SEQ ID NO:228. In some 10 embodiments, the first nucleotide sequence comprises, or consists of, SEQ ID NO:10. In some embodiments, the third nucleotide sequence consists of a nucleotide sequence according to SEQ ID NO:226. In some embodiments, the third nucleotide sequence consists of SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:223 or SEQ ID NO:224. In some embodiments, the third nucleotide sequence 15 consists of a nucleotide sequence according to SEQ ID NO:26. In some embodiments, the third nucleotide sequence consists of SEQ ID NO:13 or SEQ ID NO:27. In some embodiments, the fourth nucleotide sequence comprises SEQ ID NO:15 or SEQ ID NO:379 at its 5’ end, and comprises SEQ ID NO:16 at its 3’ end. In someembodiments, the fourth nucleotide sequence 20 consists of fewer than 500 nucleotides. In some embodiments, the fourth nucleotide sequence comprises, or consists of, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:227 or SEQ ID NO:340. In some embodiments, the fourth nucleotide sequence comprises, or consists of, SEQ ID NO:17. In some embodiments, the fifth nucleotide sequence: (a) consists of the dinucleotide ‘GA’ or ‘TG’, or (b) 25 comprises, or consists of, a nucleotide sequence according to SEQ ID NO:19. In some embodiments, the fifth nucleotide sequence: (a) consists of the dinucleotide ‘GA’ or ‘TG’, or (b) comprises, or consists of, SEQ ID NO:20 or SEQ ID NO:21. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% 30 sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:111, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:164 and SEQ ID NO:171. In some embodiments,the polynucleotide comprises at least 80% sequence identity to SEQ ID NO:28 or SEQ ID NO:29. 35 In some embodiments, the polynucleotide further comprises a promoter sequence 5’ to the start codon. In some embodiments, the polynucleotide further comprises a polyadenylation sequence 3’ to the nucleotide sequence encoding a polypeptide of interest. 40 In some embodiments, the polynucleotide comprises an inverted terminal repeat (ITR) sequence at its 5’ end, and an ITR sequence at its 3’ end. 4 WO 2024 / 251925 PCT / EP2024 / 065689 The present disclosure also provides a vector comprising a polynucleotide according to the present disclosure. In some embodiments, the vector is an adeno-associated virus (AAV) vector. The present disclosure also provides a pharmaceutical composition comprising a polynucleotide or vector 5 according to the present disclosure, and a pharmaceutically-acceptable carrier, diluent, excipient or adjuvant. The present disclosure also provides a cell comprising apolynucleotide or vector according to the present disclosure. In some embodiments, the cell further comprises a splicing modifier that promotes SMN2 10 exon 7 inclusion. In some embodiments, the splicing modifier that promotes SMN2 exon 7 inclusion is risdiplam. The present disclosure also provides a method for modifying a cell to express a polypeptide of interest, comprising: 15 (i) introducing into a cell a polynucleotide or vector according to the present disclosure; and (ii) subsequently contacting the cell with a splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the splicing modifier that promotes SMN2 exon 7 inclusion is risdiplam. The present disclosure also provides a method for expressing a polypeptide of interest in a cell, 20 comprising contacting a cell according to the present disclosure with a splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the splicing modifier that promotes SMN2 exon 7 inclusion is risdiplam. Thepresent disclosure also provides a method for inhibiting expression of a polypeptide of interest in a 25 cell, comprising contacting a cell according to the present disclosure with a splicing modifier that promotes SMNN2 exon 7 inclusion. The present disclosure also provides a method for modifying a cell to express a polypeptide of interest, comprising introducing into a cell a polynucleotide or vector according to the present disclosure. 30 The present disclosure also provides a polynucleotide, vector or pharmaceutical composition according to the present disclosure, for use in a method of medical treatment or prophylaxis. The present disclosure also provides a polynucleotide, vector or pharmaceutical composition according to 35 the present disclosure, for use in treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in the level of expression of the polypeptide of interest. The present disclosure also provides the use of apolynucleotide, vector or pharmaceutical composition 40 according to the present disclosure, in the manufacture of a medicament for treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in the level of expression of the polypeptide of interest. 5 WO 2024 / 251925 PCT / EP2024 / 065689 The present disclosure also provides a method of treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in the level of expression of the polypeptide of interest, comprising administering to a subject a polynucleotide, vector or pharmaceutical composition 5 according to the present disclosure. In some embodiments, treating or preventing the disease or condition further comprises administering to the subject a splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the splicing modifier that promotes SMANV2 exon 7 inclusion is risdiplam. 10 In some embodiments, thedisease or condition is a disease or condition characterised by deficiency of the polypeptide of interest. The present disclosure also provides a kit, comprising: 15 (i) a polynucleotide, vector or pharmaceutical composition according to the present disclosure; and (ii) a splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the splicing modifier that promotes SMA / 2 exon 7 inclusion is risdiplam. 20 Description The present disclosure relates to inducible transgene expression systems using small molecule splicing modifiers (SMSM), and based on the described mechanism of action of the Survival of Motor Neuron 2 (SMN2) splicing modifier risdiplam (and variants thereof). 25 The SMSM binding sites for SMN2 have previously been described to be two distinct sites within SMN2 exon 7 pre-mRNA: the ESE2 region and the 5’ splice donor site (5’ss) (Figure 2a)'°. Interaction of the small molecules with the mRNA-protein complex is thought to be critical for the high selectivityof the compound. This study suggested that both ESE2 and 5'ss regions are required for full activity of the SMSM compounds in a dose-dependent manner". Structural analysis using a compound from the same 30 chemical class as risdiplam (SMN-C5) has demonstrated that the drug selectively promotes the recognition of the weak 5’ splice site of SMN2 exon 7 by U1 snRNP by stabilizing an unpaired adenine at the exon-intron junction in the RNA helix’®. The present disclosure provides novel S / MMN / 2 exon 6 to exon 8-derived constructs providing for the 35 SMSM-inducible regulation of transgene expression, which are suitable to be employed for chemically- inducible regulation of the expression of gene therapies. In particular, the present disclosure provides ON-switch constructs: (i) having a size permitting their application for the SMSM-inducible expression of polypeptides to be delivered as gene therapies, (ii) 40 minimising undesirable expression of the polypeptide in the absence of the SMSM,and (ili) which are highly responsive to the SMSM, thus providing for strong induction of expression of the polypeptide in the presence of the SMSM, and (iv) that minimise the number of / completely remove extraneous amino acids 6 WO 2024 / 251925 PCT / EP2024 / 065689 at the N-terminus of the expressed polypeptide. The present disclosure also provides OFF-switch constructs: (i) having a size permitting their application for the SMSM-inducible expression of polypeptides to be delivered as gene therapies, (ii) maximising expression of the polypeptide in the absence of the SMSM, and (iii) which are highly responsive to the SMSM, thus minimising expression of 5 the polypeptide in the presence of the SMSM, and (iv) that minimise the number of / completely remove extraneous amino acids at the N-terminus of the expressed polypeptide. Polynucleotides Aspects and embodiments of the present disclosure relate to polynucleotides. 10 A 'polynucleotide' refers to a polymer chain of a plurality of nucleotidemonomers linked by bonds between the monomers, typically phosphodiester bonds (e.g. in the case of polynucleotides formed by naturally-occurring nucleotide monomers). Polynucleotides include oligonucleotides, which generally comprise £50 nucleotides. A polynucleotide may be single-stranded, or may be double-stranded (i.e. may 15 comprise a duplex formed by hydrogen-bonding between complementary nucleotides). Polynucleotides according to the present disclosure may comprise or consist of: single-stranded DNA, double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single-stranded RNA, double- stranded RNA, RNA that is mixture of single- and double-stranded regions, single-stranded molecules comprising DNA and RNA, double-stranded molecules comprising DNA and RNA, and molecules 20 comprising DNA and RNA having a mixture of single- and double-stranded regions. In some embodiments, a polynucleotide comprises or consists of DNA. In some embodiments, apolynucleotide is a polydeoxyribonucleotide. In some embodiments, a polynucleotide comprises or consists of RNA. In some embodiments, a polynucleotide is a polyribonucleotide. 25 In aspects and embodiments wherein the polynucleotide of the present disclosure is defined by reference to a given nucleotide sequence, and wherein the given nucleotide sequence comprises or consists of RNA and / or is a polyribonucleotide, it will be appreciated that instances of ‘T’ for thymidine in such sequences are replaced with ‘U’, for uracil. 30 The present disclosure also contemplates polynucleotides comprising modified nucleotides, e.g. in which the phosphonate and / or ribose and / or base of a deoxyribonucleotide or ribonucleotide is / are chemically modified. Nucleotide modifications contemplated in accordance with the present disclosure include those described in Hu et a / ., Sig. Transduc. Tar. Ther. (2020) 5(101), which is hereby incorporated by reference 35 in its entirety. Phosphonate modifications maybe selected from phosphorothioate (e.g. Rp isomer, Sp isomer), phosphorodithioate, methylphosphonate, methoxypropylphosphonate, 5'-(E)-vinylphosphonate, 5'- methylphosphonate, (S)-5'-C-methyl with phosphate, 5’-phosphorothioate, and peptide nucleic acid 40 modifications. Ribose modifications may be selected from 2'-O-methyl, 2'-O-methoxyethyl, 2’-fluoro, 2’- deoxy-2’-fluoro, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-deoxy, 2'-hydroxyl, 2'-arabino-fluoro, 2’-O-benzyl, 2’-O-methyl-4-pyridine, locked nucleic acid, (S)-cEt-BNA, tricyclo-DNA, PMO, unlocked 7 WO 2024 / 251925 PCT / EP2024 / 065689 nucleic acid, hexitol nucleic acid and glycol nucleic acid modifications. Base modifications may be selected from pseudouridine, 2'-thiouridine, N6'-methyladenosine, 5’-methylcytidine, 5'-fluoro-2’- deoxyuridine, N-ethylpiperidine 7'-EAA triazole-modified adenine, N-ethylpiperidine 6'-triazole-modified adenine, 6'-phenylpyrrolo-cytosine, 2',4’-difluorotoluyl ribonucleoside and5'-nitroindole modifications. 5 In some embodiments, a modified nucleotide may be selected from 2'-O-methyluridine-3'-phosphate, 2'- O-methyladenosine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methyluridine-3'-phosphorothioate, 2'-O-methyladenosine-3'-phosphorothioate, 2'-O- methylguanosine-3'-phosphorothioate, 2'-O-methylcytidine-3'-phosphorothioate, 2'-fluorouridine-3'- 10 phosphate, 2'-fluoroadenosine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, 2'-fluorocytidine-3'- phosphate, 2'-fluorocytidine-3'-phosphorothioate, 2'-fluoroguanosine-3'-phosphorothioate, 2'- fluoroadenosine-3'-phosphorothioate, and 2'-fluorouridine-3'-phosphorothioate. Nucleotide sequences of the polynucleotides of the present disclosure 15 Polynucleotides of the present disclosure are defined herein by reference to constituent nucleotide sequences. It will be appreciated that the constituent nucleotide sequences of polynucleotides according to the present disclosureare provided as subsequences of the complete sequence of the polynucleotide. 20 In some aspects and embodiments, the constituent nucleotide sequences of polynucleotides according to the present disclosure are provided in a particular order in the sequence of the polynucleotide, e.g. from 5’ to 3’. By way of illustration, the first nucleotide sequence is provided 5’ to (i.e. upstream of) the second nucleotide sequence, in the context of the sequence of the polynucleotide. Similarly, the second 25 nucleotide sequence is 5’ to the third nucleotide sequence, etc. The constituent nucleotide sequences of the polynucleotides of the present disclosure are non- overlapping. In some embodiments, constituent nucleotide sequences of the polynucleotides are provided in tandem in the context of the complete sequence of the polynucleotide. In some embodiments, 30 constituent nucleotide sequences of the polynucleotide are immediately adjacent to one another (i.e. the 3’ nucleotide of a givennucleotide sequence is followed immediately by the 5’ nucleotide of another given nucleotide sequence, in the context of the complete sequence of the polynucleotide). By way of illustration, in the polynucleotide of SEQ ID NO:22, positions 1 to 45 form the first nucleotide sequence, positions 46 to 309 form the second nucleotide sequence, positions 310 to 364 form the third nucleotide 35 sequence, positions 356 to 616 form the fourth nucleotide sequence, and positions 617 and 618 form the fifth nucleotide sequence. First nucleotide sequence The first nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotide 40. sequence which is a variant of human SMN2 exon 6. A ‘variant’ of a given reference nucleotide sequence comprises one or more differences relative to the reference nucleotide sequence. For example, a variant 8 WO 2024 / 251925 PCT / EP2024 / 065689 of a given reference nucleotide sequence may comprise insertion, deletion or substitution of one ormore nucleotides relative to the reference nucleotide sequence. Accordingly, in some embodiments, the first nucleotide sequence does not consist of, or does not 5 comprise, SEQ ID NO:2. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having «100% sequence identity to SEQ ID NO:2. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 10 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1. It will be appreciated that ‘a nucleotide sequence according to SEQ ID NO:1’ refers to a nucleotide sequence conforming to the consensus nucleotide sequence of SEQ ID NO:1. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:1 include SEQ ID NOs:3, 4, 5, 6 and 106. 15 In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotidesequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:3. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide 20 sequence according to SEQ ID NO:4. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 60% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:5. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 25 100%) sequence identity to SEQ ID NO:6. In some embodiments, the first nucleotide sequence comprises, or consists of, anucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:221. Exemplary 30 sequences conforming to the consensus nucleotide sequence of SEQ ID NO:1 include SEQ ID NOs:219 and 220. In some embodiments, the first nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, =95%, 296%, 297%, 298%, 35 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:222. In some embodiments, the first nucleotide sequence comprises ‘CAG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2 (cf. e.g. positions 109 to 111 of SEQ ID NO:°6). 40 As explained herein, position(s) of a nucleotide sequence which ‘corresponds to’ specified position(s) of a reference nucleotide sequence can be identified by sequence alignment of the subject sequence to thereference sequence, e.g. using sequence alignment software such as ClustalOmega (Séding, J. 2005, 9 WO 2024 / 251925 PCT / EP2024 / 065689 Bioinformatics 21, 951-960). By way of illustration, it will be appreciated that positions 43 to 45 of SEQ ID NO:3 correspond to positions 109 to 111 of SEQ ID NO:2. Similarly, positions 45 to 47 of SEQ ID NO:4 correspond to positions 109 to 111 of SEQ ID NO:2. 5 In some embodiments, the first nucleotide sequence comprises ‘CTG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2 (cf. e.g. positions 109 to 111 of SEQ ID NO:5). In some embodiments, the first nucleotide sequence comprises ‘GGC’ at the positions corresponding to positions 64 to 66 of SEQ ID NO:2 (cf. e.g. positions 64 to 66 of SEQ ID NO:5, positions 64 to 66 of SEQ 10 ID NO:6). In some embodiments, the first nucleotide sequence comprises ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2 (cf. e.g. positions 16 to 18 of SEQ ID NO:3, positions 18 to 20of SEQ ID NO:4, positions 82 to 84 of SEQ ID NO:5). 15 In some embodiments, the first nucleotide sequence comprises ‘GGC’ at the positions corresponding to positions 64 to 66 of SEQ ID NO:2, and comprises ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2. 20 In some embodiments, the first nucleotide sequence comprises ‘GTG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2. In some embadiments, the first nucleotide sequence comprises ‘TTG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2. In some embodiments, the first nucleotide sequence comprises ‘TAG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2. In some embodiments, the first nucleotide sequence comprises ‘CAG’ at the positions 25 corresponding to positions 39 to 41 of SEQ ID NO:2. In some embodiments, the first nucleotide sequence comprises ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2. In some embodiments, thefirst nucleotide sequence consists of fewer than 111 nucleotides. In some embodiments the first nucleotide sequence consists of <100 nucleotides, e.g. one of <85 nucleotides, <80 30 nucleotides, <75 nucleotides, <70 nucleotides, <65 nucleotides, <60 nucleotides, <55 nucleotides, <50 nucleotides or <45 nucleotides. In some embodiments, the first nucleotide sequence consists of 45 nucleotides. In some embodiments, the first nucleotide sequence consists of 51 nucleotides. In some embodiments, the first nucleotide 35 — sequence consists of 81 nucleotides. In some embodiments, the first nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1; and (ii) 40 comprises ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iii) consists of 45 nucleotides. Examples of such firstnucleotide sequences include SEQ ID NOs:3, 4 and 106. 10 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the first nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1; and (ii) comprises ‘GGC’ at the positions corresponding to positions 64 to 66 of SEQ ID NO:2; and (iii) comprises 5 ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iv) comprises ‘CTG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2. An example of such a first nucleotide sequence is SEQ ID NO:5. In some embodiments, the first nucleotide sequence comprises, or consists of: (i) a nucleotide sequence 10 having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ IDNO:1; and (ii) comprises ‘GGC’ at the positions corresponding to positions 64 to 66 of SEQ ID NO:2; and (iii) comprises ‘GGC at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iv) comprises ‘CAG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2. An example of such a first 15 nucleotide sequence is SEQ ID NO:6. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 20 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:3, 5, 6, 219, 220, and 230 to 237. In some embodiments, a polynucleotide according to the present disclosure does not comprise the nucleotide sequence of SEQ ID NO:2. 25 In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotidesequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:3. In some embodiments, a polynucleotide according to the 30 present disclosure comprises a nucleotide sequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, =97%, 298%, =99% or 100%) sequence identity to SEQ ID NO:5. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% 35 = (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:6. In some embodiments, a polynucleotide according to the present disclosure comprises anucleotide sequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:219. In some embodiments, 40 a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a first nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one 11 WO 2024 / 251925 PCT / EP2024 / 065689 of 285%, =90%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:220. Second nucleotide sequence 5 The second nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotide sequence which is a variant of human SMA intron 6. Accordingly, in some embodiments, the second nucleotide sequence does not consist of, or does not comprise, SEQ ID NO:30. In some embodiments, the second nucleotide sequence comprises, orconsists 10 of, a nucleotide sequence having <100% sequence identity to SEQ ID NO:30. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end. 15 In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 204%, 295%, 296%, 297%, 208%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:378 at its 3’ end. It will be appreciated that ‘a nucleotide sequence according to SEQ ID NO:378’ refers to a nucleotide sequence 20 conforming to the consensus nucleotide sequence of SEQ ID NO:378. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:378 include SEQ ID NO:8 and SEQ ID NO:377. In some embodiments, the Second nucleotide sequence comprises a nucleotide sequence havingat least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) 25 sequence identity to SEQ ID NO: at its 3’ end. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:377 at its 3’ end. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 30 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end, and comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 35 294%, 295%, 296%, 297%,298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end, and comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:377 atits 3’ end. As used herein, the ‘5’ end’ of a given nucleotide sequence refers to the region of the nucleotide 40 sequence formed by nucleotides 5’ to (ie. upstream of, in the context of the complete sequence of the given nucleotide sequence) the midpoint of the given nucleotide sequence, or a subsequence of this region. 12 WO 2024 / 251925 PCT / EP2024 / 065689 In a nucleotide sequence having an even number of nucleotides, the region 5’ to the ‘midpoint’ includes the nucleotide immediately preceding the midpoint. For example, in a nucleotide sequence consisting of 10 nucleotides, the region 5’ to the midpoint consists of positions 1 to 5. Similarly, in a nucleotide 5 sequence having an even number of nucleotides, the region 3’ to the ‘midpoint’includes the nucleotide immediately after the midpoint. For example, in a nucleotide sequence consisting of 10 nucleotides, the region 3’ to the midpoint consists of positions 6 to 10. In a nucleotide sequence having an odd number of nucleotides, the region 5’ to the ‘midpoint’ includes the nucleotides 5’ to (i.e. upstream of) the nucleotide provided at the midpoint. For example, in a nucleotide sequence consisting of 9 nucleotides, the region 5’ 10 tothe midpoint consists of positions 1 to 4. Similarly, in a nucleotide sequence having an odd number of nucleotides, the region 3’ to the ‘midpoint’ includes the nucleotides 3’ to (£e. downstream of) the nucleotide provided at the midpoint. For example, in a nucleotide sequence consisting of 9 nucleotides, the region 3’ to the midpoint consists of positions 6 to 9. 15‘ By way of illustration, in SEQ ID NO:9, which consists of 414 nucleotides, a sequence provided at the 5’ end of SEQ ID NO:9 refers to a nucleotide sequence formed bypositions 1 to 207 of SEQ ID NO:9, ora subsequence thereof. Conversely, the ‘3’ end’ of a given nucleotide sequence refers to the region of the nucleotide sequence 20 formed by nucleotides 3’ to (.e. downstream of, in the context of the complete sequence of the given nucleotide sequence) the midpoint of the given nucleotide sequence, or a subsequence of this region. By way Of illustration, in SEQ ID NO:9, a sequence provided at the 3’ end of SEQ ID NO:9 refers to a nucleotide sequence formed by positions 208 to 414 of SEQ ID NO:9, or a subsequence thereof. 25 In some embodiments, a subsequence of a given nucleotide sequence provided at the 5’ end of the given nucleotide sequence includes at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region of the nucleotide sequence formed by nucleotides 5’ to ( / .e. upstream of, in the context of the complete sequence of the givennucleotide sequence) the midpoint of the given nucleotide sequence. By way of 30 illustration, a sequence provided at the 5’ end of SEQ ID NO:9 may comprise at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region formed by positions 1 to 207 of SEQ ID NO:9. In some embodiments, a subsequence of a given nucleotide sequence provided at the 3’ end of the given 35 nucleotide sequence includes at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region of the nucleotide sequence formed by nucleotides 3’ to (i.e. downstream of, in the context of the complete sequence of the given nucleotide sequence) the midpoint of the given nucleotide sequence. By way of illustration, a sequence provided at the 3’ end of SEQ ID NO:9 may comprise at least 5%, e.g. one of at 40 least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region formed by positions 208 to 414 of SEQ ID NO:9. 13 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, a subsequence of a given nucleotide sequence provided at the 5’ end of the given nucleotide sequence includes one or more nucleotides provided within 25 nucleotides, e.g. within one of 20, 15, 10 or 5 nucleotides, of the 5’ nucleotide of the given nucleotide sequence. In some embodiments, a subsequence of a given nucleotide sequence provided at the 5’ end of the given nucleotide sequence 5 includes the 5’ nucleotide of the given nucleotide sequence. By way of illustration, a sequence provided at the 5’ end of SEQ ID NO:9 may comprise one or more nucleotides provided within positions 1 to 25, e.g. within positions 1 to 20, 1 to 15, 1 to 10, or 1 to 5 of SEQ ID NO:9. By way of illustration, a sequence provided at the 5’ end of SEQ ID NO:9 maycomprise position 1 of SEQ ID NO:9. 10 In some embodiments, a subsequence of a given nucleotide sequence provided at the 3’ end of the given nucleotide sequence includes one or more nucleotides provided within 25 nucleotides, e.g. within one of 20, 15, 10 or 5 nucleotides, of the 3’ nucleotide of the given nucleotide sequence. In some embodiments, a subsequence of a given nucleotide sequence provided at the 3’ end of the given nucleotide sequence includes the 3’ nucleotide of the given nucleotide sequence. By way of illustration, a Sequence provided at 15 the 3’ end of SEQ ID NO:9 may comprise one or more nucleotides provided within positions 389 to 414, e.g. within positions 394 to 414, 399 to 414, 404 to 414, or 409 to 414 of SEQ ID NO:9. By way of illustration, a sequence provided at the 3’ end of SEQ ID NO:9 may comprise position 414 of SEQ ID NO:9. 20 In some embodiments the second nucleotide sequence comprises a nucleotide sequence having at least 80% sequence identity to SEQ IDNO:7 in the region 5’ to its midpoint. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 or SEQ ID NO:377 in the region 3’ to its midpoint. 25 In some embodiments, the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:7 accounts for at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region 5’ to the midpoint of the second nucleotide sequence. In some embodiments, the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 or SEQ ID NO:377 accounts for at least 5%, e.g. one of at least 10%, 30 at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region 3’ to the midpoint of the second nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequenceidentity to SEQ ID NO:7 comprises one or more nucleotides provided within 25, e.g. within positions 20, 15, 10, or 5 nucleotides of 35 ‘the 5’ nucleotide of the second nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:7 comprises the 5’ nucleotide of the second nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 or SEQ ID NO:377 comprises one or more nucleotides provided within 25, e.g. within positions 20, 15, 10, or 5 nucleotides of the 3’ nucleotide of the second nucleotide sequence. In 40 some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 or SEQ ID NO:377 comprises the 3’ nucleotide of the second nucleotide sequence. 14 WO 2024 / 251925 PCT / EP2024 / 065689 An exemplary sequence comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:7 at its 5’ end is SEQ ID NO:9. Positions 1 to 102 ofSEQ ID NO:9 correspond to positions 1 to 102 of SEQ ID NO:7. 5 An exemplary sequence comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:8 at its 3’ end is SEQ ID NO:9. Positions 253 to 414 of SEQ ID NO:9 correspond to positions 1 to 162 of SEQ ID NO:8. In some embodiments, the second nucleotide sequence comprises, or consists of, a nucleotide sequence 10 having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:229. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:229 include SEQ ID NOs:10 and 228. 15 In some embodiments, the second nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:9. In some embodiments, the second nucleotide sequence comprises, orconsists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID 20 = NO:10. In some embodiments, the second nucleotide sequence comprises ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30 (cf. e.g. position 411 of SEQ ID NO:9, position 261 of SEQ ID NO:10). 25 In some embodiments, the second nucleotide sequence consists of fewer than 1044 nucleotides, e.g. one of <1000 nucleotides, <900 nucleotides, <800 nucleotides, <750 nucleotides, <700 nucleotides, <650 nucleotides, <600 nucleotides, <550 nucleotides or <500 nucleotides. In some embodiments, the second nucleotide sequence consists of fewer than 500 nucleotides, e.g. one 30 of <450 nucleotides, <400 nucleotides, <350 nucleotides, <300 nucleotides, <250 nucleotides or <200 nucleotides. In some embodiments, the second nucleotide sequence consists of 1044 nucleotides. In some embodiments, the second nucleotidesequence consists of 414 nucleotides. In some embodiments, the second nucleotide sequence consists of 264 nucleotides. In some embodiments, the second nucleotide sequence consists of 189 nucleotides. 35 In some embodiments, the second nucleotide sequence comprises: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, =90%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, =98%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 40 sequence identity to SEQ ID NO:8 at its 3’ end; and (iii) comprises ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consists of fewer than 1044 nucleotides. Examples of such second nucleotide sequences include SEQ ID NOs:9 and 10. 15 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the second nucleotide sequence comprises: (i) a nucleotide sequence having at least 80% (e.g.one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) a nucleotide sequence having at least 80% 5 (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (iii) comprises ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consists of fewer than 500 nucleotides. An example of such a second nucleotide sequence is SEQ ID NO:9. 10 In some embodiments, the second nucleotide sequence comprises: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO‘8 at its 3’ end; and (iii) comprises ‘C’ at the positioncorresponding to 15 position 5766 of SEQ ID NO:30; and (iv) consists of fewer than 300 nucleotides. An example of such a second nucleotide sequence is SEQ ID NO:10. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a second nucleotide sequence) comprising, or consisting of, a nucleotide sequence 20 shaving at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs°:9, 10, 228, 238 to 255, 375 and 376. In some embodiments, a polynucleotide according to the present disclosure does not comprise the 25 nucleotide sequence of SEQ ID NO:240. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a Second nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%,299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:9, 10, 228, 238, 239, 241 to 255, 375 and 376. 30 In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a second nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:9. In some embodiments, a polynucleotide according to 35 the present disclosure comprises a nucleotide sequence (e.g. a second nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a second nucleotide sequence) comprising, or consisting of, a nucleotide sequencehaving at least 40 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:228. 16 WO 2024 / 251925 PCT / EP2024 / 065689 Third nucleotide sequence The third nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotide sequence which is a variant of human SMN2 exon 7. 5 Accordingly, in some embodiments, the third nucleotide sequence does not consist of, or does not comprise, SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence having <100% sequence identity to SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence 10 having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11. It will be appreciated that ‘a nucleotide sequence according to SEQ ID NO:11’' refersto a nucleotide sequence conforming to the consensus nucleotide sequence of SEQ ID NO:11. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:11 include SEQ ID NOs:13 and 14. 15 In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:26. It will be appreciated that ‘a nucleotide sequence according to SEQ ID NO:26' refers to a nucleotide sequence 20 conforming to the consensus nucleotide sequence of SEQ ID NO:26. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:26 include SEQ ID NOs:13 and 27. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 25 299% or 100%) sequenceidentity to a nucleotide sequence according to SEQ ID NO:225. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:225 include SEQ ID NOs:223 and 224. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence 30. ~—sihaving at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:226. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 35 299% or 100%) sequence identity to SEQ ID NO:13. In some embodiments, the third nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:14. In some embodiments, the third nucleotidesequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 40 298%, 299% or 100%) sequence identity to SEQ ID NO:27. 17 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the third nucleotide sequence comprises ‘A’ at the position corresponding to position 2 of SEQ ID NO:12 (cf. e.g. position 2 of SEQ ID NOs:11, 13, 14, 26 and 27). In some embodiments, the third nucleotide sequence comprises insertion of ‘GCCACC’ after the position 5 corresponding to position 6 of SEQ ID NO:12 (cf. e.g. positions 7 to 12 of SEQ ID NO:14). In some embodiments, the third nucleotide sequence comprises ‘TG’ at the positions corresponding to positions 8 to 9 of SEQ ID NO:12 (cf. e.g. positions 14 and 15 of SEQ ID NO:14). 10 In some embodiments, the third nucleotide sequence comprises insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12 (cf. e.g. position 49 of SEQ ID NO:13, position 55 of SEQID NO:14). In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to 15 position 24 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the nucleotide at the position corresponding to position 20 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘T’ at the position corresponding to position 27 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘T’ at the position corresponding to position 28 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position 20 corresponding to position 21 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘A’ at the position corresponding to position 29 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘T’ at the position corresponding to position 21 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘A’ at theposition corresponding to position 31 of SEQ ID NO:12, and comprises ‘A’ at the position corresponding to position 34 of SEQ ID NO:12. In 25 some embodiments, the third nucleotide sequence comprises deletion of the positions corresponding to positions 9 to 20 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the positions corresponding to positions 33 to 41 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘CAC’ at the positions corresponding to positions 34 to 36 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘G’ after the position 30 corresponding to position 39 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘GC’ at the positions corresponding to positions 47 to 48 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘CACCATG’ after the position corresponding to position 48 of SEQ ID NO:12. In someembodiments, the third nucleotide sequence comprises ‘C’ at the position corresponding to position 48 of SEQ ID NO:12. In some embodiments, the 35 third nucleotide sequence comprises insertion of ‘AA’ after the position corresponding to position 48 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘CAT’ at the positions corresponding to positions 49 to 51 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘GCC’ at the positions corresponding to positions 46 to 48 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘CCA’ at the positions corresponding to 40 positions 49 to 51 of SEQ ID NO:12. In some embociments, the third nucleotide sequence comprises insertion of ‘T’ after the position corresponding to position 51 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘GC’ at the positions corresponding to positions 39 to 40 of SEQ 18 WO 2024 / 251925 PCT / EP2024 / 065689 ID NO:12. Insome embodiments, the third nucleotide sequence comprises insertion of ‘CA’ after the position corresponding to position 40 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘ATG’ at the positions corresponding to positions 43 to 45 of SEQ ID NO:12, and deletion of the position corresponding to position 46 of SEQ ID NO:12. In some embodiments, the third 5 nucleotide sequence comprises insertion of ‘'GCCACCATG ’ after the position corresponding to position 9 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘AGCACCATG’ after the position corresponding to position 15 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 16 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘CACCATG’ after the 10 position corresponding to position 15 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprisesinsertion of ‘ATG’ after the position corresponding to position 15 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘ATG’ after the position corresponding to position 21 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘GG’ after the position corresponding to position 48 of SEQ ID NO:12. In some 15 embodiments, the third nucleotide sequence comprises insertion of ‘AT’ after the position corresponding to position 30 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 31 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘G’ after the position corresponding to position 33 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘A’ after the position 20 corresponding to position 43 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises‘GG’ at the positions corresponding to positions 45 and 46 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘AT’ after the position corresponding to position 52 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the positions corresponding to positions 49 and 50 of SEQ ID NO:12. In some embodiments, the third 25 nucleotide sequence comprises ‘G’ at the position corresponding to position 51 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 40 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘A’ at the position corresponding to position 35 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘A’ after the position corresponding to position 39 of SEQ ID NO:12. In some 30 embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 41of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘C’ at the position corresponding to position 43 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘ATG’ after the position corresponding to position 42 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘TG’ after the position corresponding 35 __ to position 45 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘ATGGA’ after the position corresponding to position 44 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘A’ at the position corresponding to position 44 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 49 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence 40 comprises deletion of the position corresponding to position 50 of SEQ ID NO:12. In some embodiments, thethird nucleotide sequence comprises ‘A’ at the position corresponding to position 48 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding 19 WO 2024 / 251925 PCT / EP2024 / 065689 to position 50 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises ‘G’ at the position corresponding to position 44 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the position corresponding to position 49 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the positions corresponding to 5 _ positions 42 to 44 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises insertion of ‘G’ after the position corresponding to position 39 of SEQ ID NO:12. In some embodiments, the third nucleotide sequence comprises deletion of the position corresponding to position 48 of SEQ ID NO:12. In some embodiments, the third nucleotide sequencecomprises insertion of ‘GA’ after the position corresponding to position 48 of SEQ ID NO:12. 10 In some embodiments, the third nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprises ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; and (iii) comprises insertion of 15 ‘A’ after the position corresponding to position 48 of SEQ ID NO:12. An example of such a third nucleotide sequence is SEQ ID NO:13. In some embodiments, the third nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 20 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprises ‘A’ at the position corresponding to position 2 of SEQ ID NO:12;and (iii) comprises insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; and (iv) comprises insertion of ‘GCCACC’ after the position corresponding to position 6 of SEQ ID NO:12; and (v) comprises ‘TG’ at the positions corresponding to positions 8 and 9 of SEQ ID NO:12. An example of such a third nucleotide 25 sequence is SEQ ID NO:14. In some embodiments, the third nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:26; and (ii) 30 comprises ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; and (iii) comprises deletion of the position corresponding to position 20 of SEQ ID NO:12; and (iv) comprises insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12. An example of such a third nucleotide sequence is SEQ ID NO:27. 35 In someembodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleatide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:13, 14, 27, 223, 224 and 256 to 329. 40 In some embodiments, a polynucleotide according to the present disclosure does not comprise the nucleotide sequence of SEQ ID NO:13. In some embodiments, a polynucleotide according to the present 20 WO 2024 / 251925 PCT / EP2024 / 065689 disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:14, 27, 223, 224 and 256 to 329. 5 In some embodiments, apolynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:13. In some embadiments, a polynucleotide according to the 10 present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:14. In some embodiments, a polynuclectide according to the present disclosure comprises a nucleotide sequence (e.g. athird nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 15 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:27. In someembodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:223. In some embodiments, 20 a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:224. 25 Fourth nucleotide sequence The fourth nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotide sequence which is a variant of human SMA intron 7. Accordingly, in some embodiments, the fourth nucleotide sequence does not consist of, or does not 30 comprise, SEQ ID NO:18. In some embodiments,the fourth nucleotide sequence comprises, or consists of, a nucleotide sequence having <100% sequence identity to SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 35 — sequence identity to a nucleotide sequence according to SEQ ID NO:380 at its 5’ end. It will be appreciated that ‘a nucleotide sequence according to SEQ ID NO:380’ refers to a nucleotide sequence conforming to the consensus nucleotide sequence of SEQ ID NO:380. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:380 include SEQ ID NO:15 and SEQ ID NO:379. 40 In some embodiments, the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end. In some embodiments, the fourth nucleotidesequence 21 WO 2024 / 251925 PCT / EP2024 / 065689 comprises a nucleotide sequence having at least 80% (e.g. one of 285%, =90%, 291%, =92%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:379 at its 5' end. In some embodiments, the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) 5 sequence identity to SEQ ID NO:16 at its 3’ end. In some embodiments, the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end, and comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3’ end. In 10 some embodiments, the fourth nucleotide sequence comprises a nuclectide sequencehaving at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:379 at its 5’ end, and comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:16 at its 3’ end. 15 In some embodiments the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:15 or SEQ ID NO:379 in the region 5’ to its midpoint. In some embodiments, the fourth nucleotide sequence comprises a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:16 in the region 3’ to its midpoint. 20 In some embodiments, the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:15 or SEQ ID NO:379 accounts for at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or100% of the region 5’ to the midpoint of the fourth nucleotide sequence. In some embodiments, the nucleotide sequence having at 25 least 80% sequence identity to SEQ ID NO:16 accounts for at least 5%, e.g. one of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% of the region 3’ to the midpoint of the fourth nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:15 30 or SEQ ID NO:379 comprises one or more nucleotides provided within 25, e.g. within positions 20, 15, 10, or 5 nucleotides of the 5’ nucleotide of the fourth nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:15 or SEQ ID NO:379 comprises the 5’ nucleotide of the fourth nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:16 comprises one or morenucleotides 35 provided within 25, e.g. within positions 20, 15, 10, or 5 nucleotides of the 3’ nucleotide of the fourth nucleotide sequence. In some embodiments the nucleotide sequence having at least 80% sequence identity to SEQ ID NO:16 comprises the 3’ nucleotide of the fourth nucleotide sequence. An exemplary sequence comprising a nucleotide sequence having at least 80% sequence identity to SEQ 40 ID NO:15 at its 5’ end is SEQ ID NO:17. Positions 1 to 102 of SEQ ID NO:17 correspond to positions 1 to 102 of SEQ ID NO:15. 22 WO 2024 / 251925 PCT / EP2024 / 065689 An exemplary sequence comprising a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:16 at its 3° end is SEQ ID NO:18. Positions 295 to 444 of SEQ ID NO:18 correspond to positions 1 to 150 of SEQ ID NO:16. 5 In some embodiments, the fourth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or100%) sequence identity to SEQ ID NO:16. In some embodiments, the fourth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID 10 NO:17. In some embodiments, the fourth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence consists of fewer than 444 nucleotides, e.g. one of 15 <425 nucleotides, <400 nucleotides, <350 nucleotides, <300 nucleotides, <250 nucleotides or <200 nucleotides. In some embodiments, the fourth nucleotide sequence consists of fewer than 255 nucleotides. In some embodiments, the fourth nucleotide sequence consists of 252 nucleotides. In some embodiments, the fourth nucleotide sequence consists of 177 nucleotides.20 In some embodiments, the fourth nucleotide sequence consists of greater than 444 nucleotides, e.g. one of >450 nucleotides, >475 nucleotides or >500 nucleotides. In some embodiments, the fourth nucleotide sequence consists of 508 nucleotides. In some embodiments, the fourth nucleotide sequence comprises ‘C’ at the position corresponding to 25 position 441 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises ‘T’ at the position corresponding to position 441 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises ‘TT’ at the positions corresponding to positions 436 and 437 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises ‘TCCTC' at the positions corresponding to positions 11 to 15 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises 30 insertion of ‘TTT’ after the position corresponding to position 10 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprisesinsertion of ‘CCC’ after the position corresponding to position 10 of SEQ ID NO:18. In some embodiments, the fourth nucleotide sequence comprises: (i) a nucleotide sequence having at 35 _— least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:16 at its 3’ end; and (iii) consists of fewer than 500 nucleotides. Examples of such fourth nucleotide sequences include SEQ ID NOs:17 and 18. 40 In some embodiments, the fourth nucleotide sequence comprises: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 23 WO 2024 / 251925 PCT / EP2024 / 065689 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) a nucleotide sequence having at least 80% (e.g. one of 285%,290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consists of fewer than 255 nucleotides. An example of such a fourth nucleotide sequence is SEQ ID NO:17. 5 In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fourth nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:18, 227, 330 to 370 and 10 381. In some embodiments, a polynucleotide according to the present disclosure does not comprise the nucleotide sequence of SEQ ID NO:337. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a third nucleotide sequence) comprising, or 15 consisting of, a nucleotide sequence having at least 80% (e.g. one of285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:18, 227, 330 to 336, 338 to 370 and 381. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide 20 sequence (e.g. a fourth nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:18. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fourth nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, =93%, 25 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:227. Fifth nucleotide sequence The fifth nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotidesequence which is a variant of human SMN2 exon 8. 30 Accordingly, in some embodiments, the fifth nucleotide sequence does not consist of, or does not comprise, SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having <100% sequence identity to SEQ ID NO:32. 35 In some embodiments, the fifth nucleotide sequence consists of the dinucleotide ‘GA’, ‘TG’ or ‘TT’. In some embodiments, the fifth nucleotide sequence consists of the dinucleotide ‘GA’. In some embodiments, the fifth nucleotide sequence consists of the dinucleotide ‘TG’. In some embodiments, the fifth nucleotide sequence consists of the dinucleotide ‘TT’. 40 In some embodiments, the fifth nucleotide sequence consists of the trinucleotide ‘GAG’. In some embodiments, the fifth nucleotide sequence consists of the nucleotide ‘A’. 24 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the fifth nucleotide sequence encodes a polypeptide of interest (e.g. as describedhereinbelow). In some embodiments, the fifth nucleotide sequence encodes a polypeptide of interest, and comprises ‘GA’, 'TG' or ‘TT’ at positions 1 and 2. In some embodiments, the fifth nucleotide sequence 5 encodes a polypeptide of interest, and comprises ‘GA’ at positions 1 and 2. In some embodiments, the fifth nucleotide sequence encodes a polypeptide of interest, and comprises ‘TG’ at positions 1 and 2. In some embodiments, the fifth nucleotide sequence encodes a polypeptide of interest, and comprises ‘TT’ at positions 1 and 2. 10 In some embodiments, the fifth nucleotide sequence encodes a polypeptide of interest, and comprises ‘GAG’ at positions 1 to 3. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 15 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:19. It will be appreciated that ‘a nucleotide sequenceaccording to SEQ ID NO:19' refers to a nucleotide sequence conforming to the consensus nucleotide sequence of SEQ ID NO:19. Exemplary sequences conforming to the consensus nucleotide sequence of SEQ ID NO:19 include SEQ ID NOs:20 and 21. 20 In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:20. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:21. 25 In some embodiments, the fifth nucleotide sequence comprises ‘GA’ at the positions corresponding to positions 1 and 2 of SEQ ID NO:32 (cf. e.g. positions 1 and 2 of SEQ ID NO:20). In some embodiments, the fifth nucleotide sequence comprises ‘TG’ at the positionscorresponding to 30 positions 1 and 2 of SEQ ID NO:32 (cf. e.g. positions 1 and 2 of SEQ ID NO:21). In some embodiments, the fifth nucleotide sequence comprises fewer than 577 nucleotides. In some embodiments the fifth nucleotide sequence consists of <500 nucleotides, e.g. one of <400 nucleotides, <300 nucleotides, <200 nucleotides, <100 nucleotides or <50 nucleotides. 35 In some embodiments, the fifth nucleotide sequence comprises fewer than 25 nucleotides, e.g. one of <20 nucleotides, <15 nucleotides, <10 nucleotides or <5 nucleotides. In some embodiments, the fifth nucleotide sequence comprises 23 nucleotides. In some embodiments, 40 __ the fifth nucleotide sequence comprises 2 nucleotides. 25 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the fifth nucleotide sequence comprises 11 nucleotides. In some embodiments, the fifth nucleotide sequence comprises 8 nucleotides. In some embodiments, the fifth nucleotide sequence comprises 5 nucleotides. 5 In some embodiments, the fifthnucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 295% or 100%) sequence identity to positions 1 to 23 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises insertion of ‘G’ after the position 10 corresponding to position 2 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. 290% or 100%) sequence identity to positions 1 to 11 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence 15 having at least 80% (e.g. 100%) sequence identity to positions 1 to 8 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises, or consists of, a nucleotide sequence having at least 80% (e.g. 100%) sequence identity to positions 1 to 5 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises, or consists of, positions 1 and 2 ofSEQ ID NO:32. 20 In some embodiments, the fifth nucleotide sequence comprises ‘A’ at the position corresponding to position 1 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises insertion of ‘T’ after the position corresponding to position 1 of SEQ ID NO:32. In some embodiments, the fifth nucleotide sequence comprises ‘G’ at the position corresponding to position 3 of SEQ ID NO:32. 25 In some embodiments, the fifth nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:19; and (ii) comprises ‘GA’ at the positions corresponding to positions 1 and 2 of SEQ ID NO:32. An example of such a fifth nucleotide sequence is SEQ ID NO:20. 30 In some embodiments, the fifth nucleotide sequence comprises, or consists of: (i) a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%,296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:19; and (ii) comprises ‘TG’ at the positions corresponding to positions 1 and 2 of SEQ ID NO:32. An example of such a fifth nucleotide sequence is 35 SEQIDNO:21. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of: the dinucleotide ‘TG’, the dinucleotide ‘GA’, the dinucleotide ‘TT’, the trinucleotide ‘GAG’, the nucleotide ‘A’, or a nucleotide 40 sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:20, 21 and 371 to 374. 26 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, a polynucleotide according to the present disclosure does not comprise the nucleotide sequence of SEQ ID NO:20. In some embodiments, a polynucleotide according to the present disclosure comprises anucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting 5 of: the dinucleotide ‘TG’, the dinucleotide ‘GA’, the dinucleotide ‘TT’, the trinucleotide ‘GAG’, the nucleotide ‘A’, or a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from SEQ ID NOs:21 and 371 to 374. 10 In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of the dinucleotide ‘TG’. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of the dinucleotide ‘GA’. In some embodiments, a polynuclectide according to the present disclosure comprises a nucleotide sequence 15 (e.g. a fifth nucleotide sequence) comprising, or consisting of the dinucleotide‘TT’. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of the trinucleotide ‘GAG’. In some embodiments, a polynuclectide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% 20 = (eg. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:20. In some embodiments, a polynucleotide according to the present disclosure comprises a nucleotide sequence (e.g. a fifth nucleotide sequence) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:21. 25 Nucleotide sequences encoding a polypeptide of interest In some embodiments, the fifth nucleotide sequence according tothe present disclosure comprises, or consists of, a nucleotide sequence encoding a polypeptide of interest. Where present, the sixth nucleotide sequence according to the present disclosure comprises, or consists of, a nucleotide sequence encoding 30 a polypeptide of interest. A polypeptide of interest may be any polypeptide. In some embodiments, a polypeptide of interest according to the present disclosure may be an antigen- 35 binding polypeptide, an aptamer, an antigen-binding polypeptide complex, an antibody or an antigen- binding fragment or derivative thereof, an Fc fusion protein, an anticoagulant, a blood factor, a bone morphogenetic protein, a decoy receptor for a ligand, a decoy ligand for a receptor, an enzyme, a growth factor, a hormone, an interferon, an interleukin, a thrombolytic, a transcription factor, an epigenetic modifier, a constituent protein of a site-specific nuclease nucleic acid editing system (e.g. a 40 CRISPR / CasQ9 system, a CRISPR / Cpf1 system, a CRISPR / C2c1system, a CRISPR / C2c2 system, a CRISPR / C2c3 system, a ZFN system or a TALEN system), a constituent protein of a ribonucleoprotein, or a viral protein (e.g. a capsid protein or a viral enzyme). 27 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, a polypeptide of interest according to the present disclosure may be an antigen- binding polypeptide or an antigen-binding polypeptide complex. In some embodiments, a polypeptide of interest may be a chimeric antigen-receptor (CAR). 5 In some embodiments, a polypeptide of interest is a polypeptide suitable for use in therapy or prophylaxis of a disease / condition. In some embodiments, a polypeptide of interest is a detectable polypeptide or a polypeptide having detectable activity. 10 A polypeptide suitable for use in therapy or prophylaxis of a disease / condition may be any polypeptide whose administration is useful for the treatment or prevention of a disease / condition. In some embodiments, a polypeptide suitable for use in therapy orprophylaxis of a disease / condition may be a polypeptide for which deficiency thereof is positively associated with, or implicated in the pathology of, a disease or condition. By way of illustration, in some embodiments, the polypeptide of interest may be 15 MeCP2. Deficiency of MeCP2 is associated with Rett syndrome. In some embodiments, a polypeptide suitable for use in therapy or prophylaxis of a disease / condition may be a polypeptide which inhibits the expression and / or activity of a factor whose expression or activity is positively associated with, or implicated in the pathology of, a disease or condition. 20 A detectable polypeptide may be or comprise a fluorescent polypeptide. Fluorescent polypeptides include green fluorescent protein and variants thereof (e.g. enhanced green fluorescent protein), yellow fluorescent protein (e.g. citrine), red fluorescent protein and variants thereof (e.g. mOrange, mCherry), blue fluorescent protein and variants thereof (e.g. TagBFP), cyanfluorescent protein and variants thereof 25 (e.g. mTurquoise, cerulean), allophycocyanin, phycocyanin, phycoerythrin and phycoerythrocyanin. A detectable polypeptide may be or comprise an epitope tag. Epitope tags include e.g. His, (e.g. 6XHis), FLAG, c-Myc, StrepTag, haemagglutinin, E, calmodulin-binding protein (CBP), glutathione-s-transferase (GST), maltose-binding protein (MBP), thioredoxin, S-peptide, T7 peptide, SH2 domain, avidin, 30 streptavidin, and haptens (e.g. biotin, digoxigenin, dinitrophenol). A polypeptide having detectable activity may be or comprise an enzymatic moiety. Enzymatic moieties include e.g. luciferases, glucose oxidases, galactosidases (e.g. beta-galactosidase), glucorinidases, phosphatases (e.g. alkaline phosphatase), peroxidases (e.g. horseradish peroxidase) and 35 cholinesterases. A polypeptide of interest expressed from a polynucleotide of the present disclosure may additionally comprises one or more extraneous amino acids added at the N-terminus of thepolypeptide, i.e. immediately upstream of the amino acid sequence of the polypeptide of interest. Such extraneous amino 40 acids may be characterised as forming an N-terminal tag on the polypeptide of interest. It may be desirable to minimise the size of, or completely remove, such extraneous amino acids / N-terminal tags on the polypeptide of interest. 28 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the N-terminal tag consists of fewer than 50 amino acids, e.g. one of $40 amino acids, <30 amino acids, <25 amino acids, <20 amino acids, <15 amino acids, <10 amino acids, <9 amino acids, $8 amino acids, <7 amino acids, <6 amino acids, <5 amino acids, <4 amino acids, $3 amino acids, 5 $2 amino acids or 1 amino acid. In some embodiments, the polypeptide of interest lacks an N-terminal tag. In some embodiments, the polypeptide of the present disclosure comprises one or more cleavage sites. A cleavage site refers to a sequence of amino acids that acts as a substrate for an enzymecapable of 10 cleaving peptide bonds. Many such cleavage sites are known to, and can be employed by, the person skilled in the art of molecular biology. In some embodiments, the cleavage sequence comprises an autocleavage site. Autocleavage sites include the 2A cleavage sequence from Picornavirus ‘NPGP’, which is cleaved at ’G / P’. Further autocleavage sites are described e.g. in Kim e¢ af, PLoS ONE (2011) 6: €18556 (hereby incorporated by reference in its entirety), and include e.g. T2A, E2A, P2A and F2A 15 cleavage sites. The amino acid sequences of T2A, E2A, P2A and F2A cleavage sites are shown in SEQ ID NOs: 107, 108, 109 and 110, respectively. A cleavage site may be included in a polypeptide according to the present disclosure to provide for removal of extraneous amino acids added at the N-terminus of the polypeptide, i.e. immediately upstream 20 of the amino acid sequence of the polypeptide of interest. That is, a cleavage site may be included for the removal of an N-terminal tagas described hereinabove. Accordingly, in some embodiments, a polypeptide according to the present disclosure comprises a cleavage site adjacent to (i.e. inthe amino acid sequence of the polypeptide, e.g. immediately downstream of) extraneous amino acid(s), e.g. extraneous amino acid(s) forming an N-terminal tag. 25 In some embodiments, a cleavage site according to the present disclosure is a 2A cleavage site, e.g. selected from a T2A, E2A, P2A and F2A cleavage site. In some embodiments, the cleavage site is a T2A cleavage site. In some embodiments, a polypeptide according to the present disclosure comprises an amino acid sequence having at least 60%, preferably one of 270%, 275%, =80%, 285%, 290%, 291%, 30 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100% amino acid sequence identity to SEQ ID NO:107, 108, 109 or 110. In some embodiments, a nucleotide sequence encoding a polypeptide of interest according to the present disclosure comprises, or consists of, a nucleotide sequencehaving at least 80% (e.g. one of 285%, 35 = 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:213 or 217. Further nucleotide sequences of the polynucleotide Polynucleotides according to the present disclosure may comprise additional nucleotide sequences 40 and / or sequence features in addition to the first, second, third, fourth, fifth and / or sixth nucleotide sequences as described hereinabove. 29 WO 2024 / 251925 PCT / EP2024 / 065689 The polynucleotides of the present disclosure comprise a start codon 5’ to ( / .e. upstream of, in the context of the nucleotide sequence of the polynucleotide) the nucleotide sequence encoding a polypeptide of interest. The start codon is preferably the trinucleotide ‘ATG’. 5 In some embodiments, a start codon is provided in the polynucleotide such that following splicing (e.g. where the polynucleotide is a polyribonucleotide, or splicing of a polyribonucleotide transcribed from the polynucleotide where thepolynucleotide is a polydeoxyribonucleotide), the start codon is provided in the mature MRNA molecule in such a way as to serve as the initiator codon for translation of the polypeptide of interest (encoded by the fifth or sixth nucleotide sequence). 10 In some embodiments, the splicing referred to in the preceding paragraph is splicing performed in the presence of a splicing modifier (e.g. as described herein). By way of illustration, splicing of the polyribonucleotide having the nucleotide sequence of SEQ ID NO:22 in the presence of RG7800 / RG76196 results in the production of a mature MRNA molecule comprising an initiator codon for 15 translation of a polypeptide of interest. In some embodiments, the splicing referred to in the preceding paragraph is splicing performed in the absence of a splicing modifier (e.g. as described herein). By way of illustration, splicing of the polyribonucleotide having the nucleotide sequence of SEQ ID NO:28 in the absence of a splicing modifier resultsin the production of a mature MRNA molecule comprising an initiator codon for translation of a polypeptide of interest. 20 In some embodiments, the polynucleotide further comprises a Kozak sequence. In preferred embodiments, the Kozak sequence is provided immediately upstream of the start codon for initiating translation of the polypeptide of interest. In some embodiments, the Kozak sequence consists of a nucleotide sequence conforming to the consensus of SEQ ID NO:33. In some embodiments, the Kozak 25 sequence consists of SEQ ID NO:34. In some embodiments, the polynucleotide comprises a nucleotide sequence consisting of SEQ ID NO:35 5’ to the nucleotide sequence encoding a polypeptide of interest. 30 In some embodiments, SEQ ID NO:35 is provided in the polynucleotide such that following splicing (¢@.g. where the polynucleotide is a polyribonucleotide, or splicing of a polyribonucleotide transcribed from the polynucleotide where the polynucleotide is a polydeoxyribonucleotide), thestart codon of SEQ ID NO:35 is provided in the mature MRNA molecule in such a way as to serve as the initiator codon for translation of the polypeptide of interest (encoded by the fifth or sixth nucleotide sequence). 35 In some embodiments, the splicing referred to in the preceding paragraph is splicing performed in the presence of a splicing modifier (e.g. as described herein). In some embodiments, the splicing referred to in the preceding paragraph is splicing performed in the absence of a splicing modifier (e.g. as described herein). 40 In some embodiments, the polynucleotide further comprises a promoter sequence. The promoter sequence is preferably 5’ to the first nucleotide sequence. In some embodiments, the polynucleotide 30 WO 2024 / 251925 PCT / EP2024 / 065689 further comprises one or more enhancer sequences. The one or more enhancer sequences are preferably 5’ to the first nucleotide sequence. In some embodiments, the polynucleotide further comprises a stop codon. The stop codon ispreferably 5 provided immediately 3’ to (i.e. downstream of, in the context of the nucleotide sequence of the polynucleotide) the trinucleotide encoding the terminal amino acid of the polypeptide encoded by the fifth or sixth nucleotide sequence. In some embodiments, the polynucleotide further comprises a polyadenylation signal sequence. In 10 preferred embodiments, the polyadenylation signal sequence is provided 3’ to (i.e. downstream of, in the context of the nucleotide sequence of the polynucleotide) the nucleotide sequence encoding a polypeptide of interest. In some embodiments, the polynucleotide further comprises a terminator sequence. The terminator sequence is preferably 3’ to the nucleotide sequence encoding a polypeptide of interest (and 3’ to the polyadenylation signal sequence, when present). 15 In preferred embodiments, the constituent nucleotide sequences of the polynucleotides (i.e. the first, second, third, fourth, fifth and / or sixth nucleotide sequences as describedhereinabove) are provided immediately adjacent to one another. However, in some embodiments, the polynucleotide further comprises one or more linker nucleotide sequences between one or more of the constituent nucleotide 20 sequences of the polynucleotide. Linker nucleotide sequences may comprise, or consist of, 1-10, e.g. one of 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1- 3, or 1-2 nucleotides. 25 Where a polynucleotide according to the present disclosure comprises one more linker nucleotide sequences ( / .e. provided between the first, second, third, fourth, fifth and / or sixth nucleotide sequences), the linker sequences are preferably selected such that they do not substantially affect post-transcriptional processing of the polynucleotide when the polynucleotide is a polyribonucleotide. In preferred embodiments, where a polynucleotide according to the present disclosure comprises one more linker 30 sequences, splicing of the polynucleotide when the polynucleotide is a polyribonucleotide issubstantially the same as splicing of an equivalent polyribonucleotide lacking the linker nucleotide sequence(s). Similarly, where a polynucleotide according to the present disclosure comprises one more linker nucleotide sequences (i.e. provided between the first, second, third, fourth, fifth and / or sixth nucleotide 35 — sequences), the linker sequences are preferably selected such that they do not alter the amino acid sequence of a polypeptide encoded by the polynucleotide. In preferred embodiments, where a polynucleotide according to the present disclosure comprises one more linker sequences, the polynucleotide encodes the same polypeptide as the equivalent polyribonucleotide lacking the linker nucleotide sequence(s). 40 In some embodiments, the polynucleotide further comprises inverted terminal repeat (ITR) sequences. In some embodiments, the polynucleotide comprises an ITR 5’ to the first nucleotide sequence (and 5’ to the 31 WO 2024 / 251925 PCT / EP2024 / 065689 promoter and / orenhancer sequences, when present). In some embodiments, the polynuclectide comprises an ITR 3’ to the nucleotide sequence encoding a polypeptide of interest (and 3’ to the stop codon, polyadenylation signal sequence and / or terminator sequence, when present). 5 In some embodiments, the polynucleotide comprises an ITR sequence at its 5’ end, and an ITR sequences at its 3’ end. In some embodiments, the first nucleotide of the ITR sequence provided at the 5’ end of the polynucleotide is provided within 1 to 25 nucleotides, e.g. within one of 1 to 20, 1 to 15, 1 to 10, or 1 to 5 nucleotides of the first nucleotide of the polynucleotide (i.e. position 1 of the nucleotide sequence of the polynucleotide). In some embodiments, the final nucleotide of the ITR sequence provided at the 3’ 10 end of the polynucleotide is provided within 1 to 25 nucleotides, e.g. within one of 1 to 20, 1 to 15, 1 to 10, or 1 to 5 nucleotides of the final nucleotide of the polynucleotide (i.e. the terminal positionof the nucleotide sequence of the polynucleotide). In some embodiments, the polynucleotide of the present disclosure ( / .e. comprising the first, second, 15 third, fourth, fifth and / or sixth nucleotide sequences described herein) has a size permitting its delivery as a gene therapy, fe. in a suitable vector. In some embodiments, the polynucleotide consists of a nucleotide sequence having a size within the packaging limit of a vector for delivering the polynucleotide. In some embodiments, the polynucleotide has a size within the packaging limit of an AAV vector. In some 20 embodiments, the polynucleotide has a size within the packaging limit of an AAV vector of one of the following serotypes: AAV9, AAV9.45, AAV-PHP.B, AAV1, AAV2, AAV2i8, AAV5, AAV6, AAV8, AAV10 or AAVrh74. In some embodiments, the polynucleotide has a size within the packaging limit of an AAV vector of one of the following serotypes: AAV9, AAV9.45, AAV-PHP.B, AAV1, AAV2, AAV2.7m8, AAV2i8, AAV5, AAV6, AAV8, AAV10 orAAVrh74. 25 In some embodiments, the polynucleotide of the present disclosure ( / .e. comprising the first, second, third, fourth, fifth and / or sixth nucleotide sequences described herein) consists of fewer than 6,000 nucleotides, e.g. one of $5,000, <4,750, <4,500, <4,250, <4,000, <3,750, $3,500, $3,250, $3,000, <2,750, $2,500, <2,250, <2,000, <1,750, $1,500, $1,250 or <1,000 nucleotides. 30 In preferred embodiments, the polynucleotide of the present disclosure consists of fewer nucleotides than the number of nucleotides of a known SMN2 exon 6 to exon 8-derived transgene expression system (e.g. an SMN2 exon 6 to exon 8-derived transgene expression system described in Zhang, ef a / ., Gene Ther. (2001) 8: 1532-1538, WO 2022 / 204471 A1, Monteys ef al. Nature (2021) 596: 291-295 or WO 35 2021 / 163556 A1). In some embodiments, the polynucleotide of the present disclosure consists of fewer nucleotides than a polynucleotide comprising: (i) SEQ ID NO:36 and (ii) a nucleotide sequence encoding apolypeptide of interest ( / .e. adjacent and 3’ to SEQ ID NO:36, the context of the complete sequence of the 40 polynucleotide). Such polynucleotides are described e.g. in WO 2021 / 163556 A1. 32 WO 2024 / 251925 PCT / EP2024 / 065689 Herein, for conciseness, ‘a polynucleotide comprising: (i) SEQ ID NO:36 and (ii) a nucleotide sequence encoding a polypeptide of interest (.e. adjacent and 3’ to SEQ ID NO:36, in the context of the complete sequence of the polynucleotide)’ is also referred to herein simply as ‘a SMN2ind minigene polynucleotide’. 5 In some embodiments, the polynucleotide of the present disclosure consists of a number of nucleotides that is less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times or $0.25 times the number of nucleotides of a SMN2ind minigene polynucleotide. 10 In some embodiments, the region of a polynucleotide ofthe present disclosure formed by the first, second, third, fourth and fifth nucleotide sequences consists of fewer nucleotides than the number of nucleotides in SEQ ID NO:36. In some embodiments, the region of a polynucleotide of the present disclosure formed by the first, second, third, fourth and fifth nucleotide sequences consists of a number of 15 nucleotides that is less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, $0.5 times, <0.45 times, $0.4 times, 0.35 times, <0.3 times or £0.25 times the number of nucleotides in SEQ ID NO:36. The polynucleotide of the present disclosure may comprise 5’ cap, 5’ UTR, 3’ UTR and / or PolyA tail 20 nucleotide sequences. In some embodiments, the polynucleotide comprises a 5’ UTR 5’ to (Le. upstream of, in the context of the nucleotide sequence of the polynucleotide) a start codon. 25 In some embodiments, the polynucleotide comprises a 3’ UTR 3’ to( / .e. downstream of, in the context of the nucleotide sequence of the polynucleotide) a stop codon. In some embodiments, the polynucleotide comprises a 3’ UTR 5’ to a polyadenylation signal sequence. In some embodiments, the polynucleotide comprises a 3’ UTR 3’ to a stop codon and 5’ to a polyadenylation signal sequence. 30 In some embodiments, the polynucleotide of the present disclosure comprises one or more nucleotide sequences encoding a selectable marker, to facilitate identification and / or selection of cells comprising / expressing the polynucleotide. Selectable markers include proteins that confer resistance to antibiotics or other toxins, ¢.g., blasticidin, ampicillin, neomycin, methotrexate, or tetracycline, and proteins that complement auxctrophic deficiencies. 35 In some embodiments, the polynucleotide of the present disclosure comprises a nucleotide sequence encoding an internal ribosome entry site (IRES). In some embodiments, the polynucleotide comprises a nucleotidesequence permitting two or more polypeptides to be translated separately from a single polyribonucleotide. 40 The polynucleotides of the present disclosure may be provided in purified or isolated form, i.e. from other nucleic acid, or naturally-occurring biological material. 33 WO 2024 / 251925 PCT / EP2024 / 065689 Particular exemplary polynucleotides In some embodiments, a polynucleotide according to the present disclosure comprises: 5 a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from Column A of Table A; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 10 100%) sequence identity to a nucleotide sequence selected from Column B of Table A; a third nucleotide sequencecomprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from Column C of Table A; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 15 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from Column D of Table A; and a fifth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence selected from Column E of Table A. 20 In accordance with the preceding paragraph, in some embodiments the nucleotide sequence selected from Column A of Table A, and the nucleotide sequence selected from Column B of Table A, and the nucleotide sequence selectedfrom Column C of Table A, and the nucleotide sequence selected from Column B of Table A, and the nucleotide sequence selected fram Column D of Table A, and the 25 nucleotide sequence selected from Column B of Table A, and the nucleotide sequence selected from Column E of Table A are all selected form the same row of Table A. By way of illustration, in some embodiments the nucleotide sequences selected from Columns A, B, C, D and E of Table A may be selected from row 3 of Table 1, and therefore may be SEQ ID NOs:5, 9 14 18 and 20, respectively. 30 In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1; and comprising ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iii) consisting of s45 nucleotides; 35 asecond nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (ii) comprising ‘C’ at the position corresponding to position 40 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300 nucleotides: a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 34 WO 2024 / 251925 PCT / EP2024 / 065689 sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; and (iii) comprising insertion of ‘A’ after the positioncorresponding to position 48 of SEQ ID NO:12; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one 5 of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consisting of fewer than 255 nucleotides; and a fifth nucleotide sequence consisting of the dinucleotide ‘GA’. 10 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:106; 15 a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%,292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 20 sequence identity to SEQ ID NO:13; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:17; and a fifth nucleotide sequence consisting of the dinucleotide ‘GA’. 25 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:22. 30 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%,290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:3; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at 35 _— least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:13; 40 a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:17; and 35 WO 2024 / 251925 PCT / EP2024 / 065689 a fifth nucleotide sequence consisting of the dinucleotide ‘GA’. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%,291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence 5 identity to SEQ ID NO:23. In some embodiments, the palynucleotide comprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 10 sequence identity to a nucleotide sequence according to SEQ ID NO:1; and comprising ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iii) comprising ‘CTG’ at the positions corresponding to positions 109 to 111 of SEQ ID NO:2; a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence 15 identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQID NO:8 at its 3’ end; and (iii) comprising ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 500 nucleotides; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 20 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; and (iii) comprising insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; and (iv) comprising insertion of ‘“GCCACC’ after the position corresponding to position 6 of SEQ ID NO:12; and (v) comprising ‘TG’ at the positions 25 corresponding to positions 8 and 9 of SEQ ID NO:12; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, =90%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequenceidentity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 30 sequence identity to SEQ ID NO:16 at its 3’ end; and (iii) consisting of fewer than 500 nucleotides; and a fifth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:20. 35 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:5; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at 40 — least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequenceidentity to SEQ ID NO:9; 36 WO 2024 / 251925 PCT / EP2024 / 065689 a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:14; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 5 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:18; and a fifth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:20. 10 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:24. 15 In some embodiments, the polynucleotidecomprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (¢@.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1; and comprising ‘GGC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iii) comprising ‘CAG’ at the positions 20 corresponding to positions 109 to 111 of SEQ ID NO:2; a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence 25 identity to SEQ ID NO:8 at its 3’ end; and (iii) comprising ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consisting offewer than 500 nucleotides; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the 30 position corresponding to position 2 of SEQ ID NO:12; and (iii) comprising insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% 35 = (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consisting of fewer than 500 nucleotides; and a fifth nucleotide sequence comprising,or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:21. 40 In some embodiments, the polynucleotide comprises: 37 WO 2024 / 251925 PCT / EP2024 / 065689 a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:6; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at 5 least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:9; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:13; 10 a fourth nucleotide sequence comprising, or consisting of,a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:18; and a fifth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 15 sequence identity to SEQ ID NO:20. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:25. 20 In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:1; and comprising ‘GGC’ at the 25 positions corresponding to positions 82 to 84 ofSEQ ID NO:2; and (iii) consisting of <45 nucleotides; In some embodiments, the polynucleotide comprises: a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. 30 ~— one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:8 at its 3° end; and (ii) comprising ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300 nucleotides; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 35 — sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the position corresponding to position2 of SEQ ID NO:12; and (iii) comprising insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, =96%, 297%, 298%, 299% or 100%) sequence 40 identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consisting of fewer than 255 nucleotides; and 38 WO 2024 / 251925 PCT / EP2024 / 065689 a fifth nucleotide sequence consisting of the trinucleotide ‘GAG’. In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 5 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:3; a second nucleotidesequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to SEQ ID NO:10; 10 a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:13; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 15 sequence identity to SEQ ID NO:17; and a fifth nucleotide sequence consisting of the trinucleotide ‘GAG’. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence 20 __ identity to SEQ ID NO:28. In some embodiments, the polynucleotide comprises: afirst nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 25 sequence identity to a nucleotide sequence according to SEQ ID NO:1; and comprising ‘GCC’ at the positions corresponding to positions 82 to 84 of SEQ ID NO:2; and (iii) cansisting of $45 nucleotides; In some embodiments, the polynucleotide comprises: a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence 30 identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (iii) comprising ‘C’ at the position corresponding to position 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300nucleotides; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 35 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the position corresponding to position 2 of SEQ ID NO:12; and Gii) comprising deletion of the position corresponding to position 20 of SEQ ID NO:12; and (iv) comprising insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; 40 a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% 39 WO 2024 / 251925 PCT / EP2024 / 065689 (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16at its 3° end; and (iii) consisting of fewer than 255 nucleotides; and a fifth nucleotide sequence consisting of the trinucleotide ‘GAG’. 5 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. ane of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:3; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at 10 least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:27; 15 a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%,293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:17; and a fifth nucleotide sequence consisting of the trinucleotide ‘GAG’. 20 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:29. In some embodiments, the polynucleotide does not consist of, or does not comprise, SEQ ID NO:36. 25 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to one of SEQ ID NOs:37 to 105. 30 In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence accordingto SEQ ID NO:221; and (ii) consisting of <45 nucleotides; 35 a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (ii) comprising ‘C’ at the position corresponding to position 40 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300 nucleotides; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 40 WO 2024 / 251925 PCT / EP2024 / 065689 sequence identity to a nucleotide sequence according to SEQ ID NO:11; and (ii) comprising ‘A’ at the position corresponding to position 2 of SEQ IDNO:12; and (iii) comprising insertion of ‘A’ after the position corresponding to position 48 of SEQ ID NO:12; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one 5 of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consisting of fewer than 255 nucleotides; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. 10 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:219; 15 a second nucleotide sequence comprising, or consisting of, anucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 20 sequence identity to SEQ ID NO:13; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:17; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. 25 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:111. 30 In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, orconsisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:221; and (ii) consisting of <45 nucleotides; 35 a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (ii) comprising ‘C’ at the position corresponding to position 40 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300 nucleotides; 41 WO 2024 / 251925 PCT / EP2024 / 065689 a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%,294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:225; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one 5 of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:15 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:16 at its 3° end; and (iii) consisting of fewer than 255 nucleotides; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. 10 In some embodiments, the polynucleotide comprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:219; 15 a second nucleotide sequence comprising, or consisting of, anucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 20 sequence identity to SEQ ID NO:223; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:17; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. 25 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:116. 30 In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, orconsisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:221; and (ii) consisting of <45 nucleotides; 35 a second nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:7 at its 5’ end; and (ii) comprising a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:8 at its 3’ end; and (ii) comprising ‘C’ at the position corresponding to position 40 5766 of SEQ ID NO:30; and (iv) consisting of fewer than 300 nucleotides; 42 WO 2024 / 251925 PCT / EP2024 / 065689 a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%,294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:225; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one 5 of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:227; and (iii) consisting of fewer than 280 nucleotides; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. In some embodiments, the polynucleotide comprises: 10 a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:220; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 15 100%) sequence identity to SEQ ID NO:10; a third nucleotide sequence comprising, orconsisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:224; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 20 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:227; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. 25 ~— one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:164. In some embodiments, the polynucleotide comprises: a first nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 30 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to a nucleotide sequence according toSEQ ID NO:221; and (ii) consisting of <45 nucleotides; a second nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 35 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:229; a third nucleotide sequence (i) comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, =99% or 100%) sequence identity to a nucleotide sequence according to SEQ ID NO:225; a fourth nucleotide sequence (i) comprising a nucleotide sequence having at least 80% (e.g. one 40 of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:227; and (iii) consisting of fewer than 280 nucleotides; and a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. 43 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, the polynucleotidecomprises: a first nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) 5 — sequence identity to SEQ ID NO:220; a second nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:228: a third nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 10 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:224; a fourth nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:227: and 15 a fifth nucleotide sequence consisting of the dinucleotide ‘TG’. In someembodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:171. 20 In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to one of SEQ ID NOs:111 to 200. In some embodiments, the polynucleotide comprises a nucleotide sequence having at least 80% (e.g. one of 285%, =90%, 291%, 292%, 293%, 294%, 295%, 25 296%, 297%, 298%, 299% or 100%) sequence identity to one of SEQ ID NOs:37 to 105, or 111 to 200. Splicing modifiers Aspects and embodiments of the present disclosure pertain to splicing modifiers. Splicing modifiers are 30 molecules that influence splicing of polyribonucleotides. Such molecules are reviewed e.g. in Tang ef ai., Molecules (2021) 26(8):2263 and Schneider-Poetsch ef a / ., The Journal ofAntibiotics (2021) 74:603-616, both of which are hereby incorporated by reference in their entirety. Splicing modifiers generally reduce / prevent association of factors required for normal post-transcriptional 35 processing (e.g. components of the spliceosome) with RNA. Splicing modifiers typically bind to a nucleotide sequence of a polyribonucleotide and either inhibit or promote the association of RNA-binding proteins and / or non-coding RNAs which function as splicing activators or repressors. Through competitive inhibition of the recruitment of splicing activators and splicing repressors to the polyribonucleotide, splicing modifiers can alter the equilibrium of the splicing-regulatory RNA structures, and thus promote an 40 increase or decrease in skipping or inclusion of an exon and / or retention or excision of an intron in the mature RNA molecule produced by splicing. 44 WO 2024 / 251925 PCT / EP2024 / 065689 In some embodiments, a splicing modifier is a small molecule or a splice-switchingnucleic acid (e.g. a splice-switching oligonucleotide). A ‘small molecule’ refers to a low molecular weight (<1000 daltons, typically about 300 to about 700 5 daltons) organic compound. Splice-switching nucleic acids are reviewed e.g. in Haves and Hastings, Nucleic Acids Res. (2016) 44(14): 6549-6563, which is hereby incorporated by reference in its entirety. Splice-switching nucleic acids include e.g. splice-switching oligonucleotides (SSOs). They disrupt the normal splicing of target 10 RNA transcripts by blocking the RNA:RNA base-pairing and / or protein:RNA binding interactions that occur between components of the splicing machinery and pre-mRNA. Splice-switching nucleic acids may be designed to target a specific region of the target transcript, e.g. to promote skipping of exon(s) of interest and / or to promote inclusion of exon(s) of interest and / or to promote retention of introns of interest and / or to promote excision of introns of interest. SSOs often comprise alterations tooligonucleotide 15 sugar-phosphate backbones in order to reduce / prevent RNAseh degradation, such as e.g. phosphorothioate linkages, phosphorodiamidate linkages such as phosphorodiamidate morpholino (PMQs), and may comprise e.g. peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methoxyethyl nucleotide modifications, e.g. 2’'0-methyl (2’OMe) and 2'-O-methoxyethyl (MOE) ribose modifications and / or 5’-methylcytosine modifications. 20 Small molecule splicing modifiers contemplated in accordance with the present disclosure include RG- 7800 and RG-7916 (also known as risdiplam), and analogs thereof. RG-7800 and RG-7916 bind to the 5’ splice site of intron 7 and exonic splicing enhancer 2 of exon 7 of human SMN2, thereby stabilising the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 snRNP complex, and 25 promoting inclusion of exon 7 in the mature RNA molecule obtained following splicing of pre-mRNA transcribed from SMN2. RG-7800 and RG-7916 are useful torestore functional SMN2 protein expression from SMN2 alleles comprising the spinal muscular atrophy (SMA)-associated polymorphism c.840C>T (which potentiates skipping of exon 7). RG-7916 (DrugBank Acc. No. DB15305) is a close structural analog of RG-7800 having improved potency, pharmacokinetics and safety profile than RG-7800, and is 30 approved by the FDA for the treatment of SMA. Further analogs of RG-7800 and RG-7916 having similar splicing modifier activity include SMN-C2, SMN-C3, SMN-C5 and TEC-1. Branaplam (DrugBank Acc. No. DB14918; also known as LMI-070) is another small molecule splicing modifier that promotes inclusion of exon 7 in the mature RNA expressed from SMN2. Like RG-7800 and 35 RG-7916, branaplam binds to the 5’ splice site of intron 7 of human SMNZ2. PK4C9 (also known as homocarbonyltopsentin) is another small molecule splicing modifier that promotes inclusion of exon 7 in the mature RNA expressed from SMINZ. It is thought to bind to the 5’ splice site of exon 7and TSL2, and improve accessibility of the 5’ splice site via stabilising a triloop structure of TSL2. 40 Small molecule splicing modifiers that promote inclusion of exon 7 in the mature RNA expressed from SMN2 are described e.g. in WO 2015 / 173181 A1 and WO 2009 / 151546 A2, which are hereby 45 WO 2024 / 251925 PCT / EP2024 / 065689 incorporated by reference in their entirety. Further small molecule splicing modifiers that promote inclusion of exon 7 in the mature RNA expressed from SMN2 are described e.g. in WO 2022 / 204471 A1, which is hereby incorporated by reference in its entirety. 5 Nusinersen (DrugBank Acc. No. DB13161) is a splice-switching oligonucleotide that promotes exon 7 retention in mature RNA expressed from human S / MN2. Nusinersen is an 18-mer 2’°-MOe phosphorothioate antisense oligonucleotide that hybridises to intronic splicing silencer site 1 of intron 7, occupying the site and thereby inhibiting the association of the splicing suppressor ribonucleoproteins hnRNPs A1 / A2, thuspromoting inclusion of exon 7 in the mature RNA molecule. 10 The splicing modifier according to the present disclosure preferably promotes inclusion of SMN2 exon 7 in RNA obtained following splicing of pre-mRNA transcribed from human SMN2. Such molecules increase the proportion of RNA molecules comprising SMN2 exon 7 among RNA molecules obtained following splicing of pre-mRNA transcribed from human SMN2 (ie. relative to the proportion obtained in the 15 absence of the splicing modifier). For conciseness, ‘a splicing modifier that promotes inclusion of SMN2 exon 7 in RNA obtained following splicing of pre-mRNA transcribed from human SMN2’ may be referred to herein simply as ‘a splicing modifier that promotes SMN2 exon 7 inclusion’ In some embodiments, the splicing modifier promotes inclusion of exon 7 in RNA obtained following 20 splicing of pre-mRNA transcribed from an allele of human SMN2 comprising c.840C>T. That is, in some embodiments, the splicing modifier increases the proportionof RNA molecules comprising SMN2 exon 7 among RNA molecules obtained following splicing of pre-mRNA transcribed from an allele of human SMN2 comprising c.840C>T (i.e. relative to the proportion obtained in the absence of the splicing modifier). 25 In some embodiments, the splicing modifier increases the level of human SMN2 protein comprising amino acids encoded by exon 7 of human SMA2 (i.e. relative to the level detected in the absence of the splicing modifier). In some embodiments, the splicing modifier increases the proportion of polypeptides comprising amino acids encoded by exon 7 of human SMN2 among polypeptides expressed from human 30 SMN2 (i.e. relative to the proportion obtained in the absence of the splicing modifier). In some embodiments, the splicing modifier increases the proportion of polypeptides comprising amino acids encoded by exon 7 of human SMA / 2 among polypeptides expressed from an allele of human SMN2 comprising c.840C>T (i.e. relative to the proportion obtained inthe absence of the splicing modifier). 35 In some embodiments, the splicing modifier promotes inclusion of the third nucleotide sequence in the product of splicing of a polynucleotide according to the present disclosure (i.e. where the polynucleotide is a polyribonucleotide). In some embodiments, the splicing modifier increases the proportion of molecules comprising the third nucleotide sequence among molecules obtained following splicing of a polynucleotide according to the present disclosure (i.e. where the polynucleotide is a polyribonucleotide). 40 In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of SEQ ID NO:13 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence 46 WO 2024 / 251925 PCT / EP2024 / 065689 of SEQ ID NO:22. In some embodiments, the splicing modifier increases the proportion of molecules comprising the nucleotide sequence consisting of SEQ ID NO:13 among molecules obtained followingsplicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:22. 5 In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of SEQ ID NO:13 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:23. In some embodiments, the splicing modifier increases the proportion of molecules comprising the nucleotide sequence consisting of SEQ ID NO:13 among molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:23. 10 In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of SEQ ID NO:14 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:24. In some embodiments, the splicing modifier increases the proportion of molecules comprising the nucleotide sequence consisting of SEQ ID NO:14 among molecules obtained following 15 splicing of a polyribonucleotideconsisting of the sequence of SEQ ID NO:24. In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of SEQ ID NO:13 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:25. In some embodiments, the splicing modifier increases the proportion of molecules 20 comprising the nucleotide sequence consisting of SEQ ID NO:13 among molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:25. In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of SEQ ID NO:13 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence 25 of SEQ ID NO:28. In some embodiments, the splicing modifier increases the proportion of molecules comprising the nucleotide sequence consisting of SEQ ID NO:13 among molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQID NO:28. In some embodiments, the splicing modifier promotes inclusion of the nucleotide sequence consisting of 30 SEQ ID NO:27 in molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:29. In some embodiments, the splicing modifier increases the proportion of molecules comprising the nucleotide sequence consisting of SEQ ID NO:27 among molecules obtained following splicing of a polyribonucleotide consisting of the sequence of SEQ ID NO:29. 35 Splicing modifiers having such functional properties can be identified by analysis e.g. in suitable in vitro assays. Such assays may comprise culturing cells in vitro in the presence or absence of a candidate splicing modifier, and analysing the RNA and / or protein produced after an appropriate period of time for an effect of the candidate splicing modifier to be observed. By way of illustration, cells can be transfected with a vector comprising DNA having the sequence of SEQ ID NO:22 and cultured inthe presence or 40 absence of a candidate splicing modifier for a suitable period of time (e.g. 24, 48, 72 hours). RNA can subsequently be isolated from the cells, and analysed (e.g. by (RT-PCR) to determine the 47 WO 2024 / 251925 PCT / EP2024 / 065689 level / proportion of mature RNA molecules comprising the nucleotide sequence consisting of SEQ ID NO:13. In some embodiments, a splicing modifier that promotes SMN2 exon 7 inclusion according to the present 5 disclosure is a compound of formula (I) of WO 2015 / 173181 A1. In some embodiments, a splicing modifier that promotes SMNV2 exon 7 inclusion according to the present disclosure is a compound selected from those listed in claim 39 of WO 2015 / 173181 A1. In same embodiments, a splicing modifier that promotes SMN2 exon 7 inclusion according to the present disclosure is a compound selected from those listed in claim 40 of WO 2015 / 173181 A1. 10 In some embodiments, the splicing modifier according to the present disclosure is selected from: RG-7916, RG-7800, SMN-C2, SMN-C3, SMN-C5, TEC-1, branaplam, PK4C9 and nusinersen. In some embodiments, the splicing modifier is selected from: RG-7916, RG-7800, SMN-C2, SMN-C3, SMN-C5 and TEC-1. In some embodiments, the splicing modifier is selected from RG-7916 and RG-78&C0. In 15 preferred embodiments, the splicing modifier is risdiplam (RG-7916). Functional properties of the polynucleotides In aspects and embodiments of the present disclosure, the polynucleotides of the present disclosure may be characterised by reference to one or more functional properties. 20 In some embodiments, where the polynucleotide is a polyribonucleotide, splicing of the polyribonucleotide in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion yields polyribonucleotides substantially lacking the third nucleotide sequence. In some embodiments, where the polynucleotide is a polyribonucleotide, splicing of the polyribonucleotide in the presence of a splicing modifier that promotes 25 SMN2 exon7 inclusion yields polyribonucleotides comprising the third nucleotide sequence. In some embodiments, in the presence of a splicing modifier that promotes SMAN / 2 exon 7 inclusion, inclusion of the third nucleotide sequence is promoted in splicing of the polyribonucleotide, favouring the production of mature RNA molecules encoding the polypeptide of interest, and thus expression of the 30 polypeptide of interest at the protein level. Such polynucleotides may be referred to herein as ‘ON-switch’ polynucleotides. In some embodiments, cells comprising an ON-switch polynucleotide of the present disclosure substantially do not express the polypeptide of interest in the absence of a splicing modifier that promotes 35 SMN2 exon 7 inclusion. In some embodiments, cells comprising the ON-switch polynucleotide express the polypeptide of interest in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion. Exemplary ON-switch polynucleotides according to the present disclosureinclude polynucleotides comprising SEQ ID NO:22, 23, 24 or 25. Further exemplary ON-switch polynucleotides according to the 40 present disclosure include polynucleotides comprising one of SEQ ID NOs:37 to 105. 48 WO 2024 / 251925 PCT / EP2024 / 065689 Inclusion of the third nucleotide sequence as described herein in the products of splicing of a polyribonucleotide according to the present disclosure can be evaluated using methods that are well known to the person skilled in the art. Such methods include qRT-PCR based methods for the detection and / or quantification of RNA molecules comprising nucleotide sequences of interest. 5 For example, cells may be transduced in vitro with a vector comprising a polynucleotide according to the present disclosure and subsequently cultured in vitro in the presence or absence of a splicing modifier that promotes SMN2 exon 7 inclusion for a period of time appropriate for an effect on splicing cf a polyribonucleotide according to the present disclosure to beobserved. After such period of time, total 10 RNA may be isolated from the cells, cDNA may be prepared from the total RNA, and the number / proportion of mature RNA molecules comprising the third nucleotide sequence may be evaluated by qPCR using oligonucleotides providing for the specific amplification and / or detection of the products of splicing of the polyribonucleotide (e.g. oligonucleotides hybridising to nucleotide sequences spanning exon:exon boundaries). The qPCR analysis may employ oligonucleotides enabling distinction between 15 RNA molecules comprising the third nucleotide sequence, and RNA molecules lacking the third nucleotide sequence. Such gRT-PCR-based methods for analysing the products of splicing of a polyribonucleotide are described in the experimental examples of the present disclosure. Expression of a polypeptide of interest can be evaluated using any suitable technique for the detection 20 and / or quantification of the relevant polypeptide. Such techniques includee.g. antibody-based methods, (for example flow cytometry, immunocytochemistry, western blot, ELISA), fluorescence microscopy and flow cytometry. In some embodiments, expression of a polypeptide of interest can be evaluated as described in the experimental examples of the present disclosure. In preferred embodiments, expression of a polypeptide of interest may be evaluated by flow cytometry. 25 Herein, within a plurality / population of polyribonucleotides obtained after splicing that ‘substantially lack’ the third nucleotide sequence, the third nucleotide sequence may be present in fewer than 15%, e.g. one of $10%, <5%, $4%, $3%, $2% or $1% of the polyribonucleotides. Conversely, within a plurality / population of polyribonucleotides obtained after splicing that ‘comprise’ the third nucleotide 30 sequence, the third nucleotide sequence may be present in more than 80%, e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100% of the polyribonuclectides. Herein,within a plurality / population of cells that ‘substantially do not express’ a polypeptide of interest, the polypeptide may be expressed by fewer than 15%, é.g. one of $10%, 5%, 34%, $3%, $2% or s1% of the 35 cells. Conversely, within a plurality / population of cells that ‘express’ a polypeptide of interest, the polypeptide may be expressed by more than 80%, e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100% of the cells. In some embodiments, cells that ‘substantially do not express’ a polypeptide of interest may display a 40 level of expression of the polypeptide of interest which is less than 0.2 times, e.g. one of <0.1 times, <0.09 times, <0.08 times, <0.07 times, <0.06 times, <0.05 times, <0.04 times, <0.03 times, <0.02 times, or <0.01 times the level of expression by cells that express the polypeptide of interest. In some 49 WO 2024 / 251925 PCT / EP2024 / 065689 embodiments, cells that ‘express’ a polypeptide of interest may display a level of expressionof the polypeptide of interest which is greater than 5 times, e.g. one of 210 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or 210000 times level of expression by cells that ‘substantially do not express’ the polypeptide of interest. 5 In some embodiments, the level of RNA comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 in cells comprising a polynucleotide according to the present disclosure following culture in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 22 times, 23 times, 24 times, 25 times, 210 10 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or 210000 times the level in equivalent cells cultured in the absence of the splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the level of RNA comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequenceaccording to SEQ ID NO:11 in cells comprising a polynuclectide 15 according to the present disclosure following culture in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 100 times, e.g. one of $50 times, $20 times, $10 times, <5 times, $4 times, <3 times, <2 times or <1 times the level of RNA comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 in equivalent cells not comprising the polynucleotide. 20 In some embodiments, the level of a polypeptide of interest in cells comprising a polynucleotide according to the present disclosure (e.g. an ON-switch polynucleotide) in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 22 times, 23 times, 24 times, 25 times, 210 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or =10000 times the level 25 in equivalent cells cultured in the absence of the splicing modifierthat promotes SMN2 exon 7 inclusion. In some embodiments, the level of expression of a polypeptide of interest by cells comprising a polynucleotide according to the present disclosure (e.g. an ON-switch polynucleotide) in the absence of a splicing modifier that promotes S / MN2 exon 7 inclusion is less than 100 times, e.g. one of <50 times, <20 30 times, £10 times, <5 times, $4 times, <3 times, <2 times or <1 times the level of the polypeptide of interest in equivalent cells not comprising the polynucleotide. In some embodiments, the proportion of cells expressing a polypeptide of interest within a population of cells comprising a polynucleotide according to the present disclosure (e.g. an ON-switch polynucleotide) 35 cultured in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 22 times, 23 times, 24 times, 25 times, 210 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or 210000 times the proportion of suchcells expressing the polypeptide of interest cultured in the absence of the splicing modifier that promotes SMN2 exon 7 inclusion. 40 In some embodiments, the proportion of cells expressing a polypeptide of interest within a population of cells comprising a polynucleotide according to the present disclosure (e.g. an ON-switch polynucleotide) cultured in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 100 50 WO 2024 / 251925 PCT / EP2024 / 065689 times, é.g. one of <50 times, <20 times, <10 times, <5 times, <4 times, <3 times, <2 times or <1 times the proportion of such cells expressing the polypeptide of interest cultured in the presence of the splicing modifier that promotes SMA / 2 exon 7 inclusion. 5 In some embodiments, in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion, inclusion of the third nucleotide sequence is promoted in splicing of the polyribonucleotide, favouring the production of mature RNA molecules encoding apremature stop codon, and thus preventing expression of the polypeptide of interest at the protein level. Such polynucleotides may be referred to herein as ‘OFF- switch’ polynucleotides. 10 In some embodiments, cells comprising an OFF-switch polynucleotide of the present disclosure express the polypeptide of interest in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, cells comprising the OFF-switch polynucleotide do not express the polypeptide of interest in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion. 15 Exemplary OFF-switch polynucleotides according to the present disclosure include polynucleotides comprising SEQ ID NO:28 or 29. In some embodiments, the level of RNA comprising a nucleotide sequence having at least 80% sequence 20 identity to a nucleotide sequence according to SEQ ID NO:26 in cells comprising a polynuclectide according to the present disclosure following culture in the presence of a splicingmodifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 22 times, 23 times, 24 times, 25 times, =10 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or 210000 times the level in equivalent cells cultured in the absence of the splicing modifier that promotes SMN2 exon 7 inclusion. 25 In some embodiments, the level of RNA comprising a nucleotide sequence having at least 80% Sequence identity to a nucleotide sequence according to SEQ ID NO:26 in cells comprising a polynuclectide according to the present disclosure following culture in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 100 times, e.g. one of <50 times, <20 times, <10 times, <5 times, <4 30 __—ittimes, $3 times, <2 times or <1 times the level of the polypeptide of interest in equivalent cells not comprising the polynucleotide. In some embodiments, the level of a polypeptide of interest in cells comprising a polynucleotide according to the presentdisclosure (e.g. an OFF-switch polynucleotide) in the absence of a splicing modifier that 35 promotes SMN2 exon 7 inclusion is greater than 1 times, é.g. one of 22 times, 23 times, 24 times, 25 times, 210 times, 220 times, 250 times, 2100 times, 21000 times, =5000 times or 210000 times the level in equivalent cells cultured in the presence of the splicing modifier that promotes SMN2 exon 7 inclusion. In some embodiments, the level of expression of a polypeptide of interest by cells comprising a 40 polynucleotide according to the present disclosure (e.g. an OFF-switch polynucleotide) in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 100 times, e.g. one of $50 times, 51 WO 2024 / 251925 PCT / EP2024 / 065689 <20 times, <10 times, <5 times, <4 times, <3 times, <2 times or <1 times the level of the polypeptide of interest in equivalent cells not comprising the polynucleotide. In some embodiments, the proportion of cells expressing a polypeptide of interestwithin a population of 5 cells comprising a polynucleotide according to the present disclosure (¢.g. an OFF-switch polynucleotide) cultured in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 22 times, 23 times, 24 times, 25 times, 210 times, 220 times, 250 times, 2100 times, 21000 times, 25000 times or 210000 times the proportion of such cells expressing the polypeptide of interest cultured in the presence of the splicing modifier that promotes SMN2 exon 7 inclusion. 10 In some embodiments, the proportion of cells expressing a polypeptide of interest within a population of cells comprising a polynucleotide according to the present disclosure (e.g. an OFF-switch polynucleotide) cultured in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 100 times, e.g. one of <50 times, <20 times, <10 times, <5 times, <4 times, <3 times, $2 times or <1 times the 15 proportion of such cells expressing thepolypeptide of interest cultured in the absence of the splicing modifier that promotes SMAV / 2 exon 7 inclusion. The polynucleotides of the present disclosure possess novel and / or improved properties relative to known transgene expression systems, e.g. known transgene expression systems comprising a SMSM-mediated 20 switch derived from SMN2 exons 6 to 8 (e.g. SMN2Z exon 6 to exon &-derived transgene expression systems described in Zhang, ef a / ., Gene Ther. (2001) 8: 1532-1538, WO 2022 / 204471 A1, Monteys et al. Nature (2021) 596: 291-295 or WO 2021 / 163556 A1). In some embodiments, the polynucleotides of the present disclosure possess novel and / or improved 25 properties relative to a SMN2ind minigene polynucleotide (which is defined hereinabove). In some embodiments, cells comprising a polynucleotide of the present disclosure cultured in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion produce a population of RNA molecules having an increased proportion of RNAmolecules comprising a nucleotide sequence having at 30 least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26, compared to the population of RNA molecules produced by cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. That is, in some embodiments the polynucleotide of the present disclosure is more effective at promoting inclusion of a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26 in the presence of a 35 splicing modifier that promotes SMN2 exon 7 inclusion, compared to a SMN2ind minigene polynucleotide. That is, the polynucleotides of the present disclosure are more responsive to induction of SMN / 2 exon 7 variant inclusion in the products of splicing in response to a splicing modifier that promotes SMWN2 exon 7 inclusion than SMN2ind minigene polynucleotides. 40 In some embodiments, the proportion of RNA molecules comprising a nucleotide sequencehaving at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26 among RNA molecules obtained from cells comprising a polynucleotide of the present disclosure cultured in the 52 WO 2024 / 251925 PCT / EP2024 / 065689 presence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 21.01 times, 21.02 times, 21.03 times, 21.04 times, 21.05 times, 21.1 times, 21.2 times, 21.3 times, 21.4 times, 21.5 times, 21.6 times, 21.7 times, 21.8 times, 21.9 times, =2 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times or 210 times the proportion of RNA molecules comprising a 5 nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26 among RNA molecules obtained from cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. It will be appreciated that the functional properties described herein are evaluated employing thesame 10 experimental conditions for the evaluation of cells comprising the different polynucleotides (i.e. the polynucleotide of the present disclosure, and the SMN2ind minigene polynucleotide). For example, the same cell type, the same splicing modifier that promotes SMN2 exon 7 inclusion, the same concentration of the splicing modifier that promotes SMN2 exon 7 inclusion, efc. are used, the same culture period is provided, and the cells are analysed in order to determine the proportion of RNA molecules comprising 15 the relevant nucleotide sequence and / or the level of the polypeptide of interest in the same way. In some embodiments, cells comprising a polynucleotide of the present disclosure cultured in the absence of a splicing modifier that promotes SMN / 2 exon 7 inclusion produce a population of RNA molecules having a decreased proportion of RNA molecules comprising a nucleotide sequence having at 20 least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or26, compared to the population of RNA molecules produced by cells comprising a SMNZ2ind minigene polynucleotide and cultured under the same conditions. That is, in some embodiments the polynucleotide of the present disclosure is more effective at excluding 25 a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26 in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion, compared to a SMN2ind minigene polynucleotide. That is, the polynucleotides of the present disclosure are less ‘leaky’ with respect to SMN2 exon 7 variant inclusion in the products of splicing in the absence of a splicing modifier that promotes SMNV2 exon 7 inclusion, compared to SMN2ind minigene polynucleotides. Leaky 30 production of mature RNA molecules comprising an SMN2 exon 7 variant (i.e. in the absence of a splicing modifier that promotes SMAV / 2 exon 7 inclusion) may also be referred to herein as ‘background’ production of such RNAmolecules. In some embodiments, the proportion of RNA molecules comprising a nucleotide sequence having at 35 least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 26 among RNA molecules obtained from cells comprising a polynucleotide of the present disclosure cultured in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 1 times, e.g. $0.99 times, £0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, $0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, $0.25 times, <0.2 times, $0.15 40 __ times, $0.1 times, <0.05 times, or <0.01 times the proportion of RNA molecules comprising a nucleotide sequence having at least 80% sequence identity to a nucleotide sequence according to SEQ ID NO:11 or 53 WO 2024 / 251925 PCT / EP2024 / 065689 26 among RNA molecules obtained from cells comprising a SMN2ind minigene polynucleotide and cultured under the same concitions. In someembodiments, cells comprising a polynucleotide of the present disclosure (e.g. an ON-switch 5 polynucleotide) cultured in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion display an increased level of protein expression of the polypeptide of interest, compared to the level of protein expression of the polypeptide of interest by cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. That is, in some embodiments the polynucleotide of the present disclosure is more effective at promoting protein expression of the polypeptide of interest in the presence 10 of a splicing modifier that promotes SMN2 exon 7 inclusion, compared to a SMN2ind minigene polynucleotide. That is, the polynucleotides of the present disclosure are more responsive to induction of expression of the polypeptide of interest in the presence of a splicing modifier that promotes SMN / 2 exon 7 inclusion, compared to SMN2ind minigene polynucleotides. 15 It will beappreciated that for the purposes of such comparison, the different polynucleotides (i.e. the polynucleotide of the present disclosure, and the SMN2ind minigene polynucleotide) preferably encode the same polypeptide of interest. In some embodiments, the level of protein expression of the polypeptide of interest from cells comprising 20 a polynucleotide of the present disclosure (e.g. an ON-switch polynucleotide) cultured in the presence of a splicing modifier that promotes SMN2 exon 7 inclusion is greater than 1 times, e.g. one of 21.01 times, 21.02 times, 21.03 times, 21.04 times, =1.05 times, =1.1 times, 21.2 times, 21.3 times, =1.4 times, 21.5 times, 21.6 times, 21.7 times, 21.8 times, 21.9 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times or 210 times the level of protein expression of the polypeptide of interest from 25 cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. In some embodiments, cellscomprising a polynucleotide of the present disclosure (e.g. an ON-switch polynucleotide) cultured in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion display a decreased level of protein expression of the polypeptide of interest, compared to the level of 30 protein expression of the polypeptide of interest by cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. That is, in some embodiments the polynucleotide of the present disclosure is more effective at preventing protein expression of the polypeptide of interest in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion, compared to a SMN2ind minigene polynucleotide. That is, the polynucleotides of the present disclosure are less ‘leaky’ with respect to 35 expression of the polypeptide of interest in the absence of a splicing modifier that promotes SMNZ2 exon 7 inclusion, compared to SMN2ind minigene polynucleotides. Leaky expression of the polypeptide ofinterest (.e. in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion) may also be referred to herein as ‘background’ expression of the polypeptide. 40 In some embodiments, the level of protein expression of the polypeptide of interest from cells comprising a polynucleotide of the present disclosure (e.g. an ON-switch polynucleotide) cultured in the absence of a splicing modifier that promotes SMN2 exon 7 inclusion is less than 1 times, e.g. <0.99 times, <0.95 times, 54 WO 2024 / 251925 PCT / EP2024 / 065689 <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, £0.45 times, <0.4 times, £0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or $0.01 times the level of protein expression of the polypeptide of interest from cells comprising a SMN2ind minigene polynucleotide and cultured under the same conditions. 5 In some embodiments, a polypeptide of interest expressed from apolynucleotide of the present disclosure comprises fewer extraneous additional amino acids (i.e. amino acids additional to the amino acid sequence of the polypeptide of interest) compared to a polypeptide of interest expressed from SMN2Zind minigene polynucleotide. In some embodiments, a polypeptide of interest expressed from a 10 polynucleotide of the present disclosure comprises a smaller N-terminal tag (i.e. formed of extraneous, additional amino acids in addition to the amino acid sequence of the polypeptide of interest) than a polypeptide of interest expressed from SMN2ind minigene polynucleotide. That is, in some embodiments, the polynucleotides of the present disclosure provide for the inducible expression of polypeptides of interest comprising fewer extraneous additional amino acids, relative to polypeptides of interest 15 expressed from SMN2ind minigene polynucleotide. Vectors The present disclosure provides vectors comprising the polynucleotides according to the presentdisclosure. It will be appreciated that a vector is also a polynucleotide, and so in some embodiments a 20 polynucleotide according to the present disclosure may be a vector. A ‘vector’ as used herein refers to a polynucleotide used as a vehicle to transfer exogenous nucleic acid into a cell. The vector may be a vector for expression of the nucleic acid in the cell (i.e. the vector may be an expression vector). Such vectors may include a promoter sequence operably linked to the nucleotide 25 sequence to be expressed. Vectors may also include a termination codon and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used in a vector according to the present disclosure. The term ‘operably linked’ may include the situation where nucleic acid encoding a polypeptide of interest 30 according to the present disclosure and regulatory nucleic acid sequence(s) (e.g. a promoter and / or enhancers) are covalently linked in such a way as toplace the expression of the nucleic acid encoding a polypeptide under the influence or control of the regulatory nucleic acid sequence(s) (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to the selected nucleic acid sequence if the regulatory sequence is capable of effecting transcription of the nucleic acid sequence. 35 ‘The resulting transcript(s) may then be translated into the desired polypeptide(s). Vectors contemplated in connection with the present disclosure include DNA vectors, RNA vectors, plasmids (¢.g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g. retroviral vectors, é.g. gammaretroviral vectors (e.g. murine 40 Leukemia virus (MLV)-derived vectors, é.g. SFG vector), lentiviral vectors, adenovirus vectors, adeno- associated virus vectors, vaccinia virus vectors, baculoviral vectors and herpesvirus vectors), transposon- based vectors, and artificial chromosomes(e.g. yeast artificial chromosomes), e.g. as described in Maus 55 WO 2024 / 251925 PCT / EP2024 / 065689 et al., Annu Rev Immunol (2014) 32:189-225 and Morgan and Boyerinas, Biomedicines (2016) 4:9, which are both hereby incorporated by reference in their entirety. In some embodiments, the vector may be a eukaryotic vector, ie. a vector comprising the elements 5 necessary for expression of protein from the vector in a eukaryotic cell. In some embodiments, the vector may be a mammalian vector, €.g. comprising a cytomegalovirus (CMV) or SV40 promoter to drive protein expression. In some embodiments, the vector comprises a CMV (e.g. MCMV), SV40, RSV or PGK promoter. 10 In some embodiments, the polynucleotide according to the present disclosure (e.g. the vector according to the present disclosure) comprises a CMV promoter, a CAG promoter, a hEF1a promoter, a hUbiC promoter, an RSV promoter, a TK promoter, a PGK promoter, or a CAG minimal promoter. In some embodiments, the polynucleotideaccording to the present disclosure (e.g. the vector according 15 to the present disclosure) comprises a promoter having a nucleotide sequence comprising, or consisting of, a nucleotide sequence having at least 80% (e.g. one of 285%, 290%, 291%, 292%, 293%, 294%, 295%, 296%, 297%, 298%, 299% or 100%) sequence identity to SEQ ID NO:201, 202, 203, 204, 205, 206, 207 or 208. 20 In some embodiments, a vector is selected based on tropism for a cell type / tissue / organ to which it is desired to deliver the polynucleotide according to the present disclosure. In some embodiments, a vector is selected based on tropism for a cell type / tissue / organ in which it is desired to express the polypeptide of interest. For example, it may be desired to deliver the polynucleotide to, and / or express the polypeptide of interest in, a cell type / tissue / organ affected by a disease / condition to be treated / prevented in 25 accordance with the present disclosure (e.g. a cell type / tissue / organ in which the symptoms ofthe disease / condition manifest). For example, it might be desirable to deliver a polynucleotide of the present disclosure encoding a polypeptide of interest to neuronal cells / tissue, and vectors having a tropism for such cells / tissue may be 30 employed in such instances (i.e. neurotropic vectors). In preferred embodiments, the vector is an adeno-associated virus (AAV) vector. Adeno-associated virus vectors and their use to vector gene therapy is reviewed e.g. in Wang et al., Nat. Rev. Drug Discov. (2019) 18: 358-378 and Li and Samulski, Nat. Rev. Genet. (2020) 12: 255-272, both of which are hereby 35 incorporated by reference in their entirety. In some embodiments, a vector may be an adeno-associated virus vector described in Wang ef al., Nat. Rev. Drug Discov. (2019) 18: 358-378. In some embodiments, a vector may be an adeno-associated virus vector described in Li and Samulski, Nat. Rev. Genet. (2020) 12: 255-272. 40 In some embodiments, the vector is a self-complementaryadeno-associated virus (ScAAV) vector. Self- complementary adeno-associated virus vectors are described e.g. in McCarty, Mol Ther. (2008) 16(10):1648-56, which is hereby incorporated by reference in its entirety. Conventional AAV have a 56 WO 2024 / 251925 PCT / EP2024 / 065689 single-stranded DNA genome, and depend on the DNA replication machinery of a transduced cell to synthesise the complementary strand, delaying transgene expression. By contrast, scAAV contain complementary sequences that spontaneously anneal upon infection, eliminating the requirement for DNA synthesis in the transduced host cell. Compared to classical, single-stranded AAV vectors, scAAV 5 vectors have been shown to provide for accelerated onset of transgene expression, and an increased level of transgene expression. In some embodiments, a vector may be an adeno-associated viral vector of one of the following serotypes: AAV9 (including AAV9 variants AAV-PHP.B and AAV9.45), AAV1, AAV2 (including AAV2 10 variant AAV2i8),AAV5, AAV6, AAV8, AAV10 or AAVrh74. In some embodiments, a vector may be an adeno-associated viral vector of one of the following serotypes: AAV9 (including AAV9 variants AAV- PHP.B and AAV9.45), AAV1, AAV2 (including AAV2 variants AAV2.7m8 and AAV2i8), AAV5, AAV6, AAV8, AAV10 or AAVrh74. In some embodiments, the vector is an AAV9 vector. 15 In some embodiments a vector comprises modification to increase binding to and / or transduction of a cell-type of interest (.e. as compared to the level of binding / transduction by the unmodified vector). In some embodiments modification is to a capsid protein. In some embodiments a vector comprises a capsid protein comprising a cell-targeting peptide. In some 20 embodiments the cell-targeting peptide is a cell-targeting peptide described in Buning and Srivastava, Molecular Therapy: Methods & Clinical Development (2019) 12: 248-265, which is hereby incorporated by reference in its entirety, €.g. a cell-targeting peptide shown in Table 1, 2, 3 or 4thereof. In some embodiments a vector comprises a capsid protein comprising substitution to one or more 25 tyrosine residues, e.g. one or more surface-exposed tyrosine residues. In some embodiments, one or more tyrosine residues of the capsid protein are substituted with phenylalanine. In some embodiments a vector comprises a capsid protein in which one or more tyrosine residues are substituted with another amino acid as described in lida ef a / ., Biomed Res Int. (2013) 2013: 974819, which is hereby incorporated by reference in its entirety. 30 In some embodiments, a vector may be an adeno-associated virus vector described in Biining and Srivastava, supra. In some embodiments, a vector may be an adeno-associated virus vector described in lida ef al., supra. 35 In some embodiments the vector comprises a control element for inducible expression of the polynucleotide of the disclosure. A sequence for controlling expression of the polynucleotide may provide for expression of thepolynucleotide by cells of a particular type or tissue. For example, expression may be under the control of 40 a cell type- or tissue-specific promoter. 57 WO 2024 / 251925 PCT / EP2024 / 065689 Promoters for cell type- or tissue-specific expression of a polynucleotide in accordance with the present disclosure can be selected in accordance with a disease / condition to be treated / prevented. For example, the promoter may drive expression in a cell type / tissue / an organ affected by the disease / condition (e.g. a cell type / tissue / an organ in which the symptoms of the disease / condition manifest). 5 In some embodiments, a promoter may provide for expression of the polynucleotide in neuronal cells / tissue. In some embodiments, a promoter may be a neuron-specific promoter (¢.g. a CaMKIl, NSE or Synl-miniCMV promoter) In some embodiments, a promoter may provide for expression of the polynucleotide in muscle cells / tissue (€.g. cardiac and / or skeletal muscle cells / tissue). In some 10 embodiments, apromoter may be a cardiac or cardiomyocte-specific promoter (e.g. a CTNT, a-MHC or MLC2v promoter). In some embodiments, a promoter may be a skeletal muscle / striated muscle cell- specific promoter (e.g. a MCK, MHCK7 or desmin promoter). In some embodiments, a promoter may be a vascular endothelial cell-specific promoter (e.g. a Tie2 promoter). In some embodiments, a promoter may be a vascular smooth muscle cell-specific promoter (e.g. a SM22a promoter). In some embodiments, a 15 promoter may be a monocyte / macrophage-specific promoter (e.g. a LysM promoter). A sequence for controlling expression of the polynucleotide may provide for expression of the polynucleotide in response to e.g. a given agent / signal. For example, expression may be under the control of inducible promoter. The agent may provide for inducible expression of the polynucleotide in vivo 20 by administration of the agent to a subject having been administered with a modified cell according to the disclosure, or ex vivo / invitro by administration of the agent to cells in culture ex vivo or in vitro. In some embodiments a polynucleotide or vector according to the present disclosure may employ a conditional expression system for controlling expression of the polynucleotide by cells comprising the 25 polynucleotide / vector. ‘Conditional expression’ may also be referred to herein as ‘inducible expression’, and refers to expression contingent on certain conditions, e.g. the presence of a particular agent. Conditional expression systems are well known in the art and are reviewed e.g. in Ryding et a / . Journal of Endocrinology (2001) 171, 1-14, which is hereby incorporated by reference in its entirety. 30 = Cells The present disclosure also provides a cell comprising or expressing a polynucleotide according to the present disclosure. Also provided is a cell comprising or expressing vector according to the present disclosure. 35 A polynucleotide according to the present disclosure (e.g. a polyribonucleotide) maybe produced within a cell by transcription from a polynucleotide (e.g. a polydeoxyribonucleotide) encoding the polynucleotide. The cell may be a eukaryotic cell, e.g. a mammalian cell. The mammal may be a primate (rhesus, cynomolgous, non-human primate or human) or a non-human mammal (e.g. rabbit, guinea pig, rat, 40 mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cows, e.g. dairy cows, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate). In preferred embodiments, the cell may be a human cell. 58 WO 2024 / 251925 PCT / EP2024 / 065689 The cell may be an immune cell. The cell may be a cell of hematopoietic origin, e.g. a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte. The lymphacyte may be e.g. a T cell, B cell, NK cell, NKT cell or innate lymphoid cell (ILC), or a precursor thereof. The cell may express e.g. CD3 5 polypeptides (e.g. CD3yCD3¢ CD3Z or CD30), TCR polypeptides (TCRa or TCRB), CD27, CD28, CD4 or CD8. In some embodiments, the cell is a T cell. In some embodiments, the T cell is a CD3+ T cell. In some embodiments, the T cell is a CD3+, CD8+ T cell. In some embodiments, the T cell is a cytotoxic T cell (e.g. a cytotoxic T lymphacyte (CTL)). 10 The present disclosure also provides a method for producing a cell comprising or expressing a polynucleotide / vector according to the present disclosure, the method comprising introducing a polynucleotide / vector of the present disclosure into a cell. In some embodiments, introducing a polynucleotide / vector according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. adeno-associated viral transduction). In some 15 embodiments, the polynucleotide / vector is introduced to the cell in vivo, e.g. by administration of a vector according to the present disclosure (e.g. a viral vector, e.g. an adeno-asscciatedviral vector) to a subject. In some embodiments, the polynucleotide / vector is introduced into cells in culture ex vivo or in vitro. Any suitable method may be employed to produce a cell according to the present disclosure. Such 20 methods may comprise nucleic acid transfer for permanent ( / .e. stable) or transient expression of the polynucleotide of the present disclosure. In some embodiments, following introduction into a cell, the polynucleotide may be integrated into or form part of the genomic DNA of the cell. In some embodiments, following introduction into a cell, the polynucleotide may be maintained extrachromosomally. 25 Any suitable genetic engineering platform may be used, and include gammaretroviral vectors, lentiviral vectors, adenovirus vectors, DNA transfection, transposon-based gene delivery and RNA transfection, for example as described in Maus e¢ a / l., Annu Rev Immunol. (2014) 32:189-225, hereby incorporated by reference in its entirety. Methods also include thosedescribed e.g. in Wang and Riviére Mol Ther Oncolytics. (2016) 3:16015, which is hereby incorporated by reference in its entirety. Suitable methods for 30 introducing nucleic acid(s) / vector(s) into cells include transduction, transfection and electroporation. In some embodiments, the methods additionally comprise maintaining the cell under conditions suitable for expression of the polynucleotide / vector by the cell. 35 ‘The present disclosure also provides cells obtained or obtainable by the methods according to the present disclosure. Compositions The present disclosure also provides compositions comprising the polynucleotides, vectors and cells 40 = described herein. In particular, the present disclosure provides pharmaceutical compositions and medicaments comprising the polynucleotides, vectors and cells of the present disclosure. 59 WO 2024 / 251925 PCT / EP2024 / 065689 Such compositions may comprise the relevant article (..e. the polynucleotide / vector / cell) in a formulation suitable forclinical use. The present disclosure is concerned in particular with pharmaceutical compositions / medicaments comprising polynucleotides and vectors according to the present disclosure. 5 The compositions of the present disclosure may comprise one or more pharmaceutically-acceptable carriers (€.g. liposomes, micelles, microspheres, nanoparticles), diluents / excipients (¢.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), anti-oxidants (e.g. vitamin A, vitamin E, vitamin C, 10 retinyl palmitate, selenium), lubricants (e.g. magnesium stearate, talc, silica, stearic acid, vegetable stearin), binders (e.g. sucrose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents or colouring agents (e.g. titanium oxide). 15 The term ‘pharmaceutically-acceptable’ as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, efc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (¢.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, 20 lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent of a composition according to the present disclosure must also be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives,anti-oxidants, lubricants, binders, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents or sweetening agents can 25 be found in standard pharmaceutical texts, for example, Remington's ‘The Science and Practice of Pharmacy’ (Ed.(A)Adejare), 23rd Edition (2020), Academic Press. The pharmaceutical compositions / medicaments according to the present disclosure may be formulated for administration to a subject, e.g. administration via a route of administration as appropriate for the 30 nature of the therapeutic agent and the disease to be treated / prevented. In some embodiments, a pharmaceutical composition / medicament may be formulated for parenteral, systemic, topical, intracavitary, intravascular, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal,, oral or transdermal administration. In some embodiments, a pharmaceutical composition / medicament may be formulated foradministration by 35 injection or infusion, or administration by ingestion. Medicaments and pharmaceutical compositions may be formulated for administration to a blood vessel, or to a tissue / organ of interest (e.g. a tissue / organ affected by a disease / condition, e.g. a tissue / organ in which symptoms of the disease / condition manifest). 40 The pharmaceutical compositions / medicaments may comprise the polynuclectide / vector / cell in a sterile or isotonic medium. The pharmaceutical compositions / medicaments may be provided in fluid, including gel, 60 WO 2024 / 251925 PCT / EP2024 / 065689 form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via cannula) to a blood vessel, or a selected region of the human or animal body. The pharmaceutical compositions / medicaments may be provided in solid form, e.g. in lyophilised form. 5 The present disclosure also provides methods for producing pharmaceutical compositions / medicaments according to the present disclosure. Suchmethods may comprise mixing a polynucleotide / vector / cell described herein with a pharmaceutically-acceptable carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent. Such methods generally include the step of bringing into 10 association the polynucleotide / vector / cell with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active compound with carriers (€.g., liquid carriers, finely divided solid carrier, efc.), and then shaping the product, if necessary. 15 Polynucleotides, vectors, cells and compositions according to the present disclosure may be modified and / or formulated to facilitate delivery to, and / or uptake by, a cell type / tissue / organ of interest (e.g. a cell type / tissue / organ in which symptoms of a disease / conditionmanifest). Strategies for targeted delivery of polynucleotides are reviewed e.g. in Li ef af, Int. J. Mol. Sci. (2015) 16: 20 19518-19536 and Fu ef a / ., Bioconjug Chem. (2014) 25(9): 1602-1608, which are hereby incorporated by reference in their entirety. In some embodiments, articles of the present disclosure may be encapsulated in a nanoparticle or a liposome. In some embodiments, articles of the present disclosure may be (covalently or non-covalently) 25 associated with a cell-penetrating peptide (e.g. a protein transduction domain, trojan peptide, arginine-rich peptide, vectocell peptide), a cationic polymer, a cationic lipid or a viral carrier. Nanoparticles may be organic, e.g. micelles, liposomes, proteins, solid-lipid particles, solid polymer particles, dendrimers, and polymer therapeutics. Nanoparticles may be inorganic, e.g. such as nanotubes 30 or metal particles, optionally with organic molecules added. In some embodiments, a nanoparticle is a nanoparticle described in Chenef a / ., Mol Ther Methods Clin Dev. (2016) 3:16023, which is hereby incorporated by reference in its entirety. In some embodiments, a nanoparticle is a PLGA, polypeptide, poly(B-amino ester), DOPE, B-cyclodextrin-containing polycation, linear PE], PAMAM dendrimer, branched PEI, chitosan or polyphosophoester nanoparticle. 35 In some embodiments, polynucleotides and vectors according to the present disclosure comprise modification to incorporate one or more moieties facilitating delivery to, and / or uptake by, a cell type, organ or tissue of interest (e.g. a cell type / tissue / organ in which symptoms of a disease / condition manifest). In some embodiments, polynucleotides or vectors according to the present disclosure are 40 linked (e.g. chemically conjugated to) one or more moieties facilitating delivery to, and / or uptake by, a cell type, tissue or organ of interest. 61 WO 2024 / 251925 PCT / EP2024 / 065689 Moieties facilitating delivery to, and / or uptake by, cell types, tissues or organs ofinterest are described e.g. in Benizri et a / ., Bioconjug Chem. (2019) 30(2): 366-383, which is hereby incorporated by reference in its entirety. Such moieties include e.g. N-acetylgalactosamine (GalNAc), a-tocopherol, cell-penetrating peptides, nucleic acid aptamers, antibodies and antigen-binding fragments / derivatives thereof, 5 cholesterol, squalene, polyethylene glycol (PEG), fatty acids (e.g. palmitic acid) and nucleolipid moieties. Articles of the present disclosure may be formulated in a sustained release delivery system, in order to release the polynucleotide, vector, cell or composition at a predetermined rate. Sustained release delivery systems may maintain a constant drug / therapeutic / prophylactic concentration for a specified period of 10 ‘time. In some embodiments, articles of the present disclosure are formulated in a liposome, gel, implant, device, or drug-polymer conjugate e.g. hydrogel. In some embodiments, a composition according to the present disclosure may furthercomprise a splicing modifier that promotes SMAV / 2 exon 7 inclusion (e.g. as described herein). 15 Therapeutic / prophylactic applications The polynucleotides, vectors, cells and compositions of the present disclosure find use in therapy and prophylaxis. 20 Accordingly, the present disclosure provides a polynucleotide, vector, cell or composition described herein for use in a method of medical treatment or prophylaxis. Also provided is a polynucleotide, vector, cell or composition described herein for use in a method of treating or preventing a disease / condition described herein. Also provided is the use of a polynucleotide, vector, cell or composition described herein in the manufacture of a medicament for treating or preventing a disease or condition described 25 herein. Also provided is a method of treating or preventing a disease or condition described herein, comprising administering to a subject a therapeutically- or prophylactically- effective amount of a polynucleotide, vector,cell or composition described herein. The intervention described in the preceding paragraph may be effective to reduce the development or 30 progression of a disease / condition, alleviate the symptoms of a disease / condition or reduce the pathology of a disease / condition. The intervention may be effective to prevent progression of the disease / condition, é.g. to prevent worsening of, or to slow the rate of development of, the disease / condition. In some embodiments, the intervention may lead to an improvement in the cisease / condition, e.g. a reduction in the symptoms of the disease / condition or reduction in some other correlate of the severity / activity of the 35 — disease / condition. In some embodiments, the intervention may prevent progression / development of the disease / condition a later stage (e.g. a chronic stage). It will be appreciated that the polynucleotides, vectors, cells and compositions described herein may be used for the treatment / prevention of any disease / condition that wouldderive therapeutic or prophylactic 40 benefit from an increase in the level of the polypeptide of interest ( / .e. the polypeptide of interest encoded by the polynucleotide). 62 WO 2024 / 251925 PCT / EP2024 / 065689 For example, the disease / condition may be a disease / condition associated with and / or characterised by deficiency / insufficiency of the polypeptide of interest. Deficiency / insufficiency of the polypeptide of interest may be positively associated with the onset, development or progression of the disease / condition, and / or positively associated with the severity of one or more symptoms of the disease / condition. 5 Deficiency / insufficiency of the polypeptide of interest may be a risk factor for the onset, development or progression of the disease / condition. The disease / condition may be characterised by a decreased level of expression or activity of the polypeptide of interest, e.g. as compared to the level of expression / activity in the absence of the disease / condition. In someembodiments, the disease / condition may be characterised by a decrease in the number / proportion / activity of cells expressing the polypeptide of interest, e.g. as 10 compared to the level / number / proportion / activity in the absence of the disease / condition (e.g. in a healthy subject, or in equivalent non-diseased tissue). By way of illustration, in some embodiments, the polypeptide of interest may be MeCP2, and the disease / condition to be treated / prevented in accordance with the present disclosure may be a 15 disease / condition caused by deficiency / insufficiency of MeCP2, e.g. Rett syndrome. By way of further example, in embodiments wherein the polypeptide of interest is a polypeptide capable of inhibiting the expression and / or activity of a target antigen of interest, the disease / condition may be a disease / condition in which the target antigen, or cells comprising / expressing the target antigen are 20 pathologically-implicated, e.g. a disease / condition in which an increased level / activityof the target antigen, or an increase in the number / proportion / activity of cells comprising / expressing the target antigen is positively associated with the onset, development or progression of the disease / condition, and / or severity of one or more symptoms of the disease / condition. In some embodiments, an increased level / activity of the target antigen, or an increase in the number / proportion / activity of cells 25 comprising / expressing the target antigen may be a risk factor for the onset, development or progression of the disease / condition. The disease / condition may be characterised by an increase in the level of expression or activity of the target antigen, e.g. as compared to the level of expression / activity in the absence of the disease / condition. In some embodiments, the disease / condition may be characterised by an increase in the number / proportion / activity of cells expressing the target antigen, e.g. as compared to 30 the level / number / proportion / activity in the absence of thedisease / condition (e.g. in a healthy subject, or in equivalent non-diseased tissue). Therapeutic / prophylactic intervention in accordance with the present disclosure may achieve one or more of the following in a subject (compared to an equivalent untreated subject, or subject treated with an appropriate control): a reduction in the level of the target antigen; a reduction in the activity of the target antigen; and / or a reduction in the number / proportion / activity of cells 35 comprising / expressing the target antigen. By way of further example, the disease / condition may be a disease / condition to be treated by nucleic acid editing, and the polypeptide of interest may be a constituent protein of an appropriate site-specific nuclease nucleic acid editing system. 40 The present disclosure provides the articles of the present disclosure for use, uses of articles of the present disclosure, and methods comprising administering polynucleotides, vectors, cells and 63 WO 2024 / 251925PCT / EP2024 / 065689 compositions according to the present disclosure to a subject (¢.g. a subject in need of treatment). In some embodiments, the methods comprise administering to the subject a splicing modifier that promotes SMN2 exon 7 inclusion (e.g. a splicing modifier that promotes SMN2 exon 7 inclusion as described herein). 5 Administration of the articles of the present disclosure is preferably in a ‘therapeutically-effective’ or ‘prophylactically-effective’ amount, this being sufficient to show therapeutic or prophylactic benefit to the subject. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease / condition and the particular article administered. Prescription of 10 treatment, e.g. decisions on dosage efc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disease / disorder to be treated, the condition of the individual subject, the site ofdelivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s ‘The Science and Practice of Pharmacy’ (ed.(A)Adejare), 23rd Edition (2020), Academic Press. 15 Administration of the articles of the present disclosure may be parenteral, systemic, intravenous, intra- arterial, intramuscular, intracavitary, intrathecal, intraocular, intravitreal, intraconjunctival, subretinal, suprachcroidal, subcutaneous, intradermal, intrathecal, oral, nasal, topical or transdermal. Administration may be by injection or infusion, Administration of the articles of the present disclosure may be 20 intratumoral. In some cases, the articles of the present disclosure may be formulated for targeted delivery to specific cells, a tissue, an organ and / or a tumor. Multiple doses of an article of the present disclosure may be provided. Multiple doses may be separated by a predetermined time interval, which may beselected to be one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 25 = 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. In some embodiments, the present disclosure provides the articles of the present disclosure for use, uses of articles of the present disclosure, and methods comprising administering: (i) a polynucleotide, vector, 30 cell or composition according to the present disclosure, and (ii) a splicing modifier that promotes SMN2 exon 7 inclusion, to a subject (e.g. a subject in need of treatment). In embodiments in accordance with aspects of the preceding paragraph, provision of (i) and (ii) may be as a combination therapy. In some embodiments, (i) and (ii) may be provided simultaneously or sequentially. 35 Simultaneous administration refers to administration of the two or more agents (e.g. a polynucleotide, vector, cell or composition according to the present disclosure, and a splicing modifier that promotes SMN2exon 7 inclusion) together, for example as a pharmaceutical composition containing both agents (i.e. aS a combined preparation), or immediately after each other (e.g. within 1, 4, 6, 8 or 12 hours), and 40 optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel. Sequential administration refers to administration of one of the agents followed after a given time interval 64 WO 2024 / 251925 PCT / EP2024 / 065689 by separate administration of another agent. It is not required that the agents are administered by the same route, although this is the case in some embodiments. The time interval may be any time interval. In some embodiments, a splicing modifier that promotes SMN2 exon 7 inclusion is administered to a 5 subject after administration of a polynucleotide, vector, cell or composition according to the present disclosure. In some embodiments, a polynucleotide, vector, cell or composition according to the present disclosure is administered to asubject, and a splicing modifier that promotes SMN2 exon 7 inclusion is administered continuously to the subject thereafter. 10 In some embodiments, the splicing modifier that promotes SMN2 exon 7 inclusion is administered in a quantity, and / or with a periodicity, selected to achieve a desired level of expression of the polypeptide of interest. That is, in some embodiments the quantity of, and / or periodicity with which, a splicing modifier that promotes SMN2 exon 7 inclusion administered to a subject in accordance with the present disclosure is selected to achieve a desired level of expression of the polypeptide of interest. In some embodiments, 15 the quantity of, and / or periodicity with which, a splicing modifier that promotes SMNZ exon 7 inclusion is administered to a subject is adjusted through the course of its administration to change (i.e. decrease or increase) the level of expression of the polypeptide of interest in the subject. In embodiments wherein the polynucleotide of thedisclosure is an ON-switch polynucleotide, the quantity 20 and / or periodicity of administration of a splicing modifier that promotes SMNV2 exon 7 inclusion may be increased to increase the level of expression of the polypeptide of interest. Conversely, the quantity and / or periodicity of administration of a splicing modifier that promotes SMN / 2 exon 7 inclusion may be decreased to decrease the level of expression of the polypeptide of interest. 25 In embodiments wherein the polynucleotide of the disclosure is an OFF-switch polynucleotide, the quantity and / or periodicity of administration of a splicing modifier that promotes SMN2 exon 7 inclusion may be decreased to increase the level of expression of the polypeptide of interest. Conversely, the quantity and / or periodicity of administration of a splicing modifier that promotes SMN2 exon 7 inclusion may be increased to decrease the level of expression of the polypeptide of interest. 30 Further methods The present disclosure also providesa method for modifying a cell to comprise or express a polynucleotide according to the present disclosure, comprising introducing into a cell a polynucleotide or vector according to the present disclosure. 35 In some embodiments, introducing a polynucleotide or vector according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. retroviral transduction). Transfection relates to the process of introducing nucleic acid into cells using means other than viral 40 infection and is hence a non-viral method. Transfection may be performed by physical / mechanical methods (including electroporation, sonoporation, magnetofection, gene microinjection and laser irradiation) or chemical methods (liposomal-based or non-liposomal based). Liposomal-based transfection 65 WO 2024 / 251925 PCT / EP2024 / 065689 reagents are chemicals which enable the formation of positively charged lipid aggregates, which can then merge with the phospholipid bilayerof the cell to facilitate the entry of foreign genetic material. Examples of liposomal-based transfection reagents include, but are not limited to Oligofectamine®, Lipofectamine® and DharmaFECT®. Non-liposomal transfection reagents include, but are not limited to, calcium 5 phosphate, nanoparticles, polymers, dendrimers and non-liposomal lipids. One example of a non- liposomal transfection reagent is polyethylenimine (PEI). Electroporation may be performed e.g. as described in Koh et al., Molecular Therapy — Nucleic Acids (2013) 2, e114, which is hereby incorporated by reference in its entirety. 10 Transduction is a process by which nucleic acids may be introduced into a cell by a virus or a viral vector. Accordingly, in some embodiments the polynucleotide is, or is comprised in, a viral vector, or the vector is a viral vector. Transduction of immune cells with viral vectors is described e.g. in Simmons and Alberola- lla, Methods Mol Biol. (2016) 1323:99-108, which is herebyincorporated by reference in its entirety. 15 Agents may be employed in the methods of the present disclosure to enhance the efficiency of transduction. Hexadimethrine bromide (polybrene) is a cationic polymer which is commonly used to improve transduction, through neutralising charge repulsion between virions and sialic acid residues expressed on the cell surface. Other agents commonly used to enhance transduction include e.g. the poloxamer-based agents such as LentiBOOST (Sirion Biotech), Retronectin (Takara), Vectofusin (Miltenyi 20 Biotech) and also SureENTRY (Qiagen) and ViraDuctin (Cell Biolabs). In some embodiments the methods comprise centrifuging the cells into which it is desired to introduce polynucleotide or vector according to the present disclosure in the presence of cell culture medium comprising viral vector(s) comprising the polynucleotide (referred to in the art as ‘spinfection’). 25 In some embodiments, the methods comprise culturing the cell under conditionssuitable for expression of the polynucleotide or vector by the cell. In some embodiments, the methods comprise culturing the cell under conditions suitable for transcription of a polydeoxyribonucleotide. In some embodiments, the methods comprise culturing the cell under conditions suitable for post-transcriptional processing (é.g. 30 splicing) of a polyribonucleotide. In some embodiments, the methods comprise culturing the cell under conditions suitable for translation of a polypeptide from a polyribonucleotide. Methods for culturing (including generating and / or expanding) populations of cells in vitro / ex vivo — including suitable culture conditions ( / .e. cell culture media, additives, stimulations, temperature, gaseous 35 atmosphere), cell numbers, culture periods efc. — are well known to the skilled person. Conveniently, cultures of cells according to the present disclosure may be maintained at 37°C in a humidified atmosphere containing 5% CC. The present disclosure also provides amethod for modifying a cell to express a polypeptide of interest, 40 comprising introducing into a cell a polynucleotide or vector according to the present disclosure. Where the polynucleotide is, or wherein the vector comprises / encodes, an OFF-switch, the cell may express the polypeptide of interest following introduction of the polynucleotide / vector into the cell. 66 WO 2024 / 251925 PCT / EP2024 / 065689 Where the polynucleotide is, or wherein the vector comprises / encodes, an ON-switch, the method may further comprise contacting the cell with a splicing modifier that promotes SMN2 exon 7 inclusion as described herein. Thus, in some embodiments, the method comprises (i) introducing into a cell a 5 polynucleotide or vector according to the present disclosure; and (ii) subsequently contacting the cell with a splicing modifier that promotes SMN2 exon 7 inclusion. ‘Contacting’ a cell with a splicing modifier may comprise bringing a cell into contact with a splicing modifier in a cell culture,and may be achieved by applying the splicing modifier to the cells in culture. 10 The present disclosure also provides a method for inhibiting expression of a polypeptide of interest in a cell. The method comprises contacting a cell comprising a polynucleotide or vector according to the present disclosure comprising / encoding an OFF-switch with a splicing modifier that promotes SMN2 exon 7 inclusion as described herein. 15 Any suitable quantity / concentration of a splicing modifier may be employed in the methods of the present disclosure. It will be appreciated that the quantity / concentration of the splicing modifier is preferably selected such as to achieve the desired effect, ie. increased inclusion of the SMN2 exon 7 variant nucleotide sequence in the products of splicing of the relevant polyribonucleotide. 20 Subjects A subject in accordance with the various aspects of the present disclosure may be any animal or human. Therapeutic and prophylactic applications may be in human oranimals (veterinary use). 25 The subject to be administered with an article of the present disclosure (e.g. in accordance with therapeutic or prophylactic intervention) may be a subject in need of such intervention. The subject is preferably mammalian, more preferably human. The subject may be a non-human mammal, but is more preferably human. The subject may be male or female. The subject may be a patient. 30 A subject may have (e.g. may have been diagnosed with) a disease or condition described herein, may be suspected of having such a disease / condition, or may be at risk of developing / contracting such a disease / condition. In embodiments according to the present disclosure, a subject may be selected for treatment according to the methods based on characterisation for one or more markers of such a disease / condition. 35 Kits The present disclosure also provides kits of parts. In some aspects and embodiments, a kit of parts according to the present disclosure comprises (i) a 40polynucleotide, vector, or a pharmaceutical composition according to the present disclosure, and (ii) a splicing modifier that promotes SMN2 exon 7 inclusion. 67 WO 2024 / 251925 PCT / EP2024 / 065689 Kits of parts according to the present disclosure may comprise a predetermined quantity of articles according to (i) and / or (ii), as described in the preceding paragraph. In some embodiments, articles accarding to (i) and / or (ii) are provided in containers (e.g. in vials or bottles). The kit may provide articles according to (i) and / or (ii) together with instructions (€.g. a protocol) as to how to employ them in 5 accordance with a therapeutic or prophylactic intervention as described herein. In some embodiments, the kit of parts may comprise a polynucleotide or vector according to the present disclosure, and optionally materials for introducing the polynucleotide / vector into a cell. In some embodiments, the kit of parts may comprise a system for producing a cell according to the present 10 =disclosure. In some embodiments, the kit of parts may comprise a (closed) bag cell incubation system in which a polynucleotide or vector can be introduced into a cell. In some embodiments, the kit of parts may comprise materials for formulating a polynucleotide or vector according to the present disclosure to a pharmaceutical composition, e.g. a pharmaceutically-acceptable 15 carrier, diluent, excipient or adjuvant. In some embodiments, the kit of parts further comprises reagents, buffers and / or standards required for execution of a method according to the present disclosure. Kits according to the present disclosure may include instructions for use, e.g. in the form of an instruction booklet or leaflet. The instructions may 20 include a protocol for performing any one or more of the methods described herein. The manufacture of kits of parts according to the present disclosure preferably follows standard procedures which are known to the person skilled in the art. 25 Sequence identityThe ‘sequence identity’ between a given nucleotide sequence (e.g. of a polynucleotide) and a reference nucleotide sequence is calculated by determining the percentage of the nucleotides in the given nucleotide sequence that are identical to those of the reference nucleotide sequence, after aligning the sequences and, if necessary, introducing gaps, to achieve the maximum percentage sequence identity 30 between the two sequences. Similarly, ‘sequence identity’ between a given amino acid sequence (e.g. of a polypeptide) and a reference amino acid sequence is calculated by determining the percentage of the amino acids in the given amino acid sequence that are identical to those of the reference amino acid sequence, after aligning the sequences and, if necessary, introducing gaps, to achieve the maximum percentage sequence identity between the two sequences. 35 Pairwise and multiple sequence alignment for the purposes of evaluating sequence identity between two or more nucleotide or aminoacid sequences can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalOmega (Sdding, J. 2005, Bioinformatics 21, 951-960), T-coffee (Notredame ef a / . 2000, J. Mol. Biol. (2000) 302, 205-217), 40 Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298)) and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4) 772-780) software. When using such software, the default parameters, e.g. for gap penalty and extension penalty, are preferably used. 68 WO 2024 / 251925 PCT / EP2024 / 065689 Sequences Elen fee GCX zAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATX3.4G 4 SMN2 exon 6 variant consensus 1 wherein X12 = absent or TT; X34 =AT, CT or CA AGTATGTTAATTTCATGGTACATGAGTGGCTATCATACTGGCTATTATATG 45 nucleotide SMN2 exon 6 comprising 3 | ATG>GGC at positions | GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATG 82 to 84 (SMN2 exon 6 variant 1) GCTIAATTICATGGTIACGGCAGTIGGCTATCATACTGGCIATIATOXG 4 SMN2 exon6 variant consensus 2 wherein X, =TorA SMN2 exon 6 comprising ATG>GGC at positions 5 bosttions Mer Oe at | ATAATTCCCCCACCACCTCCCATATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA ATG>CTG at positions | AGTSGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTG 109 to 111 (SIMN2 exon 6 variant 2) SMN2 exon 6 comprising ATG>GGC at poston ae 6. ATAATTCCCCCACCACCTCCCATATGTCCAGATTCTCTIGATGATGCTGATGCTTTGGGA positions | AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAG 82 to 84 and ATG>CAG at positions 109 to 111 SMN2 exon 6 variant 3 SMN2 intron 6 AAATTTATAAAATACTACTIGCTICTCTCTTTATATTACT 3’ 162 positions of SMN2 intron 6, comprising A>C_ | TTAAAAGACTATCAACTTAATTTCTGATCATATITTIGTTGAATAAAATAAGTAAAATGTCTT 4 positions from the 3’ GTGAAACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATATAGCTATCTATATCTAT end (position 5766 of ATAGCTATTTTTTTTAACTICCTTTATTTTCCTTCCAG intron 6 414 nucleotide SMN2 GTAAGTAATCACTCAGCATCTITTCCTGACAATTTTITTITGIAGTIATGTGACTTITGTTTIGT intron 6, comprising A>C_ |AAATTTATAAAATACTACTTGCTTCTCTCTTTATATTACTAAAAAATAAAAATAAAAAAATAC 4 positions from the 3 AACTGTCTGAGGCTTAAATTACTCTIGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAA end (position 5766 of AAGCTTTCATGCTATCTTAACTGCAGCCTAATAATTGTTTICTTTGGGATAACTTTTAAAGT intron 6) (intron 6 variant | ACATTAAAAGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGT 1) CTTGTGAAACAAAATGCTTITTTAACATCCATATARAGCTATCTATATATAGCTATCTATATC TATATAGCTATTTTTITTAACTICCTITATTTTCCTTCCAG intron 6, comprising asc | CTAAGTAATCACTCAGCATCTITTCCTGACAATTTTTTIGTAGTIATGTGACTITGTTTTGT 4 positions from the 3 AAATTTATAAAATACTACTIGCTICTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTT 410 | ond (position 5766 of CTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTITTTAACA ! TCCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGCTATTTITTTITAACTTCCTT intron 6) (intron 6 variant TATTTTCCTTICCAG 2 GATTT1X:.cAX;eCAAAA TCAAAAAGAAGGAAGGTIGCICACATICCTIAAATATAAGGA 4 SMN2 exon 7 variant consensus 1 wherein X16 = absent or GCCACC: X73 =GA or TG SMN2 exon 7 comprising G>A at position2, and GATTTTAGACAAAATCAAAGAAGGAAGGTGCTCACATICCTTAAATATAAGGA 13 insertion of A after position 48 (exon 7 variant 1 insertion of ccacc | A 69 WO 2024 / 251925 PCT / EP2024 / 065689 after position 6, GA>TG at positions 8 and 9, and insertion of A after position 48 (exon 7 variant 2) SMN2 intron 7 AACAAATGTTTTTGAACATTTAAAAAGTTCAGATGTTAGAA 3! AGCCTCTGGTTCTAATTTCTCATTTGCAG GTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAA 252 nucleotide SIMN2 AACAAATGTTTTTGAACATTTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATATGG 17 intron 7 GATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAA CTGGTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCT CATTTGCAG GTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTTGTAAAACTTTATGGTTTGTGGAA AACAAATGTTTTTGAACATTTAAAAAGTTCAGATGTTAGAAAGTTGAAAGGTTAATGTAAA ACAATCAATATTAAAGAATTTTGATGCCAAAACTATTAGATAAAAGGTTAATCTACATCCC418 444 nucleotide SMN2 TACTAGAATTCTCATACTTAACTGGTTGGTTGTGTGGAAGAAACATACTTTCACAATAAAG intron 7 (wildtype) AGCTTTAGGATATGATGCCATTTTATATCACTAGTAGGCAGACCAGCAGACTTTTTTT TA TGTGATATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAG TCAAGTTTAACTGGTGTCCACAGAGGACATGGTT TAACTGGAATTCGTCAAGCCTCTGGT TCTAATTTCTCATTTGCAG X12AATGCTGGCATAGAGCAGCAC 49 Positions 1 to 23 of SMN2 exon 8 consensus wherein X1.2 = GA or TG; Positions 1 to 23 of 20 | SMN2 exon 8 (exon 8 GAAATGCTGGCATAGAGCAGCAC variant 1) Positions 1 to 23 of SMN2 exon 8, 21 | comprising GA>TG at TGAATGCTGGCATAGAGCAGCAC positions 1 to 2 (exon 8 variant 2 GCCACCATGGCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGT AATCACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTT ATAAAATACTACTTGCTTCTCTCTTTATATTACTT TAAAAGACTATCAACTTAATTTCTGAT CATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCAT ATAAAGCTATCTATATATAGCTATCTATATCTATATAGCTATTTTTTTTAACTICCTTTATTT 22 | pMM112 ON-switch TCCTTCCAGGATTTTAGACAAAAATCAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAA GGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTG GAAAAACAAATGTTTTTGAACATTTAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATA TGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTT TAACTGGTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTCTAATT TCTCATTTGCAGGA GCAATTCATGGTACGGCAGTGGCTATCATCTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTT TAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAAATAAGTAAAATGTCTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTITTTTTTAACTTCCTTTATTTCCTTICCAGG 23 | pMM130 ON-switch ATTTTAGACAAAATCAAAAGAAGGAAGGTGCTCCACATTCCTTAAATATAAGGAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTAAAACAAA TGTTTTIGAACATT TAAAAGTTCAGATGTTAGAACTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTGTTATGTGACTTTGTTTTTTTACTTACTTACCTTTTATTTATTTATGCTTTGTTTTTACTTACTTACCTTTTATTAGGTAGTAAT TACTAAAAAATAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTT TAAAAAGC T TC 24 | pMM59 ON-switch ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACABAATGCTTTAACATCCATATAAAGCTATCTTATTATTAGCTTACTATTAGCTATTA TATTTTTTITAACTTCCTTTATTITTCCTTCCAGGATTTTGCCACCATGCAAAATCAAAAAGA AGGAAGGTGCTCACATTCCTTAATAAGGAGTAAGTGCCAGCATTATGAAAGTGAA TCTTACTTTTGTAAAACTTTATGGTTTGGAAAACAAATGTTTTTGAACATT THIS A GTTAT CAGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTTTGATGCCA 70 WO 2024 / 251925 PCT / EP2024 / 065689 AAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGG TTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATC ACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTG GCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTTGATGATGTTGATTGATTG AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AATACTACTTGCTTCTCTCTTTTATTATTAATTAABAAT ABAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT C ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATAAAGCTATCTATATAGCTATCTATATCTATATAGC 26 | pMM198 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTTAATAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCT TAC TTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTGAACTTTAGTTTAAGTAAGTAAGTTAATCT TAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAAATTTGATGCCAAAACTAT TAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACTAGTA GGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTA CACTCTGACATATGAAGTGCICTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGTTT AACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGCAGTGAATGCTGGCATAGA GCAGCAC GATTTTAGACAAAATCAAAX{AGAAGGAAGGTGCTCACATTCCTTAAATATAAGGA 26 SMN2 exon 7 variant consensus 2 wherein X; = absent or A SMN2 exon 7 comprising G>A at position 2, comprising deletion of GATTT TAGACAAAATCAAAAGAAGGAAGGTGCT CACATTCCTTAAATATAAGGA 27 | position 20, and comprising insertion of A after position 48 (exon 7 variant 3 GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTITATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTTCCAGG 28 | pMM193 OFF-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAG GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTT GTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTITTTAACTTCCTTTATTTT CC TCCAGG 29 | pMM194 OFF-switch ATTTTAGACAAAATCAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTCT GCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAASAACAAATG TTTTTGAACATTTAAAAAGTTCAGAATGTTAGAACTTTTTTTTATTGTGATATGGGATAACCT AGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTC CACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGCA GGAG GTAAGTAATCACTCAGCATCTTTTCCTGACAATTTITTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATACTACTTGCTTCTCTCTTTATAT TACTAAAAAATAAAAATAAAAAAATAC AACTGTCTGAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAA AAGCTTTCATGCTATTGTTAGATTATTTTGATTATACACTTTTGAATTGAAATTATACTTTTT CTAAATAATGTTTTAATCTCTGATTTGAAATT GAT GTAG G A GGAAAAGATGGGATAA 30 | SMN2 intron 6 (wildtype) TTTTTCATAAATGAAAAATGAAATTCTTTTTTTTTTTTTTTTTTTT TT TGAGACGGAGTCTTGC TCTGTTIGCCCAGGCTGGAGTGCAATGGCGTGATCTTGGCTCACAGCAAGCTCTGCCTCC TGGATTCACGCCATTCTCCTGCCTCAGCCTCAGAGGTAGCT GGGACTACAGGTGCCTGC CACCACGCCTGTCTAATTTTTTGTATTTTTTTGTAAAGACAGGGTTTCACTGTGTTAGCCA GGATGGTCTCAATCTCCTGACCCCGTGATCCACCCGCCTCGGCCTTCCAAGAGAAATGA AATTTTTTTAATGCACAAAGATCTGGGGTAATGTGTACCACATT GAACCTT GGGGAG AT GGCTTCAAACTTGTCACTTTATACGTTAGTCTCCTACGGACATGTTCTATTGTATTTTAGT 71 WO 2024 / 251925 PCT / EP2024 / 065689 CAGAACATTTAAAATTATTTTATTTTATTTITATTITITTTTTTITTT TGAGACGGAGTCTCGC TCTGTCACCCAGGCTGGAGSTACAGTGGCGCAGTCTCGGCTCACTGCAAGCTCCGCCTC CCGGGTTCACGCCATTCTCCTGCCTCAGCCTCTCCGAGTAGCTGGGACTACAGGCGCCCGCCACCACGCCCGGCTAATTTTTTTTTATTTTTAGTAGAGACGGGGTTTCACCGTGGTC TCGATCTCCTGACCTCGTGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAAG CGTGAGCCACCGCGCCCGGCCTAAAATTATTTTTAAAAGTAAGCTCTTGT CCTGCTAA AATTATGATGTGATATTGTAGGCACTTGTATTITTTAGTAAATTAATATAGAAGAAACAACT GACTTAAAGGTGTATGTTTTTAAATGTATCATCTGTGTGTGCCCCCATTAATATICTTATIT. AAAAGTTAAGGCCAGACATGGTGGCTTACAACTGTAATCCCAACAGTTTGTGAGGCCGA GGCAGGCAGATCACTTGAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGATGAAAC CTTGTCTCTACTAAAAATACCAAAAAAAATTTAGCCAGGCATGGTGGCACATGCCTGTAA TCCGAGCTACTTGGGAGGCTGTGGCAGGAAAATTGCTTTAATCTGGGAGGCAGAGGTTG CAGTGAGTTGAGATTGTGCCACTGCACTCCACCCTTGGTGACAGAGT GAGATTCC TCT CAAAAAAAGAAAAAGGCCT GGCACGGTGGCTCACACCTATAATCCCAGTACTTTGGGAG GTAGAGGCAGGTGGATCACTTGAGGTTAGGAGTTCAGGACCAGCCTGGCCAACATGGT GACTACTCCATTTCTACTAAATACACAAAACTTAGCCCAGTGGCGGGCAGTTGTAATCCC AGCTACTTGAGAGGTTGAGGCAGGAGAATCACTT GAACCTGGGAGGCAGAGGTTGCAG TGAGCCGAGATCACACCGCTGCACTCTAGCCTGGCCAACAGAGTGAGAATTTGCGGAG GGAAAAAAAAGTCACGCTTCAGTTGTTGTAGTATAACCTTGGTATATTGTATGTATCATGAATTCCTCATTTTAATGACCAAAGTAATAAATCAACAGCTTGTAATTTGTTTTGAGATCA GTTATCTGACTGTAACACTGTAGGCTTTTGTTTTTTAATTTATTTGAAATATT TGA A AAA TACATAATGTATATAAAGTATTGGTATATTATGTTCTAAATAACTTTCTTGAGAAATA ATTCACATTAGTTGAGTTGAGTTGAGTT GGCTGGGCCAATGGCTCA CGCCTGTAATCCCAGCACTTTGGGAGGCCAGGGCAGGTGGATCACGAGGT CAGGAGAT CGAGACCATCCTGGCTAACATGGTGAAACCCCGTCTCTACTAAAAGTACAAAACAAAT GAGTGGCGTGAACCCAGGAGGTGGAGCTTGCAGT GAGCCGAGATTGTGCCAGTGCACT CCAGCCTGGGCGACAGAGCGAGACTCTGTCTCAAAAAATAAAAAAAAAGAAAGTATA CAAGTCAGTGGTTTTGGTTTTCAGTTATGCAACCATCACTACAATTTAAGAACATTTTCATCAGACCATCACTAACCATTA GTTACCTTCATTTTCCCCAGCCCTAGGCAGT CAGTACACTT TCTGTCTCTATGAATTIGTCTATTTTAGATATTATATAAACGGAATTATACGATATGTGG TCTTTTGTGTCTGGCTTCTTTCACTTAGCATGCTATTTTCAAGATTCATCCATGCTGTAGA ATGCACCAGTACTGCATTICCTTCTTATTGCTGAATATTCTGTTGTTTGGTTATATCACATTT TATCCATTCATCAGTTCATGGACATTTAGTTGTTTTTATTTGGGCTATAATGAATAATG TTGCTATGAACATTCGTTTGTICTITTTGTTTITTTTGGTTTTGTTGTTGTTGTTGTTTTITTTGTTTTTGAGACAGTCTTGCTCTGTCTCCTAAGCTGGAGTGCAGTGGCATGATCTT GGCTTACTGCAAGCTCTGCCTCCCGGGGTTCACACCATTCTCCTGCCTCAGCCCGACAAG TAGCTGGGGACTACAGGCGTGTGCACCATGCACGGCTAATTTTTTGTATTTTTAGTAGAG ATGGGGTTTCACCGTGTTAGCCAGGATGGTTCTCGATCTCCTGACCTCGTGATCTGCCTG CCTAGGCCTCCCAAAGTGLCTGGGATTACAGGCGTGAGCCACTGCACCT GGCCTTAAGT GTTTTTAATACGTCATTIGCLTTAAGCTAACAATT CTTAACCTTTGTTCACTGAAGCCACG TGGTTGAGATAGGCTCTGAGTCTAGCTTTTAACCTCTATCTTTTTGTCTTAGAAATCTAAG CAGAATGCAAATGACTAAGAATAATGTTGTTGAAATAACATAAAATAGGTTATAACTT TGA TACTCATTAGTAACAAAT CTTTCAATACATCTTACGGTCTGTTAGGTGTAGATTAGTAATG AAGTGGGAAGCCACTGCAAGCTAGTATACATGTAGGGAAAGATAAAGCATTGAAGCCG AGAAGAGAGACAGAGGACATTTGGGCTAGATCTGACAAGAAAAACAAATGTTTTAGTATT AATTTTTGACTTTAAATTTTTTTTTTATTTAGTGAATACTGGTGTTTAATGGTCTCATTTTAA TAAGTATGACACAGGTAGTTTAAGGTCATATATTTTATTTGATGAAAATAAGGTATAGGCC GGGCACGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGATC ACCTGAGTCGGGAGTTAGAGACTAGCCTCAACATGGAGAAACCCCGTCTCACTACTAASA AAAATACAAAATTAGGCGGGCGTGGTGGTGTGCATGCCTGTAATCCCAGCTACTACGAGGCTGAGGCAGGAGAATTGCT TGAACCTGGGAGGTGGAGGTTGCGGTGAGCCGAGATCAC CTCATTGCACTCCAGCCTGGGCAACAAGAGCAAAACTCCATCTCAAAAAAAAAAAAAT A GGTATAAGCGGGCTCAGGAACATCATTGGACATACT GAAAGAAGAAAAATCAGCTGGGC GCAGTGGCTCACGCCGGTAATCCCAACACTTTGGGAGGCCAAGGCAGGCGAATCACCT GAAGTCGGGAGTTCCAGATCAGCCT GACCAACAT GGA AAACCCTGTCTCTACTAAAAA TACAAAACTAGCCGGGCATGGTGGCGCATGCCTGTAATCCCAGCTACTTGGGAGGCTG AGGCAGGAGAATTGCTTGAACCGAGAAGGCGGAGGT TGC GGTGAGCCAAGATT CACC ATTGCACTCCAGCCTGGGCAACAAGAGCGAAACTCCGTCT CAAAAAAAABSAGGAAGAAA AATATTTTTTTAAATTAATTAGTTTATTTATT TTT TAAG T GAG T TGCCCTGTCACCCA GGCTGGGGTGCAATGGTGCAATCTCGGCTCACTGCAACCTCCGCCTCCTGGGTTCAAG TGATTCTCCTGCCTCAGCTT CCCGAGTAGCTGTGATTACAGCCATATGCCACCACGCCC AGCCAGTTITTGTGTTITTGTITIGTTTTTTIGTTITTITTIT TT T AGAGGGTG CTTGCTCTGT CCCCCAAGCTGGAGTGCAGCGGCGCGATCTTGGCTCACTGCAAGCTCTGCCTCCCAGG TTCACACCATTCTCTTIGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGTGCCCGCCACC ACACCCGGCTAATTTTTTTGTGTTTTTAGTAGAGATGGGGTTTCACTGTGTTAGCCAGGA TGGTCTCGATCTCCTGACCTTT TGATCCACCCGCCTCAGCCTCCCCAAGTGCTGGGATTATAGGCGTGAGCCACTGTGCCCGGCCTAGTCTTGTATTTTTAGTAGAGT C GGATTTCT CCATGTTGGTCAGGCTGTTCTCCAAATCCGACCTCAGGTGATCCGCCCGCCTTGGCCTC CAAAAGTGCAAGGCAAGGCATTACAGGCATGAGCCACTGTGACCGGCAATGTTTTTAAA 72 WO 2024 / 251925 PCT / EP2024 / 065689 TTITTTTACATTTAAATTTTATTTTTTAGAGACCAGGTCTCACTCTATTGCTCAGGCTGGAGT GCAAGGGCACATTCACAGCTCACTGCAGCCTTGACCTCCAGGGCTCAAGCAGTCCTCTC ACCTCAGTTTCCCGAGTAGCTGGGACTACAGTGATAATGCCACTGCACCTGGCTAATTTT TATTTTTATTTATTTATTITTTTTIGAGACAGAGTCTTIGCTCTGTCACCCAGGCTGGAGTG CAGTGGTGTAAATCTCAGCTCACTGCAGCCTCCGCCTCCTGGGTTCAAGTGATTCTCCT GCCTCAACCTCCCAAGTAGCTGGGATTAGAGGTCCCCACCACCATGCCTGGCTAATTTT TTGTACTTTCAGTAGAAACGGGGTTTTGCCATGTT GGCCAGGCTGTTCTCGAACTCCTGA GCTCAGGTGATCCAACTGTCTCGGCCTCCCAAAGTGCTGGGAT TACAGGCGTGAGCCA CTGTGCCTAGCCTGAGCCACCACGCCGGCCTAATTTTTAAATTTTTTGTAGAGACAGGGT CTCATTATGTTGCCCAGGGTGGTGTCAAGCTCCAGGTCTCAAGTGATCCCCCTACCTCC GCCTCCCAAAGTTGTGGGATTGTAGGCATGAGCCACTGCAAGAAAACCTTAACTGCAGC CTAATAATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAAAGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAAT GCTTTTT CAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGCTATTTITTTIAACTTCCTIT ATTTTCCTTACAG GAAATGCTGGCATAGAGCAGCACTAAATGACACCACTAAAGAAACGAT CAG CAGATCT GGAATGTGAAGCGTTATAGAAGATAACTGGCCTCATTTCTTCAAAATATCAAGTGTT GG AAAGAAAAAAGGAAGTGGAATGGGTAACTCTT CTTGATTAAAAGTTATGTAATAACCAAAT GCAATGTGAAATATTTTACTGGACTCTATTT TGAAAAACCATCTGTAAAAGACTGAGGTG 32 | SMN2 exon 8 (wildtype) GGGGTGGGAGGCCAGCACGGTGGT GAGGCAGTTGAGAAAATTTGAATGTGGATTAGAT TTTGAATGATATTGGATAATTATTGGTAATTTTATGAGCTGTGGAAAGGGTGTTGTAGTTT ATAAAAGACTGTCTTAATTTGCATACTTAAGCATT TAGGAATGAAGTGTTAGAGTGTCTTA AAATGTTTCAAATGGTTTAACAAAATGTATGTGAGGCGTATGTGGCAAAATGTTACAGAAT CTAACTGGTGGACATGGCTGTTCATTGTACTGTTTTTTTCTATCTTCTATATGTT AAAG ATATAATAAAAATATTTAATTITTTTTTTTAAATTA GCCXiCC 33 | Kozak consensus whereinAATACTACTTGCTTCTCTCTTTTATTAAAAATAAAATAAAAAAAATACAACTGTCTG AGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATAATTTTAATTTTAAAAGCTTTCA TGCTATTGTTAGATTTTTGATTATACACTTTGAATTTGAATTACTTTTTCTTAATAAT GTTTTAATCTCTGATTTGAAATTGATTGTGGAATGGAAAAGATGGGATAATTTTTTCATA AATGAAAAATGAAATTCTTTTTTTTTTTTTTTTTTTGACGGAGTCTTGCTCTGTTGC CCAGGCTGGAGTGCAATGGCGTGATCTTGGCTCACAGCAAGCTGCTGCCTTGCCTT CGCCATTCTCCTGCCTCAGCCTCAGAGGTAGCTGGGACTACAGGTGCCT GCCAC ACG CCTGGCTAGCTGGGATTAGAGGTCCCCACCACCATGCCTGGCTAATTTTTTGTACTTTCA GTAGAAACGGGGTTTTGCCATGTTGGCCAGGCTGTICTCGAACTCCTGAGGTGAGGTCGAGTCGAGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGGCTGCTGCTGCTGCTGCT in minigene2 TCCAACTGTCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCTAGC WO 2021163556 Al CTGAGCCACCACGCCGGCTAATTTTAAATTTTTTGTAGAGACAGGGTCTCATTATGTT 36 (SEQ ID NO:2 of WO GCCCAGGGTGGTGTCAAGCTCCAGGTCTCAAGTGATCCCCCTACCTCCGCCTCCCAAA 2021 / 1635 56 A) GTTGTGGGATTGTAGGCATGAGCCACTGCAAGAAAACCTTAACTGCAGCCTAATAATTTGT TITCTTTGGGATAACTTTTAAAGTACATTAAATCTACTTACTTATTATTATTATTTTAAAGTACATTAAATTTATTATTATTATTATTATTATTATTATTAT TGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATAAAAGCTATCTATATATAGCTATCTATCTTATAGCTATTTTTTTTTAACTTCCTTTTTTCCTTC CAGGATTTTAGACAAAATCAAAAAAGGAAGGTGCTCACATTCCTTAATATAAGGAGT AAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTGTAAACTTTATGGTTGGATTGATTTAGTTATTAGTTATTAGTTATGAGGATTTAGTTTAGATTTAGTTATGAGT TAGAAAGTTGA AGGTTA T TAAAAC AATCAATATTAAAAATTTGATGCCAAAACTATTAGATAAAAGGTTAATCTACATCCCTA CTAGAATTCTCATACTTAACTGGTTGGTTGTGTGGAAAACATACTTCCAATAAAGAG CTTTAGGATATGATGCCATTTTATATCTAGTAGCCGATTCATTGATTGTTGTT TGATATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTC AAGTTTAACTGGTGTCCACAGAGGACATGGTTTAACTGGATCTGACATATGAAGTGCTCT AGTCAAGTTTAACTGGTCCACAGAGGACATGGTTTAACTGGAATCCAGTCCTG GTTCTAATTTCTCATTTGCAGGAAATGCTGGCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGCTGATGCTTTGGGA AGTATGTTAATTTCATGGTACATGAGTGGCTATCATACTGGCTATTATATGGTAAGTAATC ACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAA AATACTACTTGCTTCTCTCTTTATAT TACTAAAAAATAAAATAAAAAAAATACAACTGTCTG 37 | pLS41 ON-switch AGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT TCATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAA GACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTTGTGAAAA CAAAATGCTTTTAACATCCATATAAAGCTATCTATATATAGCTATCTATATAGCT ATTTTTTAACTTCTTTTATTTTCCTTACAGGGTTTT TAGACAAAATCAAAAGAAGGAAGGG 73 WO 2024 / 251925 PCT / EP2024 / 065689 TGCTCACATTCCTTAAATATAAGGAGAAATGCTGGCATAGAGCAGCAGCACGTAAGTCTGCCA GCATTATGAAAGTGAATCTTACTTTGTAAACTITATGGTTGGAASAACAAATGTTTTT GAACATTTAAAAAAGTTCAGATGTTAGAAAGTTGAAAGGTTTAATGTAAAACAATCAATCAATATTTA AAGAATTTTGATGCCAAAACTATTAGGCAAAAGGTTAATCTACATCCCTACTAGAATICTC ATACTTAACTGGTTGGTTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATAT GATGCCATTTTTATATCACTAGTAGGCAGACCAGCAGACTTTTTTTATTGTGATATGGGAT AACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTG GTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTICTAATTTCTCAT TTGCAG ATAATTCCCCACCACCTCCATATGTCCAGATTCTCTTGATGATGCTGATGCTTIGGGA AGTATGTTAATTTCCATGGTACATGAGTGGCTATCATACTGGCTATTATATGGTAAGTAATC ACTCAGCATCTTTITTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTAATAAATACTACTTGCTTCTCTCTTTTATTACTAAAAAATAAAATAAAAAATACAACTGTCTG AGGCTTAAATTACTCTTTGCATTTGTCCCTAAGTATAATTTTAATTTTAAAAGCTTTCA TGCTATCTTAACTGCAGCCTAATAATGTTTTCTTTGGGATAACTTTTAAAGTACATTAAAA GACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAASATGTCTIGTGAAA CAMAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGCT 38 | pLS76 ON-owitch ATTTTTTAACTTCCTITATTICCTTCCAGGATITTAGACAAAATCAAAAAGAAGGAAGG TGCTCACATTCCTTAATAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTT TTGTAAAACTTTATGGTTTGTGGAAAACAAATGAATTTGATTGATTGATTGATTTGGAATTCTACTAT AGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGTCCAAAACTATT AGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTIGGTTIGTGTGG AAGAAACATACTTTCACAATAAAGAGCTTITAGGATGATGCCATTTTTATCACTAGTAG GCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTAC ACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGCACAGAGGACATGGTTTA ACTGGAATTCGTCAAGCCTCTGGTTICTAATTTCATTCATTIGCAGGAAATGCTGGCATAG CAGCATAG ATAATICCCCCACCACCICCCATGTCCAGATICTCTIGATGATGCTGATGCTTIGGGAAGTATGTTAATTICATGGTACATGAGTGGCTATCATACTGGCTATTATATGGTAAGTAATC ACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAA AATACTACTTGCTTICTCTCTTTATATTACTTTAAAAGACTATCAACTTAATITCTGATCATAT TTTGTTGAATAAAATAAGTAAAATGTCTIGTGAAACAAAATGCTTTTTAACATCCATATAAA 39 | pLS16¢ ON-switch GCTATCTATATATAGCTATCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTT P ~swite CCAGGATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAG TAAGTCTGCCAGCATTATGAAAGTGAATCTTIACTTITTGTAAAACTTTATGGTTTGTGGAAA ACAAATGTTTITGAACATTTAAAAAGTICAGATGTTAGAACTTTITTTTATTGTGATATGGG ATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAAC TGGTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTICTAATTTCTC ATTTGCAGGAAATGCTGGCATAGAGCAGCAC ATAATTCCCCCACCACCTICCCATATGTCCAGATTCTCTIGATGATGCTGATGCTTIGGGA AGTATGTTAATTTCATGGTACATGAGTGGCTATCATACTGGCTATTATATGGTAAGTAATC ACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAA AATACGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATA 40 | pLS160 ON-switchTAGCTATCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAG ACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTCTGCCAG CATTATGAAAGTGAATCTTACTTTTGTAAAACTTITATGGTTTGTGGAAAACAAATGTTTTTG AACTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAGAGGACATGGTTTAA CTGGAATTCGTCAAGCCTCTGGTTCTAATTICTCATTTGCAGGAAATGCTGGCATAGAGC AGCAC GATTCTCTTGATGATGCTGATGCTTTGGGAAGTATGETTAATTTCATGGTACATGAGTGGC TATCATACTGGCTATTATATGGTAAGTAATCACTCAGCATCTTTTCCTGACAATTTTTTTGT AGTTATGTGACTTTGTTTTGTAAATTTATAAAATACTACTTGCTTCTCTCTTTATATTACTAA AAAATAAAAATAAAAAAATACAACTGTCTGAGGCTTAAATTACTCTTGCATTGTCCCTAAG TATAATTTTAGTTAATTTTAAAAAGCTTTCATGCTATCTTAACTGCAGCCTAATAATTGTTT TCTTTGGGATAACTTTTAAAGTACATTAAAAGACTATCAACTTAATTTCTGATCATATTTTG TTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTA TCTATATATAGCTATCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTTCCAG 41 | pLS167 ON-switch GATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAG TCTGCCAGCATTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATTTAAAGTICAGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAAT CAATATTAAAGAATTTTGTCCAAAACTATTAGATAAAAGGTTAATCTACATCCCTACTA GAATTCTCATACTTAACTGGTTGGTTGTGTGGAAAACATACTTTCACAATAAAGAGCTT TAGGATATGATGCCATTTTATATCACTAGTGGCAGACCAGCAGACTTITTTTTATTGA TATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAG TTITAACTGGTGTCCACAGAGGACATGGTTTAACTGGAATICGTCAAGCCCTCTGGTICTAA TITCTCATTTGCAGGAAATGCTGGCATAGAGCAGCAC AGTATGTTAATTICATGGTACATGAGTGGCTATCATACTGGCTATTATATGGTAAGTAATC 22. | pLS168 ON-switch ACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAA AATACTACTTGCTTCTCTCTTTTATTTAAAAAATAAAATAAAAAATACAACTGTCTG AGGCTTAAATTACTCTTGCATIGTCCCTAAGTATTTAGTCAGTTATTTAGTTAATTAGTTAATTTAA74 WCTTATTTATTAT 2024 / 251925 PCT / EP2024 / 065689 TGCTATCTTAACTGCAGCCTAATATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAAA GACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAAATGTCTTGTGAAA CAAAATGCTTTTTAACATCCATAAAGCTATCTATATAGCTATCTATATCTTATAGCT ATTTTTITTAACTTCCTTTATTTTCCTTCCAGGAT T TAGACAAAAT CAAAAAGAAG AAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTTGAAATCTTACTTT TTGTAAAACTTTATGGTTTGTGAAAAAAATGTTTTTGAACATTTAAAAAAGTTCAGATGTT AGAAAGTTGAAAGGTTAATGTAAAAACAATCAATATTAAGAATTTT G TGCCA AC ATT AGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTIAACTGGTTGGTTGTGTGG AAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGATGCCATTTTATATCACTAGTAG GCAGACCAGCAGACTTTTTTTATTGTGGATAACCTAGGCATACTGCACTGTTAC ACTCTGACATATGAAGTGCT CTAGTCAAGTTTAACT GGTGTCCACAGAGGCATGGTTTA ACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATT IGCAGGAAATGCTGGCATAGAG CAGCAC GCAATTTCATGGTACGGCCAGTGGCTATCATACTGGCTATTATATGGAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTT TAAAAGACTATCAACTTAATT TCT GATCATATTTTGT TGAATAAAATAAG TAAAATGTCTTGTGAACAAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTITTTAACTTCCTTTATTTT CC TCCAGG 43 | pLS179 ON-switch ATTTTAGACAAATCAAAAAAGAAGGAAGGTGCT CACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATTTAAAAAGTTCAGAATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAG TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTITTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATAGCTATTTTITITTAACTTCCTTTATTT TC CCAGG 44 | pMM70 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCT CACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA, TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAG GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAAT GTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATAGCTATTTTITTTAACTTCCTTTATTTTTTCCTTCCAGG 45 | pMM71 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTITTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTT GTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAAT GTCTTGTGAAACAARATGCTTITTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATAGCTATTTTTTITTAACTTCCTTTATTT TC CCAGG 46 | pMM72 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCT GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTT GTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATTCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTT TCC CCAGG 47 | pMM73 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCT CACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA, TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAAT 75 WO 2024 / 251925 PCT / EP2024 / 065689 GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATATATAGCTATTITITTAACTTCCTTTATTT TC CCAGG ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCT CACATTCCTTAAATATAAGGAGTAAGT CTGCTCCTCTTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAACTTCAGATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATAC TACTTGCTTCTCTCTTITATATTACTT TAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATTATCTATATAGCTATTTTTTITTAACTTCCTTTATTT TC CCAGG 49 | pMM144 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTCTGCAAGGCTTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTITTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTITTTTAACTTCCTTTATTTTCCTTCCAGG 50 | pMM145 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCTAGTCTTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCACGCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTITTTAACTTCCTTTATTTTTTCCTTCCAGG 51 | pMM146 ON-switch ATTTTAGACAAAATCAAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCTTTCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTITATGGTTTGTGGAAAAC AAATGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGAT AACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTG GTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCAT TIGCAGGAAATGCT GGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTITATATTACTT TAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTITTTAACTTCCTTTATTTT CC TCCAGG 52| pMM147 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCCCCCAGCATTATGAAAGTGAATCTTACTTTT GTAAAACTTITATGGTTTGTGGAAAAC AAATGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGAT AACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTG GTGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCAT TIGCAGGAAATGCTGGCATAGAGCAGCAG GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAAT GTCTTGTGAAACAAAATGCTTITTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATAGCTATTTTTITTTAACTTCCTTTATTTTCCTTCCAGG 53 | pMM136 ON-switch ATTTTAGACAAAATCAAAAAGAAGGTAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTC TGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAAT GTTTTTGAACATTTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATAT G GATAACC TAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTT TAACTG TGTCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGC AGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA 54 | pMM137 ON-switch GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT 76 WO 2024 / 251925 PCT / EP2024 / 065689 CTATATATAGCTATCTATATCTATATAGCTATTTTTITTAACTTCCTTTATTT TCC CCAGG ATTTTAGACAAAATCAAAAAGAAGGATGGTGCTCACATTCCTTAAATATAAGGAGTAAGTC TGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAAT GTTTTTGAACATTTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATATGGGATAACC TAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTT TAACTG TGT CCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGC AGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTTCCAGG 55 | pMM138 ON-switch ATTTTAGACAAAATCAAAAGGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTAT CAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTITTTAACTTCCTTTATTTTCCTTCCAGG 56 | pMM139 ON-switch ATTTTAGACAAAAT CAAAAAGAAGGAAAGTGCTCACATTCCTTAAATATAAGGAGTAAGTC TGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAAT GTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAACG TAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTTCATTTGC AGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTTATTTATTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATAAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTTAACTTCCTTTATTCCTTCCAGG 57 | pPMM140 ON-switch ATTTTAGACAAAATCAAAAT GAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGTC TGCCAGCATTATGAAAGTGAATCTTACTTTGTAAAACTTTATGGTTTGTGGAAAACAAAT GTTTTTGAACATTTTAAAGTTCAGATGTTAGACTTAGTTTTGAGTTTAGTT TAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTTCATTTGC AGGAAATGCTGGCATAGAGCAGCAC GCAATTTTCATGGTACGGCAGTGGTCTACTGTCTAGTCTAGTCATTTGC GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTT TGTAAATTTATAAAATACTACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAARATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATTATATAGCTATTTTTTTTAACTTCCTTTATTTTCCTTCCAGG 58 | pMM141 ON-switch ATTTTAGACAAAATCAAAAAGAGGGAAGGTGCT CACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTTTTTGAAAACTTTATGGTTTGTGGAAAACAAA TGTTTTTGAACATTTAAAAAGTTCAGAGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTATATTACTTTAAAAGACTATCAACTTAATTTCTGATCATATTTTGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAARATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTITTTITTAACTTCCTTTATTT T COTTCCAGG 59 | pMM142 ON-switch ATTTTAGACAAAATCAAAAAGAAGGAAGGAGCACACATTCCTTAAATATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTGTAAAACTTTATGGTTTGTGGAAAACAABA TGTTTTTGAACATTTTAAAAGTCAGATGTTAGAACTTTTTTTTATTGTATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAGTTTAGTTTAGGGATAAC TCCACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCCATTTG CAGGAAATGCTGGCATAGAGCAGCAC GGCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGATTTAGTTTACTTAGTTATTACTAT TACTTGCTTCTCTCTTTTATTTAAAAGACTAT CAACTTAATTTCTGATCATATTTIGT pMM151 ON-switch TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTTTTTTACTCCTTGCCTTATTTGTTATTAGCTATTAAAGCTAT ATTTTAGAAGGAAGGTGCTCACATTCCTTAAATAAGGAGTAAGTCTGCCAGCATTA TGAAAGTGAATCTTACTTTTTGTAAAACTTTATGGTTITGTGGAAAACAAATGTTTTTGAACAT 77 WO 2024 / 251925 PCT / EP2024 / 065689 TTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTG CACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCCATTTGGAATTCGAGCCATGGCAGAGCAGCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAATCACTCA GCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTTTATTTATTTAAAAGACTATCAACTTAATTTCTGATCATATTTIGT TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATCTATATAGCTATTITTTITTAACTTCCTTTATTT TCOTTCCAGG 61 | pMM152 ON-switch ATTTTAGAAGGAAGGTGCTTAAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGA ATCTTACTTTTGTAAAACTTTATGGTTTGT GGA AACAAATGTT TT AACATT TAAAAAGT TCAGATGTCAGAACTTTTTTTTATTGTGATATGGGACCTAGCTAGCTAGCTGTAGTT CTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAGAGGACATGGTTTAA CTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTTCATTTGCAGGAAATGCTGGCATAGAGC AGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTGCTGATGATG AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AATACTACTTGCTTCTCTCTTTTATTATTAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATT AAAAAGCTT TCATGCTATCTTAACTGCAGCCTAATATTGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 62 | pLS174 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTTAATAATAAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCT TAC TTTGTAAAACTTTATGGTT TGTGGAAAACAAATTTTTTAGATTAAGTTTAAGTTTAAGT TAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGCCAAAACTAT TAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGTG GAAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCACTAGTA GGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTA CACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATGGTTT AACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCCATTTGCAGGAAAT C TGCAGGCACATATGA ATAATTCCCCCACCACCTCCCATATGCCCAGATT CTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTITTTTTGTAGTTATGTGACTTTGTTTTTTTTTTTAATAAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAAT AAAAATAAAAAAATACACTGTCT GAGGCTTAAATTACTCTGCATTGTCCCTAAGTATAATTTTAGTTAAT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATGTTTT CTT TGGGATATACTTACTATTAAAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATAAAGCTATCTATATAGCTATCTATATCTATAGC 63 | pMM56 ON-switch TATTTTTTTTAACTTCCTTTATTCCTTCCAGGATTTTAGACAAAATCAAAAAGAAGGAAG GTGCCACCATGTCCTTAAATATAAGGAGTTAGT CTGCCAGCATTATGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGTGGAAAGAAACAATCATTGTTATT GTTAGAAAGCTTGAAGGTTAATGTAAAACAATCAATTAAAGAATTTGATGCCAAACT ATTAGATAAAAGGTTAAT CTACATCCCTACTAGAATTCATACTTAACTGGTTGGTTGTG TAGGCAGACCAGCAGACTTTTTTTTTGTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAGTGCTCTAGTCAAGTTTAACTGGTCCACAGGGACATGGT TTAACTGGAATTCGTCAAGCCTGGTTCTAATTTCTCTCATT GCAGGGACAATCAG ATAATTCCCCCACCACCTCCCATATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGAAGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAAT AAAAAATAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTITAGTTAATT T AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTT TGGGATA CTTT TAAAG ACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC pMM60 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTT CCAGGATTTTAGACAAAAT CAAAAAGAAGGAAG GTGCTCACATTCCTTAAGCCACCATGATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGA ATCTTACTTTTGTAAAACTTTATGGTTTGT GGA AACAAATGTT TT AACA T TAAAAAGT TCAGATGTTAGAAGTTGAAAGGTTAAT GTAAAACAATCAATCAATATTAAGAATTTTGATGCC AAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTIAACTGGTTG GTTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCATTTTATAT CACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATAT GGGATAACCTAGGCATACT GCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAG GGACATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTTAATTTCTCATT TGCAGGAAATGCT GGCATAGAGCAGCAC 78 WO 2024 / 251925 PCT / EP2024 / 065689 AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGACTTTGTTTTTTTAAAAAAAAAAAA AAAAATAAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTTAGTTAATT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTT TGGGATA C TT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATATAGCTAATCTATATCTAGA TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATCAAAAGAAGGAAG GTGCTCACATTCCTTAAACAACATGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGTGAAAAAAATGTTTTGAAACATT TAAAAGTTC GAT GTTAGAAAGTTGAAAGGTTAATGTAAAAACAATCAATATTTAAAGAATTTTGATGCCAAAACT ATTAGATAAAAGGTTAAT CTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGATGCCATTTTATATCACTAG TAGGCAGACCAGCAGACTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGT TTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTGGCATA GAGCAGCAC ATAATTCCCCCACCACCTCCCATATGTCCAGATT CTCTTGATGATGATGCTGTTGTTGATT AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AATACTACTTGCTTCTCTCTTTTATTATTAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTITTATTTATT TTA AAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTT CTT TGGGATAACTTTTAAAGTACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTTGAATGTTGAAAAT ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC pMM62 ON-switch TATTTTTTTTAACTTCCTTTATT TI TCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTTAGCCACCATGGAGTAAGTCTGAGCCAGGATTGATTATTTATTAGC CTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATT TAAAAAGT TC GAT GTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATTAAAAATTGATGCCAAAACT ATTAGATAAAAGGTTAAT CTACATCCCTACTAGAATTCATACTTAACTGGTTGGTAGTTAGTTGACTGTTGATTCACAATAAAAGAGCTTTAGGATATGATGATGCCATTTTATATCACTAG TAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATT TTAACTGGAATTCGTCAAGCCTCTGGTTICAATTTCTCATT TGC GGAAA G GGCATA GAGCAGCAC ATAATTCCCCACCCTCCCATATGTCCAGATT CTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATAACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTATATTACTACTAAAAATAAAAA TAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTTAAAAAAGCTT TC ATGCTATCTTAACTGCAGCCCAATAATTTGTTTCTT TGGGATA CTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 67 | pMM63 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATC AAAAAGAAGGAAG GTGCTCACAGCCACCATGAATATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTT ACTTTTGTAAAACTTTATGGTT TGTGGAAAAACAAATGTTTTTGAACATTTAAAAAAGTTCAGATGTTAGAAGTTGAAGGTATGTAAAACAATCAATTAATTAAGAT TT GATGCCA AC TATTAGAAAAGGTTAATCTACCTACTAGAATTCTCATTACTAACTGGTTGGTTGT GTGGAAAACATTACT TCACAATAAAGCTTTGGATGATGCCATTTTATA GTAGGCAGACCAGCACTTTTTTTTATTGTGATAT GGGATAACCTAGGCATACTGCACT GTACACTCTGACATATGAGTGCTCTAGTCAAGTTTAACTGGTCCACAGGGACATGG TTTAACTGGAATTCGTCAAGCCTGGTTCTAATTTCTCTGAGGCAGACAAT ATAATTCCCCCACCACCTCCCATATGTCCAGATT CTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATATGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTAATTGTATT AAATACTACTTGCTTCTCTCTTTTATATACTAAAAAAAT AAAAATAAAAAAATACACTGTCT GAGGCTTAAATTACTCTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATGTTTTCTT TGGGATA ACAT C ATTAA TAACT AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAAT GTC TGTGAA ACAAAATGCTTTTTAACAT CCATAAAGCTATCTATATAGCTATCTATATCTATAGC pLS176 ON-switch TATTTTTTTACTTCCTTTTGATTGATTGCCAGAATT CATTAGGAAGGTGCTCACATTCCTTAATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAA TCTTACTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATT TAA A GTT CAGATGTTAGAAAGTTGAAAGGTTAATGTAACAATCAATATTAAAATTGATTTGCA AAACTATTTGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGG TTGTGTGGAAAACATACTTTCACAATAAAGAGCTTTAGGATGATGCCATTTTATATC ACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGT GATATGGGATAACCTAGCTACATCACTCATTGACTGACTGACTGACTGACTGGGG CAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTCTTCATTTGCAGGAAATGCTG 79 WO 2024 / 251925 PCT / EP2024 / 065689 PoP CATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTCTTGTAAATT TATATT AAATACTACTTGCTTCTCTCTTTTATTACTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTTGCATTGTCCCTAAGTATAATTTTAATTTTAAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTT TGGGATAACTTTAAGTACATTAATTA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAGCTATCTATATAGCTATCTATATCTATATAGC pMM108 ON-switch TATTTTTTTTAACTTCCTTTATTCCTTCCAGGAT TTTGCCACCATGCAAAAT CAAAAAGA AGGAAGGTGCCATCCTTAATAATAAGGAGTAAGT CTGACCATGATTGATTATTAGC TCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATT TAA A GTT CAGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTGATGCCA AAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTACTGGTTGTTG TTGTGTGGAAGAAACATACTTCCAATAAAGAGCTTTAGGATATGATGCCATTTTATATC ACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTG CACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTG GCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCTAGGGTATTATGGTATT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTATATTTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATATTTAGTTAATTTTAAAAAGCTT TCATGCTATCTTAACTGCAGCCTAATTTGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 70 | pMM110 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTGCCACCATGCAAAAT CAAAAAGA AGGAAGGTGCTCACATTCCTTAATAATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAA TCTTACTTTTGTAAACTTTATGGTTTGTGAAAACTTGAATTAGTTAT GGTTTGGAAAACTTGAATTAGTTAT CAGATGTTAGAAAGTTGAAAGGTTAATGTAACAATCAATATTAAAGAATTGATGCCA AAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGG TTGTGTGGAAAACATACTTTCACAATAAAGCTTTTAGGATGATGCCATTTTATATC ACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTG CACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAACTGCCATGGCATAGCCATA ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATTTGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTTGTAATTTATAATAAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAAAATAAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTTGCATTGTCCCTAAGTATAATTTTAGTTAATT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATATTGTTTT CTT TGGGATAACTTTAAGTACAT AGTACAT AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACABAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 71 | pMM111 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTGCCACCATGCAAAAT CAAAAAGA AGGAAGGTGCT CACATTCCTTAAATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAA TCTTACTTTTGTAAACTTTATGGTTTAAGTGGAAAACTTGAATTAGTTAT GGTTTATGGGAAAACATTAGTTAT CAGATGTTAGAAAGTTGAAAGGTTAATGTAACAATCAATATTAAAGAATTGATGCCA AAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGG TTGTGTGGAAAACATACTTTCACAATAAAGCTTTTAGGATGATGCCATTTTATATC ACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTG CACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGAC ATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAACTGCCATGGCATAGCCATA ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGAAGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAA A TAA AAAAA TC ACTGTATCTAT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATA CTTT TAAAG ACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCGAATT72 | pMM242 ON-switch ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTTATAGC TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGAGCCACCATGCAAAATCAAAA AGAAGGAAGGTGCACATTCCTTAAGGAGTAAGTCAGTGACCATTAGAGAGTAAGCATTCATTT GAATCTTACTTTTGTAAAACTTTATGGTTT GTGGAAAACAAATGTTTTTGAACATTTAAAA GTTCAGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGATTTGATG CCAAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCTACTTACTGGTTACTTAACT TGGTTIGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTAT ATCACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATA 80 WO 2024 / 251925 PCT / EP2024 / 065689 CTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CACAGAGGACATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATTTGCAGGAAATG CTGGCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGTACTTAGGTAGTAGGTAGTAGTA CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTATATTTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATATTTAGTTATTTAATTTTAAAAAGCTT TCCCTTAAGTTATTTAGTTATTTATTTTTAAAAAGCTT TCTATTTTTAGTCTTTATTTATTTATTTATTTAAAAAAT TGGGATA CTTT TAAAG ACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 73 | pMM243 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTAGACAAAATAGCACCATGCAAAA AGAAGGAAGGTGCTCACATTCCTTAATAAGGAGTAAGTCTGCCAGCATTATGAAAGT GAATCTTACTTGTAAAACTTTATGGTTT GTGGAAAACTTTATTAATTAATT GTTCAGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTGATG CCAAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGT TGGTTGTGTGGAAGAAACATACTTTCACAATAAAGCTTTTAGGATGATGCCATTTTATATCACTAGTAGGCAGACCAGCAGACTTTTTTTTATT GTGATATGGGATAACCTAGGCATA CTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CACAGAG GACATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCCATTTGGAATTCGAGCCATGGAGGGGGAGGGAG ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTICCTGACAATTITTTTTGTAGTTATGTGACTTTGTTATTTGTATTTATT AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTTGCATTGTCCCTAAGTATAATTTTAATTTTAAAAAGCTT G ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 74 | pMM244 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATAGCACCATGGAAAA AGAAGGAAGGTGCTCACATTCCTTAATAAGGAGTAAGTCTGCCAGCATTATGAAAGT GAATTCTTACTTTTTAAACTTTATGGTTTAA GTGGAAAACTTTAGATTAATTAATTAA GTTCAGATGTTAGAAAGT TGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTGATGCCAAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGT TGGTTGTGTGGAAAACATACTTTCACAATAAAGAGCTTTAGGATATGCCATTTTAT ATCACTAGTAGGCAGACCAGCAGACTTTTTTTTATT TGATA GGGATAACCTAGGCA A CTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CACAGAG GACATGGTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTCTCATTTGCAGGAAATG CTGGCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCGTTGTTGCTGATGGAATG AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCTGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTTATTACTAAAAAAT AAAAATAGTAAAATACTACT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTTIGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGATTGATTGATTGAATTTGAATTAGCAATTT CCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 75 | pMM245 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATCACCAT GG AAAAG AAGGAAGGTGCTCACATT CCTTAAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTITTGAACATT TA AGT TCAGATGTTAGAAAGTT GAAAGGTTAATGTAAAACAATCAATAT TAAAGAATTTTGATGCC AAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTACTGGTTG GTTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATAT CACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATAT GGGATAACCTAGGCATACT GCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAG GGA CATGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCT GGCATAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATTATAGGGTATTATGGTACTATAT CACTCAGCATCTTTTICCTGACAATTITTTTTTAGTTATGTGACTTTGTTTTGTAAATT TA A AAAATAAAAAAATACAACTGTCT GAGGCTTAAATTACCTTGCATTGTCCCTAAGTATATTTAGTTAATTTTAAATTTAGTTTAGTTTAGTTTTTAGTTTATTTATTTAGTTTTTAATTATTTAAAAAAT AAAAATAAAAAATACAACTGTCT TGGGATA C TT TAAAG ACATTAAA 76 | pMM246 ON-switch AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATAAAGCTATCTATATATAGCTATCTATATCTATAGCTATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATATGGAAAAAGAAGG AAGGTGCTCACATTCCTTAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCT TACTTTTGTAAAACTTTATGGTTT GTGGAAAACAAATGTTTTTGAACATTTAAAGTT CAGTT ATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTTTGATTTGCCAAAA CTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTG 81 WO 2024 / 251925 PCT / EP2024 / 065689 TGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACT AGTAGGCAGACCAGCAGACTTTTTTTTATTGTATATGGGATAACCTAGGCATACTGCAC TGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGATGATATGGGGATA GTTTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTTCATTTGCAGGAAATGCTGGCA TAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGTATTATTAGGTAGTATTATGCTGATGCTTTGGGA CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTTATTTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATATTTAGTTATT AAAAAGCTT TCTTAATTTTTTTAGTTTAGTTTATTTATTTATT TGGGATA C TT TAAAG ACAT AAAAGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 77 | pMM247 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATCAAAAAAT GGAAGG AAGGTGCTCACATTCCTTAATAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCT TACTTTTGTAAAACTTTATGGT TT GTGG AA CA ATTAAC ATTTAATTTATTATTAGTT ATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGCCAAAA CTATTAGATAAAAGGCTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTG TGTGGAAGAAACATACTTTCACAATAAAGCTTTTAGGATGATGCCATTTTTATCCACT AGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCAC TGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATG GTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCCATTTGCAGGAAAATGCTGCAGCCAGCATTGGCA ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTCTTGTAAATT TATATT AAATACTACTTGCTTCTCTCTTTTATTACTAAAAT AAAAATAAAAAATACAACTGTCTGAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTT CTT IGGGATAACTTTTAAAGTACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGAA ACAAAATGCTTTTTAACATCCATAAAGCTATCTATATAGCTATCTATATCTATATAGC 78 | pLS175 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTTAATAATAAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCTTACT TTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTAGATTTAGTTTAAGTAAGTAAGTAAGTGAATCTTACT TAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGCCAAAACTAT TAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGTG GAAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCACTAGTA GGCAGACCAGCAGACTTTTTITTATTGTGATATGGGATAACCTAGGCATACTGCACTGTA CACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATGGTTT AACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCCATTTGCAGGAAAT C TGCAGGCACATATGA ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAATCACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAAAATAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT C ATGCTATCTTAACTGCAGCCTAATAATTGTTTT CTT IGGGATAACTTTTAAAGTACAT AAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 79 | pMM123 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATCAAAAAAGAAGGAAG GTGCTCACATTCCTTAAATATAATGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTAC TTTTGTAAAACTTTATGGTTT GTGGAAAACAAATGTTTTTGAACATTTAAAAAGTTCAGATG TTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGATGCCAAAACTA TTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACT GGTTGGTTGTGT GGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACTAGT AGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGT ACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGTT TAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGCAGGAAAT GCTGGCATAG AGCAGCACATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTCTTGTAAATT TATATT AAATACTACTTGCTTCTCTCTTTTATTACTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT TC pMM124 ON-switch ATGCTATCTTAACTGCAGCCTAATAATTTGTTATATCTT CTTGAATTAGAATT AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC TATTTTTTTTAACTTCCTTTATTCCTTCCAGGAT TTTAGACAAAATCAAAAAGAAGGAAG GTGCTCACATTCCTTAAATGGTAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATTTAAAAGTTCAGAT 82 WO 2024 / 251925 PCT / EP2024 / 065689 GTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGCCAAAACT ATTAGATAAAAGGTTAAT CTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTATCACTAG TAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAGAGGACATGGT TTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTTCATTTGCAGGAAATGCTGGCATA GAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTGCTGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTTATTACTAAAAAAT AAAAATAGTAAAACTCAACTAT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 81 | pMM125 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTAGACAAAATCAAAAAAGGAAG GATGGCGTCACATTCCTTAAATAAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCT TACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATTTGAATTTAATTTAGTTAAGTGAATTTAAGTGAATCT ATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTGATTTGCCAAAA CTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACT AGTAGGGCAGACCAGCAGACTTTTTTTTATTGTATATGGGATAACCTAGGCATACTGCAC TGTACACTCTGACATATGAAGTGCTCTAGTCAAGTT TAACTGGTGTCCACAGAGGACATG GTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTCTCATTTGCAGGAAATGCTGGCA TAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTTATCATACTTAGGTATTATTAGGTATT CACTCAGCATCTTTICCTGACAATTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTATATTTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATATTTAGTTATTTAATTTTAAAAAGCTTTTTTTTTAGTTTAGTTTTTATTTATTTAAAAAGCTTTTTAGTTTAGTTTAGTTATTATTAT TGGGATA CTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 82 | pMM126 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATGTCCTTAAATAAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATTTGAATTTAATTGAATTTGAATTTGAAGGTTAGAAAGTTGAAAGGCTTAATGTAAAACAATCAATATTAAAGAATTTTGCCAAAACT ATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCACTAG TAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATGGT TAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCCATTTGCAGGAAAATGGCAGCTGCCATGTC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTTGTAATTTATAAT AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAAA AA AAAATAC ACTGTCT GAGGCTTAAATTACTCTTTGCATTGTCCCTAAGTATAATTTTAATTTTAAAAAGCTT C ATGCTATCTTAACTGCAGCCTAATATTGTTTT CTT TGGGATAACTTAAAGTATTAAAGTACAT AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTTATAGC 83 | pMM127 ON-switch TATTTTTTTTAACTTCCTTTATT TI TCCTTCCAGGATTTTAGACAAAATCAAAAAGAAGGAAGGTGCTCACATTCCTATGGATATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTGAACATTTTAAAGT T CAGA GTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTGATGCCAAAACT ATTAGATAAAGT CTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCAATAAAGAGCTTTAGGATATGCCATTTTATATCACTAG TAGGCAGACCAGCAGACTTTTTTTTATTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGT TTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTGGCATA GAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTGCTGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAATTTATA AAATACTACTTGCTTCTCTCTTTTATTTAAAAAAT AAAAATAAAAAATACACTGTCT 84. | pMM128 ON-switch GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATATTTAGTTAATTTTAAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATA CTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTGTTAATTGATTGATTGATTACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATAGC TATTTTTTTTAACTTICCTTTATTT TCCTTCCAGGATTTTAGACAAAATCAAAAAGAAGGAAG 83 WO 2024 / 251925 PCT / EP2024 / 0CTGAGTAGAT6GTAATCTA688 GCCAGCATTGAAGATCTTA CTTTTGTAAAACTTTATGGTTTGTGGAAAACATGTTTTTGACATT TAAAAAGTT C GTTAGAAAGTTGAAGTAATGTAAAACAATCATTAATTGATGCGCAAACT ATTAGAATAGGTTAATCTGAGATTCATCCTAACTA TGGAGAAACATACTTTCACAATAAAGAGCTTTAGGATGATGCCATTTTTTATATCACTAG TAGGCAGACCAGCACTTTTTTTTTGTGATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAGTGCTCTAGTCAAGTTTACT GGTCGTCCACAGAG TTAACTGGAATTCGTCAAGCCTGGTTCTAATTTCTCATT TGCAGGAAATGCTGGCATA GAGCAGCAC ATAATCCCCACCACCTCCCATATGTCCAGATTCTCTTGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGTACGGCAGTAGGGGTAATTATCATCATA CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTT GCTTCTCTCTTTATAT TACTAAAAAAT ABAAATAAAAATACACTGT GAGGCTTAAATTACTCTGCATTGTCCCTAAGTAATTTITAGTTAGTTAATTTTAAAAAATGCTATCTTAACTGCAGCCTAATAATGTTTTCTTTGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATAAAGC 85 | pMM129 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTT CCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTTAATGAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCTTACTT TTGTAAAACTTTATGGTTTGTGGAAAACAAATTT GTTAAACATTT CTTAAGAATTT AGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTTTGTCCAAAACTATT AGATAAAAGGTTAATCTACATCCCTACTAGAATTICTCATACTTAACTGGTTGGTTGTGTGG AAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCTAGTAG GCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTAC ACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAGAGGACATGGTTTA ACTGGAATTCGTCAAGCCCTCTGGTTCTAATTCTCATTTGCAGGAAATGCTGGCATAG CAGCATAG ATAATTCCCCCACCACCTCCCATATGCCAGATTCTCTTGATGATGCTGCTGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTGTTTAATTACTTACCTTTAGTTATTTATGACTTTGTTTTTACTTACTTACCTTATTAGGTAGTAGTAATTACTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT C ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTGATTTATTTATTGATTGATTGATTGATTGATTGATTGATTTAAAGCTT C ACAAAATGCTTTTTAACATCCATATAAGCTATCTATATAGCTATCTATATCTATATAGC pMM201 ON-switch TATTTTTTTTAACTTCCTTTATTCCTTCCAGGATTTTAGAAAAT CAAAAAGAAGGAAG GTGCTCACATGGCCTTAAATAAGGAGTAAGT CTGCCAGCAGTGATTATTAGATTATTAGC CTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATTTAAAGTT CAGA GTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAGAATTGATGCCAAAACT ATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACTAG TAGGCAGACCAGCAGACTTTTTTTTATTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGGAGGGTGGT TTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTGGCATA GAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTTATTATTATTATTATTATCACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTATAT TAC AAAAAA AAAAAAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTITAGTTAATTTTAAAAGCTTTC ATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTTTGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGGA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 87 | pMM202 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTT CCAGGATTTTAGACAAAATCAAAAGAAGGAAG GTGCTAACATGGCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTA CTTTTGTAAAACTTTATGGTTTGGAAAAACAAATGTTTTTGAACATT TAAAAGTT C GAT GTTAGAAAGTTGAAAGGTTTAAT GTAAAACAATCAATCAATCAATATTAAGAATTTTGATGCCAAAACT ATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTACTAACTGGTTGGTTGTG TGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGATGCCATTTTATATCACTAG TAGGCAGACCAGCAGACTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTG TACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACT GGTGTCCACAGAGGCATGGT TTAACTGGAATTCGTCAAGCCTCTGGTTCTAATTTICTCATTTGCAGGAAATGCTGGCATA GAGCAGCACATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTGTGTTATGTGACTTTGTATTTTTTTTAT8 | pMM203 ON-switch AAATACTACTT GCTTCTCTCTTTTATTATTAAAAAATAAAATAAAAAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATATTTITAGTTAATTTTAAAAAGCTTTC ATGCTATCTTAACTGCAGCCTAATTTGTTTTCTTTGATTTACTTACTTATTTAGTATTTATTTAATTTTAATTTTAAAAGCTTGCTACTTACTTAGATTAGATTA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA 84 WO 2024 / 251925 PCT / EP2024 / 065689 ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATCTTATTATATAGCTTTTTTTTTATTTTCC TCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATATGCCTAAATTAAGGAGTAAGTCTGCCAGCATTATGAAAGT GAATCTTAG TTTTGTAAAACTTTATGGT TT GTGGA AACAAATGT TT GAACATTTAAAAAGTT CAGATG TTAGAAAGTT GAAAGGTTAATGTAAAACAATCAATATTAAAATTTTGATGCCAAAACTA TTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGT GGAAGAAACATACTTTCACAATAAAGCTTTTAGATGATGCCATTTTTATCACTAGTAGGCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGT ACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATGGTT TAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTCTCATTTGCAGGAAAT GCTGCAGCATAGGCATAG ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTTTTAGTTATGTGACTTTGTTTTTACTTACTTACTTACTTACTTACTATTAGGCTTTTAGTACTTACTTACTATTAGGTAGCTATTAAT AAA A TAARAAAAT C ACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTAATTT AAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TIGGGATACTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTAATTGATTGATTGATTGATTGATT ACAAAATGCTTTTTAACATCCATATAAGCTATCTATATAGCTATCTATATCTATATAGC pMM204 ON-switch TATTTTTTTTAACTTCCTTTATTCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCATGTTAAATATAAGGAGTAAGTCTGCCAGCAGTGACTATTTATTAGC TACTTTTGTAAAACTTTGGTTTGTGGAAAACAAATGTTTTTGAACATT TAAAAAGTT CAG ATGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTTTGATGCCAAAACTATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTG TGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGCCATTTTATATCACT AGTAGGCAGACCAGCAGACTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACG TGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATG GTTTAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTCTTCATTTGCAGGAAATGCTGGCA TAGAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGTTGTTGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTTATTACTAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTTGTCCCTAAGTATAATTTTAGTTAATTTAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATA CTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGAATAAAATAAGTAAAAT GTC TGTGAAA ACAAAATGCTTTTTAACATCCATAAAGCTATCTATATAGCTATCTATCTTATAGC pMM205 ON-switch TATTTTTTTTAACTTCCTTTATTCCTTCCAGGATTTTAGACAAAATCAAAAAGAAGGAAG GTGCTCACATCCTTGAATATAAGGAGTAAGTCTGCCAGCATTGATTGATTATTAGCACTTTTGTAAAACTTTATGGTTTGTGGAAAACAAATGTTTTTGAACATT AAAA GTTCAGA TGTTAGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATTGATGCCAAAAC TATTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCATACTTACTGGTTGGTTGAGTTAGTTGAGTT TCACAATAAAGAGCTTTAGGATATGATGCCATTTTATATCACTA GTAGGCAGACCAGCAGACTTTTTTTTATTGTGATAT GGGATAACCTAGGCATACTGCACT GTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTCCACAGAGGACATGG TTTAACTGGAATTCGTCAAGCCCTCTGGTICTAATTCTTCATTTGCAGGAAATGCTGGCATA GAGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTTATTATTATTATTATT CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TA A AAATACTACTTGCTTCTCTCTTTATATTATTAAAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATATTTAGTTAATTTTAAAAAGCTTTTTAGCCTTTTTAGTTTATTTATTTAATTTTAAAAAGCTTTTTAGTTTAGTTTTTAGTTTATTATA TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 91 | pMM206 ON switchTATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTAGACAAAATCAAAAAGAAGGAAG GTGCTCACATTCCTTATGGAAAATAAGGAGTAAGTCTGCCAGCATTATGAAAGTGAAT CTTACTTTTGTAAAACTTTATGGTTTGT GGAAAAACAAATGTTTTTGAACATT TAAAAAGTTC AGATGTTAGAAAGTTGAAAGGTTAATGTAAAACAAT CAATATTAAAAGAATTTTGATGCCAA AACTATTAGATAAAAGGTTAATCTACATCCCTACTAGATTCTCATACTTAACTGGTT TGTGTGGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGATGCCATTTATATCA CTAGTAGGCAGACCAGCAGACTTTTTTTTTATTGATATGGGATAACCTAGGCATACTGC ACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGT CCACAGAGGACA TGGTTTAACTGGAATTCGTCAAGCCTCTGGTTCTTAATTTCTCATTTGCAGGAAATGCTGG CATAGAGCAGCA ATAATTCCCCCACCACCTCCCATATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT 92 | pMM248 ON-switch CACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAT AAAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTTAGTTAATT AAAAAGCTT TC 85 WO 2024 / 251925 PCT / EP2024 / 065689 ATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTT TGGGATA CTTTTAAAG ACAT AAA AGACTATCAACTTATTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACATCCATAAAAGCTATCTATATAGCTATCTATATCTATATAGC TATTTTTTAACTTCCTTTATTCCTTCCAGGAT TTATAGAAAGAAAATGAAG GTGCTCACATTCCTTAATTAAGATGAGTAAGTGCCAGCATTATGAAAGTGAATCTTAC TTTTGTAAAACTTTATGGTTT GTGGAAAACAAATGCTTTTTGAACATTTAAAAGTTCAGATG TTAGAAAGTTGAAAGGTTAATGTAAACATCAATTTAAAGCAAATTGATTGATTGATTGATTGAT TTAGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTGGTTGTGT GGAAGAAACATACTTTCACAATAAAGAGCTTTAGGATATGCCATTTTATATCACTAGT AGGCAGACCAGCAGACTTTTTTTTTGATATGGGATAACCTAGGCATACTGCACTGT ACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGTT TAACTGGAATTCGTCAAGCCCTCTGGTTCTAATTTICTCATTTGCAGGAAATGCTGGCATAG AGCAGCAC ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGCTGCTGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTICCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTGTAAATT TATA AAATACTACTTGCTTCTCTCTTTATAT TAC AAAAAA AAAAATAAAGTAACTAACTAACTGAGGCTTAAATTACTCTTGAATTTGTCCCTAAGTATAATTTTAGTTAATTTTAAAAAGCTT C ATGCTATCTTAACTGCAGCCTAATAATGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGATTGAATTTGAATTAGCAATTT CCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 93 | pMM249 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGAT TTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCCTAAAATGAGGAGTAAGTCTGCCAGCATTGAAAGTGAATCTTACTT TTGTAAAACTTTATGGTTT GTGGAAAACAAATTTTAGATTTAGATTTAGTTTT AGAAAGTTGAAAGGTTAATGTAAAACAATCAATATTAAAATT T GATGCCAAAACTATT AGATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTIAACTGGTTGGTTGTGTGG AAGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCACTAGTAG GCAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTAC ACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGCACAGAGGACATGGTTTA ACTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATT TGCAGGAAATGCTGGAGAGACAGCAGCATT ATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAATCACTCAGCATCTTTTCCTGACAATTTTTTTGTAGTTATGTGACTTTGTTTTTGTAAATTTATA AAATACTACTTGCTTCTCTCTTTATATTACTAAAAAAAT AAAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTGCATTGTCCCTAAGTATAATTTTAGTTTAATTTTASAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATAATTGTTTTCTT TGGGATAACTTTTAAAGTACATTAAA AGACTATCAACTTAATTTCTGATCATATTTTGTTGAATAAAATAAGTAAAATGTCTTGGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATATAGCTATCTATATCTATATAGC 94 | pMM250 ON-switch TATTTTTTTTAACTTCCTTTATTT TCCTTCCAGGATTTTAGACAAAATCAAAAGAAGGAAG GTGCTCACATCCTGAAATGAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTTT TTGTAAAACTTTATGGTTTT GTGGAAAAAAATGTTTTTGAACATT TAAAAGTTCAGATGTT AGAAAGTTGAAAGGTTAATGTAAAAACAATATAATTCCCCCACCACCTCCCATGTCCAGATTCTCTTGATGATGCTGATGCTTTGGGA AGTGGCTTAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAAT CACTCAGCATCTTTTCCTGACAATTTTTGTAGTTATGTGACTTTGTTTTGTAATTTATAAT AAATACTACTTGCTTCTCTCTTTATATTACTAAAAT AAAAATAAAAAATACAACTGTCT GAGGCTTAAATTACTCTTTGCATTGTCCCTAAGTATAATTTTAATTTTAAAAAGCTT TC ATGCTATCTTAACTGCAGCCTAATATTGTTTTCTT TGGGATA CTTT TAAAG ACATTAAA AGACTATCAACTTAATTTCTGATCATATTGTTGAATAAAATAAGTAAAATGTCTTGTGAA ACAAAATGCTTTTTAACAT CCATATAAAGCTATCTATATAGCTATCTATATCTATATAGC 95 | pMM251 ON-switch TATTTTTTTTAACTTCCTTTATTTTCCTTCCAGGATTTTAGACAAAATCAAAAAAGGAAG GTGCTCACATTCAAATGAGGAGTAAGTCTGCCAGCATTATGAAAGTGAATCTTACTT TT GTASAACTTTATGGTTTGTGGAAAACAAATGTTTAGATTTAGTTTAAGTAAGTTA GAAAGTTGAAAGGTTAATGTAAAACAAT CAATATTAAAGAATTTTGCCAAAACTATTA GATAAAAGGTTAATCTACATCCCTACTAGAATTCTCATACTTAACTGGTTIGGTIGTGTGGA AGAAACATACTTTCACAATAAAGCTTTAGGATGATGCCATTTTTATCACTAGTAG CAGACCAGCAGACTTTTTTTTATTGTGATATGGGATAACCTAGGCATACTGCACTGTACA CTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTGTCCACAGAGGACATGGTTTAA CTGGAATTCGTCAAGCCTCTGGTTCTAATTTCTCATTTGCAGGAAATGCTGGCATAGAGC AGCAC GCAATTTCATGGTACGGCAGTGGCTATCATACTGGCTATTATCAGGTAAGTAATCACTCA pMM252 ON-switch GCATCTTTTCCTGACAATTTTTTTGTAGTTATGACTTTGTTTTGTAAATTTATAAAATAC TACTTGCTTCTCTCTTITATATTACTT TAAAAGACTATCAACTTAATTTCTGATCATATTTIGT 86 WO 2024 / 251925 PCT / EP2024 / 065689 TGAATAAAATAAGTAAAATGTCTTGTGAAACAAAATGCTTTTTAACATCCATATAAAGCTAT CTATATATAGCTATCTATATAGCTATTTTTITTTAACTTCCTTTATTTTTTCCTTCCAGG ATTTTAGACAAAATCAAAAAAGAAGGAAGGTGCTCACATTCCTTAAATATAAGGAGTAAGT CTGCCAGCATTATGAAAGTGAATCTTACTT TT GTAAAACTTTATGGTTTGTGG AAACAAA TGTTTTTGAACATTTAAAAAGTTCAGATGTTAGAACTTTTTTTTATTGTGATATGGGATAAC CTAGGCATACTGCACTGTACACTCTGACATATGAAGTGCTCTAGTCAAGTTTAACTGGTG TCCACAGAGGACATGGTTTAACTGGAAT...

Claims

1. A polynucleotide comprising, in a 5' to 3' sequence: (i) A first nucleotide sequence comprising a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:222, wherein the first nucleotide sequence does not contain SEQ ID NO:2; (ii) A second nucleotide sequence comprising at least 80% sequence identity with SEQ ID NO:7 at its 5' end and at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:378 at its 3' end, and consisting of fewer than 1044 nucleotides; (iii) A third nucleotide sequence, which consists of a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:226; (iv) A fourth nucleotide sequence, wherein at its 5' end it contains a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:380 and at its 3' end it contains a nucleotide sequence having at least 80% sequence identity with SEQ ID NO:16; (v) The fifth nucleotide sequence, which is: ( a) consisting of dinucleotides 'GA', 'TG', or 'TT'; or (b) containing a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:19, wherein the nucleotide sequence contains 'GA', 'TG', or 'TT' at positions 1 and 2 corresponding to SEQ ID NO:19; or (c) encoding a target polypeptide and containing 'GA', 'TG', or 'TT' at positions 1 and 2; and (vi) The sixth nucleotide sequence encoding the target polypeptide in the case that the fifth nucleotide sequence is the nucleotide sequence according to (v)(a) or (v)(b); The polynucleotide is contained in the start codon of the 5' nucleotide sequence encoding the target polypeptide.

2. The polynucleotide of claim 1, wherein when the polynucleotide is a polynucleotide, splicing the polynucleotide in the absence of a splicing modifier that promotes the inclusion of exon 7 of SMN2 produces a polynucleotide substantially lacking the third nucleotide sequence.

3. The polynucleotide of claim 1 or claim 2, wherein the first nucleotide sequence comprises the nucleotide sequence according to SEQ ID NO:

222.

4. The polynucleotide according to any one of claims 1 to 3, wherein the first nucleotide sequence comprises or consists of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:106, SEQ ID NO:219 or SEQ ID NO:

220.

5. The polynucleotide according to any one of claims 1 to 4, wherein the second nucleotide sequence comprises SEQ ID NO:7 at its 5' end and SEQ ID NO:8 or SEQ ID NO:377 at its 3' end.

6. The polynucleotide according to any one of claims 1 to 5, wherein the second nucleotide sequence consists of fewer than 500 nucleotides.

7. The polynucleotide according to any one of claims 1 to 6, wherein the second nucleotide sequence comprises or consists of the following: SEQ ID NO:9, SEQ ID NO:10 or SEQ ID NO:

228.

8. The polynucleotide according to any one of claims 1 to 7, wherein the third nucleotide sequence comprises the nucleotide sequence according to SEQ ID NO:

226.

9. The polynucleotide according to any one of claims 1 to 8, wherein the third nucleotide sequence comprises: SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:223 or SEQ ID NO:

224.

10. The polynucleotide according to any one of claims 1 to 9, wherein the fourth nucleotide sequence comprises SEQ ID NO:15 or SEQ ID NO:379 at its 5' end and SEQ ID NO:16 at its 3' end.

11. The polynucleotide according to any one of claims 1 to 10, wherein the fourth nucleotide sequence consists of fewer than 500 nucleotides.

12. The polynucleotide according to any one of claims 1 to 11, wherein the fourth nucleotide sequence comprises or consists of the following: SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:227 or SEQ ID NO:

340.

13. The polynucleotide according to any one of claims 1 to 12, wherein the fifth nucleotide sequence: (a) consists of a dinucleotide 'GA' or 'TG', or (b) comprises or consists of: Based on the nucleotide sequence of SEQ ID NO:

19.

14. The polynucleotide according to any one of claims 1 to 13, wherein the fifth nucleotide sequence: (a) consists of a dinucleotide 'GA' or 'TG', or (b) comprises or consists of: SEQ ID NO:20 or SEQ ID NO:

21.

15. The polynucleotide according to any one of claims 1 to 14, wherein the polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with a nucleotide sequence selected from the group consisting of: SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:116, SEQ ID NO:114, SEQ ID NO:111, SEQ ID NO:25, SEQ ID NO:23, SEQ ID NO:24 and SEQ ID NO:

22.

16. The polynucleotide according to any one of claims 1 to 15, wherein the polynucleotide further comprises a promoter sequence of the start codon 5'.

17. The polynucleotide according to any one of claims 1 to 16, wherein the polynucleotide further comprises a polyadenylated sequence at the 3' of the nucleotide sequence encoding the target polypeptide.

18. The polynucleotide according to any one of claims 1 to 17, wherein the polynucleotide comprises an inverted terminal repeat (ITR) sequence at its 5' end and an ITR sequence at its 3' end.

19. A vector comprising a polynucleotide according to any one of claims 1 to 18.

20. The vector according to claim 19, wherein the vector is an adeno-associated virus (AAV) vector.

21. A pharmaceutical composition comprising: a polynucleotide according to any one of claims 1 to 18 or a carrier according to claim 19 or 20; and a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

22. A cell comprising a polynucleotide according to any one of claims 1 to 18 or a vector according to claim 19 or claim 20.

23. The cell of claim 22, wherein the cell further comprises a splicing modifier that promotes the inclusion of SMN2 exon 7, optionally wherein the splicing modifier that promotes the inclusion of SMN2 exon 7 is lisclan.

24. A method for modifying cells to express a target polypeptide, the method comprising: (i) Introducing the polynucleotide according to any one of claims 1 to 18 or the vector according to claim 19 or claim 20 into cells; as well as (ii) The cells are then contacted with a splicing modifier that promotes the splicing of exon 7 of SMN2, optionally wherein the splicing modifier that promotes the splicing of exon 7 of SMN2 is lisclan.

25. A method for expressing a target polypeptide in cells, the method comprising contacting the cells according to claim 22 with a splicing modifier that promotes the splicing of exon 7 of SMN2, optionally wherein the splicing modifier that promotes the splicing of exon 7 of SMN2 is lixithiocyanate.

26. The polynucleotide according to any one of claims 1 to 18, the carrier according to claim 19 or claim 20, or the pharmaceutical composition according to claim 21, used in a method of medical treatment or prevention.

27. The polynucleotide of any one of claims 1 to 18, the carrier of claim 19 or 20, or the pharmaceutical composition of claim 21, used for the treatment or prevention of a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of the target polypeptide.

28. Use of the polynucleotide of any one of claims 1 to 18, the carrier of claim 19 or 20, or the pharmaceutical composition of claim 21 in the manufacture of a medicament for treating or preventing a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of the target polypeptide.

29. A method for treating or preventing a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of a target polypeptide, the method comprising administering to a subject a polynucleotide according to any one of claims 1 to 18, a carrier according to claim 19 or 20, or a pharmaceutical composition according to claim 21.

30. The polynucleotide, carrier, or pharmaceutical composition used according to claim 27, the use according to claim 28, or the method according to claim 29, wherein treating or preventing the disease or condition further comprises administering to the subject a splicing modifier that promotes the inclusion of exon 7 of SMN2, optionally wherein the splicing modifier that promotes the inclusion of exon 7 of SMN2 is lixithiocyanate.

31. The polynucleotide, carrier, or pharmaceutical composition used according to claim 27 or claim 30, the use according to claim 28 or claim 30, or the method according to claim 29 or claim 30, wherein the disease or condition is characterized by a deficiency of the target polypeptide.

32. A reagent kit comprising: (i) the polynucleotide according to any one of claims 1 to 18, the carrier according to claim 19 or claim 20, or the pharmaceutical composition according to claim 21; and (ii) Promoting the splicing modifier contained in SMN2 exon 7, optionally wherein the splicing modifier promoting the splicing modifier contained in SMN2 exon 7 is lisclan.

33. A polynucleotide comprising, in a 5' to 3' sequence: (i) A first nucleotide sequence comprising a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:1, wherein the first nucleotide sequence does not contain SEQ ID NO:2; (ii) A second nucleotide sequence comprising at least 80% sequence identity with SEQ ID NO:7 at its 5' end and at least 80% sequence identity with SEQ ID NO:8 at its 3' end, and consisting of fewer than 1044 nucleotides; (iii) A third nucleotide sequence comprising a nucleotide sequence having at least 80% sequence identity with the nucleotide sequence according to SEQ ID NO:26, wherein the third nucleotide sequence contains 'A' at position 2 corresponding to SEQ ID NO:12; (iv) A fourth nucleotide sequence, which contains at least 80% sequence identity with SEQ ID NO:15 at its 5' end and at least 80% sequence identity with SEQ ID NO:16 at its 3' end; (v) The fifth nucleotide sequence, which is: ( a) Composed of the trinucleotide 'GAG', or (b) encoding the target polypeptide and containing 'GAG' at positions 1 to 3; and (vi) The sixth nucleotide sequence encoding the target polypeptide in the case where the fifth nucleotide sequence is the nucleotide sequence according to (v)(a); The polynucleotide is contained in the start codon of the 5' nucleotide sequence encoding the target polypeptide.

34. The polynucleotide of claim 33, wherein when the polynucleotide is a polynucleotide, splicing the polynucleotide in the absence of a splicing modifier that promotes the inclusion of exon 7 of SMN2 produces a polynucleotide substantially lacking the third nucleotide sequence.

35. The polynucleotide of claim 33 or claim 34, wherein the first nucleotide sequence comprises the nucleotide sequence according to SEQ ID NO:

1.

36. The polynucleotide according to any one of claims 33 to 35, wherein the first nucleotide sequence comprises or consists of the following: SEQ ID NO:

3.

37. The polynucleotide according to any one of claims 33 to 36, wherein the second nucleotide sequence comprises SEQ ID NO:7 at its 5' end and SEQ ID NO:8 at its 3' end.

38. The polynucleotide according to any one of claims 33 to 37, wherein the second nucleotide sequence consists of fewer than 500 nucleotides.

39. The polynucleotide according to any one of claims 33 to 38, wherein the second nucleotide sequence comprises or consists of the following: SEQ ID NO:

10.

40. The polynucleotide according to any one of claims 33 to 39, wherein the third nucleotide sequence comprises the nucleotide sequence according to SEQ ID NO:

26.

41. The polynucleotide according to any one of claims 33 to 40, wherein the third nucleotide sequence comprises SEQ ID NO:13 or SEQ ID NO:

27.

42. The polynucleotide according to any one of claims 33 to 41, wherein the fourth nucleotide sequence comprises SEQ ID NO:15 at its 5' end and SEQ ID NO:16 at its 3' end.

43. The polynucleotide according to any one of claims 33 to 42, wherein the fourth nucleotide sequence consists of fewer than 500 nucleotides.

44. The polynucleotide according to any one of claims 33 to 43, wherein the fourth nucleotide sequence comprises or consists of the following: SEQ ID NO:

17.

45. The polynucleotide according to any one of claims 33 to 44, wherein the polynucleotide comprises at least 80% sequence identity with SEQ ID NO:28 or SEQ ID NO:

29.

46. ​​The polynucleotide according to any one of claims 33 to 45, wherein the polynucleotide further comprises a promoter sequence of the start codon 5'.

47. The polynucleotide according to any one of claims 33 to 46, wherein the polynucleotide further comprises a polyadenylated sequence at the 3' of the nucleotide sequence encoding the target polypeptide.

48. The polynucleotide according to any one of claims 33 to 47, wherein the polynucleotide comprises an inverted terminal repeat (ITR) sequence at its 5' end and an ITR sequence at its 3' end.

49. A vector comprising the polynucleotide according to any one of claims 33 to 48.

50. The vector according to claim 49, wherein the vector is an adeno-associated virus (AAV) vector.

51. A pharmaceutical composition comprising: a polynucleotide according to any one of claims 33 to 48 or a carrier according to claim 49 or claim 50; and a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

52. A cell comprising the polynucleotide of any one of claims 33 to 48 or the vector of claim 49 or claim 50.

53. The cell of claim 52, wherein the cell further comprises a splicing modifier that promotes the inclusion of SMN2 exon 7, optionally wherein the splicing modifier that promotes the inclusion of SMN2 exon 7 is lisclan.

54. A method for modifying cells to express a target polypeptide, the method comprising introducing a polynucleotide according to any one of claims 33 to 48 or a vector according to claim 49 or claim 50 into the cell.

55. A method for inhibiting the expression of a target polypeptide in cells, the method comprising contacting the cells according to claim 52 with a splicing modifier that promotes the splicing of exon 7 of SMN2, optionally wherein the splicing modifier that promotes the splicing of exon 7 of SMN2 is lixithiocyanate.

56. The polynucleotide of any one of claims 33 to 48, the carrier of claim 49 or claim 50, or the pharmaceutical composition of claim 51, used in a method of medical treatment or prevention.

57. The polynucleotide of any one of claims 33 to 48, the carrier of claim 49 or 50, or the pharmaceutical composition of claim 51, used for the treatment or prevention of a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of the target polypeptide.

58. Use of the polynucleotide of any one of claims 33 to 48, the carrier of claim 49 or 50, or the pharmaceutical composition of claim 51 in the manufacture of a medicament for treating or preventing a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of the target polypeptide.

59. A method for treating or preventing a disease or condition from which therapeutic or preventive benefits will be derived by an increase in the expression level of a target polypeptide, the method comprising administering to a subject a polynucleotide according to any one of claims 33 to 48, a carrier according to claim 49 or claim 50, or a pharmaceutical composition according to claim 51.

60. The polynucleotide, carrier, or pharmaceutical composition used according to claim 57, the use according to claim 58, or the method according to claim 59, wherein the disease or condition is characterized by a deficiency of the target polypeptide.

61. A reagent kit comprising: (i) the polynucleotide according to any one of claims 33 to 48, the carrier according to claim 49 or claim 50, or the pharmaceutical composition according to claim 51; and (ii) Promoting the splicing modifier contained in SMN2 exon 7, optionally wherein the splicing modifier promoting the splicing modifier contained in SMN2 exon 7 is lisclan.

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