Modified oligonucleotides for reducing ATXN3 expression

Abstract

The present application relates to modified oligonucleotides and to pharmaceutical compositions comprising the same, as well to the use thereof as medicine and to the use thereof in a method of treating or preventing spinocerebellar ataxia. The present invention further relates to the use of said modified oligonucleotides and pharmaceutical compositions in reducing ATXN3 expression in a target cell expressing ATXN3.

Description

Evotec International GmbH EVO28777PCTModified Oligonucleotides for Reducing ATXN3 Expression BACKGROUND OF THE INVENTION

[0001] Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease(MJD), is a debilitating and fatal neurodegenerative disorder characterized by progressive cerebellar ataxia (Coutinho et al., Neurology., 1978, 28(7):703-9).

[0002] It is the most prevalent dominantly inherited ataxia worldwide with an estimatedprevalence between 1:50 000 to 1:100 000 that belongs to a group of nine microsatellite disorders called polyglutamine (polyQ) diseases (Klockgether et al., Nat. Rev. Dis. Primers, 2019, 5(1):24; Gardiner et al., JAMA Neurol., 2019, 76(6), 650-656; Durr, Lancet Neurol., 2010, 9(9):885-894).

[0003] The disease is caused by a CAG trinucleotide repeat expansion in exon10 of theATXN3 gene, leading to an extended polyglutamine sequence in the ataxin-3 protein (Kawaguchi et al., Nat Genet., 1994, 8(3):221-8; Haberhausen et al., J. Neurol. Sci., 1995, 132(1):71-5).

[0004] Unaffected individuals have normal repeat lengths ranging from 12-44 CAGrepeats, while SCA3 occurs when the repeat lengths exceed 55, sometimes reaching as high as 86 (Paulson, Semin Neurol, 2007, 27(2): 133-142).

[0005] Longer repeats correlate with earlier onset, faster progression, and greater severityof symptoms. The expanded mutant ATXN3 protein acts through a presumed dominant toxic mechanism that is poorly understood but it results in neuronal dysfunction and neuronal cell loss in motor nuclei spanning the brainstem, cerebellum, midbrain, spinal cord, striatum and thalamus (Rüb et al., Prog. Neurobiol., 2013, 104:38-66).

[0006] SCA3 patients exhibit a wide range of symptoms such as progressive motorimpairments, abnormal gait, impaired balance and sometimes tremor (Rüb et al., Prog. Neurobiol., 2013, 104:38-66; Paulson et al., Nat. Rev. Neurosci., 2017, 18(10):613-626).

[0007] So far, no disease modifying therapies are available and usually the disease leads todeath within 10-15 years of symptom onset (Diallo et al., Lancet Neurol., 2018, 17(4):327-334).

[0008] Several publications have shown that antisense oligonucleotides (ASOs) targetingATXN3 could reduce levels of the pathogenic ATXN3 protein both in human disease fibroblasts and in a mouse model (Moore et al., Mol. Ther. Nucleic Acids, 2017, 7:200-210). 1Evotec International GmbH EVO28777PCTWO2013 / 138353, WO2015 / 017675, WO2018 / 089805, WO2020 / 245233, WO2019 / 217708, WO2019 / 157531, WO2017 / 053781, US2023 / 0054720, WO2022 / 117747, WO2022 / 117745 and WO2020 / 172559 disclose oligonucleotides targeting human ATXN3 nucleic acid molecules in particular for use in the treatment of SCA3.

[0009] Several studies have associated ATXN3 with amyotrophic lateral sclerosis (ALS)and identified ATXN3 as a putative risk gene for ALS (Iacoangeli A. et al., Cell Reports, 2020, 33:(4):108323; Nakamura R. et al., Communications Biologie, 2020, 3(1); Xiao L. et al., Frontiers in Genetics, 2020, 11; Li C.Y. et al., BMC Medicine, 2021, 19:27; Humphrey J. et al., Nature Neurosciences, 2022, 26(1):150-162). Thus, ALS patients may benefit from oligonucleotides targeting human ATXN3 nucleic acid molecules.

[0010] However, there is still a need for useful and effective compounds for treatment ofneurodegenerative diseases such as SCA3. Further, there is still a need for useful and effective compounds for treatment of neurodegenerative diseases such as ALS. BRIEF DESCRIPTION OF THE DRAWING

[0011] Figure 1 depicts the total rearing time of C57BL / 6 WT and homozygous YAC84Qmice over experimental timeline before and after administration of saline, NTC or ASO11. SUMMARY OF THE INVENTION

[0012] The present invention relates to a modified oligonucleotide or a pharmaceuticallyacceptable salt thereof and to a pharmaceutical composition comprising the same, as well as to the modified oligonucleotide or a pharmaceutically acceptable salt thereof and the pharmaceutical composition for use in medicine, and for use in a method of treating or preventing spinocerebellar ataxia. The present invention further relates to a modified oligonucleotide or a pharmaceutically acceptable salt thereof and to a pharmaceutical composition comprising the same for use in a method of treating or preventing amyotrophic lateral sclerosis (ALS). The present invention further relates to the use of said modified oligonucleotide or a pharmaceutically acceptable salt thereof and the pharmaceutical composition in reducing ATXN3 expression in a target cell expressing ATXN3.

[0013] In one aspect, the present invention relates to a modified oligonucleotide or apharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of 2Evotec International GmbH EVO28777PCTAGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT(SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non- modified nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are non-modified nucleosides linked by phosphorothioate internucleoside linkages, and wherein (me)C denotes cytosine or 5-methyl cytosine.

[0014] In another aspect, the present invention relates to a conjugate comprising themodified oligonucleotide or a pharmaceutically acceptable salt thereof according to the present 3Evotec International GmbH EVO28777PCTinvention, and at least one conjugate moiety covalently attached to said modified oligonucleotide, or said pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present invention relates to a pharmaceuticalcomposition comprising the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, and a pharmaceutically acceptable excipient. Furthermore, the present invention relates to a pharmaceutical composition comprising the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention and a pharmaceutically acceptable excipient.

[0016] In another aspect, the present invention relates to an in vitro method for reducingATXN3 expression in a target cell expressing ATXN3, said method comprising administering a modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, or the pharmaceutical composition according to the present invention in an effective amount to said cell.Furthermore, the present invention relates to an in vitro method for reducing ATXN3 expressionin a target cell expressing ATXN3, said method comprising administering a modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the pharmaceutical composition according to the present invention in an effective amount to said cell.

[0017] In another aspect, the present invention relates to the modified oligonucleotide orpharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, or the pharmaceutical composition according to the present invention for use in medicine. Furthermore, the present invention relates to the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the pharmaceutical composition according to the present invention for use in medicine.

[0018] In another aspect, the present invention relates to the modified oligonucleotide orpharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, or the pharmaceutical composition according to the present invention for use in reducing ATXN3 expression in a target cell expressing ATXN3 in vivo. Furthermore, the present invention relates to the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the pharmaceutical composition 4Evotec International GmbH EVO28777PCTaccording to the present invention for use in reducing ATXN3 expression in a target cellexpressing ATXN3 in vivo.

[0019] Yet another aspect of the present invention is a method of treating, controlling,delaying, or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders associated with ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof, or the conjugate according to the present invention, or a pharmaceutical composition of the present invention. Furthermore, the present invention relates to a method of treating, controlling, delaying, or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders associated with ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0020] In another aspect, the present invention relates to the use of the modifiedoligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or of the conjugate according to the present invention, or of the pharmaceutical composition according to the present invention for reducing ATXN3 expression in a target cell expressingATXN3 in vitro.Furthermore, the present invention relates to the use of the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or of the pharmaceutical composition according to the present invention for reducing ATXN3 expression in a target cell expressing ATXN3 in vitro.

[0021] In another aspect, the present invention relates to the modified oligonucleotide orpharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, or the pharmaceutical composition according to the present invention for use in a method of treating or preventing spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof, or the conjugate according to the present invention, or said pharmaceutical composition to said subject. The present invention also relates to the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the conjugate according to the present invention, or the pharmaceutical composition according to the present 5Evotec International GmbH EVO28777PCTinvention for use in a method of treating or preventing ALS in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof, or the conjugate according to the present invention, or said pharmaceutical composition to said subject. Furthermore, the present invention relates to the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention, or the pharmaceutical composition according to the present invention for use in a method of treating or preventing spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof, or said pharmaceutical composition to said subject.

[0022] Yet another aspect of the present invention is a method of treating, controlling,delaying or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders mentioned herein, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof, or the conjugate according to the present invention, or a pharmaceutical composition of the present invention. Diseases or disorders amenable to treatment using the compounds and compositions of the present invention include but are not limited to neurodegenerative disorders, such as spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease). Diseases or disorders amenable to treatment using the compounds and compositions of the present invention include but are not limited to neurodegenerative disorders, such as ALS. Furthermore, the present invention is a method of treating, controlling, delaying or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders mentioned herein, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. Diseases or disorders amenable to treatment using the compounds and compositions of the present invention include but are not limited to neurodegenerative disorders, such as spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease).

[0023] Both the foregoing summary and detailed description are exemplary andexplanatory. They are intended to provide further details of the invention but are not to be 6Evotec International GmbH EVO28777PCTconstrued as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] An object of the present invention is to provide a compound and / or pharmaceuticalcomposition suitable as medicine. A further object of the present invention is to provide a compound and / or a pharmaceutical composition, which may be effective in the treatment of ATXN3 related diseases and disorders and which may show improved pharmaceuticallyrelevant properties, including reduced ATXN3 expression and / or reduced side effects (such asreduced off target effects). A further object of the present invention is to provide a compound and / or a pharmaceutical composition suitable for the treatment of neurodegenerative diseases such as SCA3, as well as the method of treating the same. A further object of the present invention is to provide a compound and / or a pharmaceutical composition suitable for the treatment of the neurodegenerative disease ALS, as well as the method of treating the same. A further object of the present invention is to provide a conjugate suitable for the treatment of neurodegenerative diseases such as SCA3 or ALS, as well as the method of treating the same. Another object of the present invention is to provide a conjugate for reducing ATXN3expression (in vitro and / or in vivo). It is a further object of the present invention to providecompounds and / or pharmaceutical compositions suitable for reducing ATXN3 expression (invitro and / or in vivo). Suitably, the present invention provides compounds and / or pharmaceuticalcompositions that provide an increased reduction of ATXN3 expression (in vitro and / or in vivo)and / or reduced side effects compared to known in the art compounds.

[0025] The inventors surprisingly found that at least one of the above objects can be solvedwith the compounds and / or pharmaceutical compositions of the present invention. In particular, the present invention provides a modified oligonucleotide or a pharmaceutically acceptable salt thereof, i.e. modified oligonucleotide in free or pharmaceutically acceptable salt form. These can be used as medicine and in the treatment of diseases or disorders mentioned herein. The same applies to a pharmaceutical composition of the present invention.I. Definitions

[0026] Within the meaning of the present invention the terms are used as follows:7Evotec International GmbH EVO28777PCT

[0027] Technical and scientific terms used herein have the meanings commonly understoodby one of ordinary skill in the art, unless otherwise defined. Any suitable materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.

[0028] As used in the description of the invention and the appended claims, the singularforms “a”, “an” and “the” are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless the context clearly indicates otherwise. Also, as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0029] As used herein, “about” will be understood by persons of ordinary skill in the artand will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term such as up to plus or minus 5% of the particular term or up to plus or minus 2% of the particular term.

[0030] The term "compound(s) of the present invention" is to be understood as equivalentto the term "compound(s) according to the invention", and also covers a pharmaceutically acceptable salt thereof. Stereoisomers, tautomers or solvates thereof may also be covered. In this context, the compound(s) of the present invention is also referred to as “modified oligonucleotide(s) of the invention”.

[0031] Pharmaceutically acceptable salts are generally known to the person skilled in theart. Salts of the compounds according to the invention (i.e. the modified oligonucleotide) are exemplarily those containing counterions present in drug products listed in the US FDA orange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.

[0032] Suitable cationic counterions are in particular the ions of alkali metals, preferablylithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals preferably manganese, copper, silver, zinc and iron, and also ammonium (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4- alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. Examples of substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, 8Evotec International GmbH EVO28777PCTtetrabutylammonium, 2-hydroxy-ethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.

[0033] The term “alkyl” as used herein denotes in each case a straight-chain or branchedsaturated hydro-carbon group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 to 2 or 1 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1- methylbutyl, 2-methylbutyl, 3-methyl-butyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl-butyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, and the like.

[0034] The term “alkoxy” as used herein denotes in each case alkyl substituents, preferablyalkyl substituents, as defined above that are connected to another structural moiety via an oxygen atom (-O-). Exemplary alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and the like.

[0035] The term “hydroxyalkyl” as used herein denotes in each case alkyl substituents,preferably alkyl substituents as defined above that are substituted with a hydroxyl group, preferably a terminal hydroxyl group.

[0036] It needs to be understood that the term "comprising" is not limiting. For the purposesof the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising of". If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group, which preferably consists of these embodiments only.

[0037] As used herein, the term “oligonucleotide” means a strand of linked nucleosidesconnected via internucleoside linkages. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications. Oligonucleotides are commonly made in the laboratory by solid-phase chemical synthesis followed by purification. When referring to a sequence of the oligonucleotide, reference is made to the sequence or order of nucleobase moieties, or modifications thereof, of the covalently linked nucleotides or nucleosides. The modified oligonucleotide of the invention is man-made, and is chemically 9Evotec International GmbH EVO28777PCTsynthesized, and is typically purified or isolated. The 5’-end of the oligonucleotide is commonly not phosphorylated or thiophosphorylated.

[0038] The term “internucleoside linkage” is known to the person skilled in the art andgenerally denotes herein the mono-phosphate or mono-thiophosphate based linkage of two nucleosides. According to the present invention, the term “internucleoside linkage” encompasses a phosphorothioate internucleoside linkage (also referred to as “PTO”; a modified internucleoside linkage) and a phosphodiester internucleoside linkage (also referred to as “PO”; an unmodified internucleoside linkage).

[0039] The term “antisense oligonucleotide(s)” (also referred to as ASO(s)) as used hereinis defined as oligonucleotides capable of modulating expression of a target gene by hybridizing to a target nucleic acid, in particular to a contiguous sequence on a target nucleic acid. The antisense oligonucleotides are not essentially double stranded and are therefore not siRNAs or shRNAs. Preferably, the antisense oligonucleotides are single stranded. It is understood that single stranded modified oligonucleotides of the invention can form hairpins or intermolecular duplex structures (duplex between two molecules of the same oligonucleotide).

[0040] The term “contiguous nucleotide sequence” refers in particular to a region of theoligonucleotide which is complementary to the target nucleic acid. The term is used interchangeably herein with the term “contiguous nucleobase sequence”. In some embodiments all the nucleotides of the oligonucleotide constitute the contiguous nucleotide sequence. Oligonucleotides may comprise the contiguous nucleotide sequence, such as a gapmer region, and may optionally comprise further nucleotide(s), for example a nucleotide linker region which may be used to attach a functional group to the contiguous nucleotide sequence. The nucleotide linker region may or may not be complementary to the target nucleic acid. Advantageously, the contiguous nucleotide sequence is 100% complementary to the target nucleic acid.

[0041] “Nucleotides” are the building blocks of oligonucleotides and polynucleotides, andfor the purposes of the present invention include both naturally occurring and non-naturally occurring nucleotides. In nature, nucleotides, such as DNA and RNA nucleotides comprise a (deoxy)ribose sugar moiety, a nucleobase moiety and one or more phosphate groups (which is absent in nucleosides).

[0042] The term “nucleoside” means a unit comprising a nucleobase and a sugar moiety.The nucleobase and sugar moiety are each, independently, unmodified or modified. Furthermore, the term “non-modified nucleoside” as used herein means a nucleoside 10Evotec International GmbH EVO28777PCTcomprising an unmodified sugar moiety and a nucleobase selected from the group consisting of A, G, T, U, and (me)C. Suitably, the unmodified sugar moiety is an unmodified DNA sugar moiety. Preferably, the nucleobase of a non-modified nucleoside is selected from the group consisting of A, G, T, and (me)C, even more preferably selected from the group consisting of A, G, T, and C.

[0043] The term “nucleobase” as used herein, includes the purine (e.g. adenine andguanine) and pyrimidine (e.g. uracil, thymine, cytosine and 5-methyl cytosine) moiety present in nucleosides and nucleotides which form hydrogen bonds in nucleic acid hybridization.

[0044] The nucleobase moieties may be indicated by the letter code for each correspondingnucleobase, e.g. A, T, G, C or U. In the exemplified oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methyl cytosine (meC). Exemplarily, for LNA gapmers, 5- methyl cytosine LNA nucleosides may be used. In this context, it is to be understood that “(me)C” as used herein denotes cytosine (C) or 5-methyl cytosine (meC).

[0045] The term “complementarity” describes the capacity for Watson-Crick base-pairingof nucleosides / nucleotides. Watson-Crick base pairs are guanine (G) - cytosine (C) / 5-methyl cytosine (meC) and adenine (A) - thymine (T) / uracil (U). It will be understood that oligonucleotides may comprise nucleosides with modified nucleobases, for example 5-methyl cytosine is often used in place of cytosine, and as such the term complementarity encompasses Watson Crick base-paring between unmodified and modified nucleobases.

[0046] The term “% complementary” as used herein, refers to the number of nucleotides inpercent of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which, at a given position, are complementary to (i.e. form Watson Crick base pairs with) a contiguous sequence of nucleotides, at a given position of a separate nucleic acid molecule (e.g. the target nucleic acid or target sequence). The percentage is calculated by counting the number of aligned bases that form pairs between the two sequences (when aligned with the target sequence 5’-3’ and the oligonucleotide sequence from 3’-5’), dividing by the total number of nucleotides in the oligonucleotide and multiplying by 100. In such a comparison a nucleobase / nucleotide which does not align (form a base pair) is termed a mismatch. Preferably, insertions and deletions are not allowed in the calculation of % complementarity of a contiguous nucleotide sequence. The term “fully complementary”, refers to 100% complementarity.

[0047] The term “hybridizing” or “hybridizes” as used herein is to be understood as twonucleic acid strands (e.g. an oligonucleotide and a target nucleic acid) forming hydrogen bonds between base pairs on opposite strands thereby forming a duplex. The affinity of the binding 11Evotec International GmbH EVO28777PCTbetween two nucleic acid strands is the strength of the hybridization. It is often described in terms of the melting temperature (Tm) defined as the temperature at which half of the oligonucleotides are duplexed with the target nucleic acid.

[0048] According to the present invention, the target nucleic acid is a nucleic acid whichencodes a mammalian ATXN3 protein and may for example be a gene or a ATXN3 RNA, inparticular a ATXN3 pre-mRNA. The target may therefore be referred to as an ATXN3 target nucleic acid.

[0049] In some embodiments, the target nucleic acid is a pre-mRNA which encodesmammalian ATXN3 protein, such as human ATXN3, e.g. a human ATXN3 pre-mRNA sequence, such as a human ATXN3 pre-mRNA in which thymine (T) as found in SEQ ID NO:4 is replaced by uracil (U). SEQ ID NO: 4 is a DNA sequence – it will be understood that target RNA sequences have uracil (U) bases in place of the thymine bases (T). SEQ ID NO: 4 is depicted as follows: GTGGGGGCCGTTGGCTCCAGACAAATAAACATGGAGTCCATCTTCCACGAGAAAGTGAGT GTCCGCGTTCGGTGGGGAGCTGTCTGCCGCGCGGTGGCGGGCGTGGAGCGCGGCATCACC GCCTCTCGGAGGGCTGGGTGGGGCCCGAGTCGCCCCCATGCCGATCTCGCCCGGCGAGGG GCGACGCCGCAGCCTCCCGCCTCCTCGGCTCGAGGAGGGGAGCATCACCTACGCCCCTAC TTCCCCCGCGGCCCCCGCCCTGGGAGCCGGGAGGGAGTATGGGCGGGGCCGGGGGCGTCT CGGGACACGGGAGTGGGGTGGCGCCCAGTGGGTTTGCTTCTGCCTTTCTCCGTCACTTTC CATCGCTTTTCGGAGGATTCCTTCACCCCTCCCCAATCCTTCCCTCTCCCTAGGGTCTAG CTAGAGTCATCTCTGGGACACCTCCCTCAACCCCTCCTACCCTAATCCTGGCAGAATTAA CTTTTCCTCCTCCGGACTGCTCAATTCTATATTGGAGTCTTCCCTACACGTAGATCTTTG GGGTCTTGTTCGTGTCTTTCCCCTGCACTAGGTCCGCGAGCCTCCCGAGGGAGGAGACCT TGGCTCGCCCACTGTAGGGCCTGACATTTAGGAAGTGAAGTAGGAAACCCGGCGTGCCCC TAAACAGGGAAGTCGTCACAAGAGTTTTTATTACGGGATGTTTGGGTTTGGTTTCTTTTG GTACTCCCATCTTTCCGGAGCAGGCGGCCAGCTTTGTTTTTAGGTATTAGGAGTGGACTG GGATGATTTTGTTGTAGTCTGCCTAGCCTGCTGTCCCTTTAACTCTTCCGTGACCATGCA CTTGAAGATACTGTTTGTGATATGTAAAGAAACTCCTCGTTTCTCTCATACTATTATCCA GCCATTTGTGTGTGAGTGAAGCCTTCCCCAGGACAGCTTTGGCACATGGTATCATGTTTC ATAATAGTTTCGTGTTTGGAAAGAGTTGCTGGTAAGGCTGTTATTTAATAGGAGGAGCAA AGGGTTTTTGTTTTATTAAATACTTATAAATGATCATTTATCCCAGACATTTAAAATTCA CACACACACAACAAATAAAGCAAAGACAAAAGAATACATTTACCAAATGTAAATCTGTAG CATAAATTTTTTTTAATTTTTATTTTAAAGATGGGGTCTCATTCTGTCACCCAGGCAGGT GTGCAATGGAGAGATCATGGCTCACTGCAGCCTTGATCTCCTAGGCACAAGCGATCCTCC CGCCTCTGCCTCCAGAGTAGCTGGGACTACAGGTGCATATCGCCAGGGCCAGGTAATGTT TTTGGGAGAGACGGGGTCTCGCTGTGTTGCCCAGGCTGGTCTCGAACTCCTGGACTCAGG TGATTCTCCCACCTCGGCCTCTCGAAGTGCTGTGATTACAGGCGTGAGCCACTGTGCCTG GAACAAATTGTTAAGTACAATGCTTTTCATTGTAGAAAACATCTCGGAAACTTTTGAAAT AGGCTGATGTTCAGTGGGGGAGGAAGGACTCAGTCGTATAGTTGTCACTAATTTTTTGAC TTGATTGACATGACTCGTAAATCATAGACAATAGAGATTTGGTTGCTTGGCTGAGTAGAG TGCGTGAAAAATACACACGTACTTTTTTTTTTTTTTTTTTGAGATGGAGTTTGGCTCTTG TCACCCAGGCTGGAGTGCAATGGCGCCATCATGGCTCACTGCAACCTCCGCCTCCCCGTT CAAGCGATTCTCCTGCCTCAGTCTCCCCAGTAGCTGAGATTACAGGCGCCCGCCACCACG CCCAGCTAATTTTTGTATTTTTAGTAGAGACAGGGTTTCACCATGTTGGCCAGGCTGGTC TCCAACTCCTGACAGGTGGTCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCG TGAGCCACCGCACCCGGCCATATTTTTGTTATTAATTTTCAAAGGCTTTGGTGTGGGACC 12Evotec International GmbH EVO28777PCTACATTTCAACATGGAAGGCCTTAAACATGTTCCACACTACTTCCTGAGAATTAGACAAGA TTTTTAACAATATTGTTACCTAGTTGGGACACATTTGTACTGACCCATGGGATGAAAAAA AGCTGAGTGCTAGCCTAGTGAAAATCTACTTACCCGAAAGAAATCCCTCTTAGTCTGGGT GCAGTGGCTCACACCAGTGCTTTGGGAGGCCCAGACGGGCGGATCATGAGGTCAGTAGTT TGAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAAATTAGC CAGGTGTGGTGGCAGGCGCCTGTAATCCCAGGTACTCTGGAGGCTGAGGCAGGAGAATTG CTTGAACCCGAGAGGCAGAGGTTGCAGTGAGCCGAGACCGTGCCACTGCACTTCAGCCTG GGCAACAGAGCGAGACTCCGTCTCAAAAAAAAGAAAAGGAAAAAAGAGTCCCTCTTAATT ATCAGCATGTGTATAGGCCTACAGATACTTCAGGAATACCTTTACCATTATCATCAACTT GTATCTACATAGCATGTGAAGATTCAACAATTTAGTTTTTTGGGCGTCCTCAAGAGTACG CACCTATAACCATATGGCCCAATTGTTAATCTCCTATACAGTCCATTCTGGGAATGTTTG GGCTTACTGTGCCATTTTTCCGTTCACTGCCTTCCCCTCTGCAATATACCTTTAACCCTT GCTAGGTCCTGGGTTTGGAGAGCCAGAGAACCAACTTTGGCCCTAAAGAAGCTGTGTAGG TAGCAATATCTGCCTACGAAGGGCCTTGCAACCATTTCCTCTTGGAACCTTGGTTTCCTC TTTCTGAGTAGTCACTTTGAGTACCCTTTATTAAGTTAGAATGTAAAAACAGTTTCTCAC TGATATATCTGCAGTGCCTGAGAGAGGGCCTGGCACAGAGTAAGTACTCAATAAATATTT GAATGGGGCCGGGCGTGGTGAGACCTGTCTCTACAAGAATGAACAAAATTAGCTGGGCGT GTTAGCACATGCCTGTAGACTTGGGAGGCTGAGGTGGGAGGATTGCATGAGTCTGGGAGG TCGAGGCTGTAGTGAGCCATGATCGCACCACTGCACTCCAGCCTAGGGGACAGAGCAAGA TCCTGTCTCAAAAGAAAAAAATGTATATATTTGAATGGATAAAGAGATGGCTTTGAGTTT CTGAGATATATATGGTGCTGTTTATCTAAAGTAAACAAGTTTTCTGTAAATATTTTAAGG CTTTGCAGGCCAGCTGTAGTCTCTGTCACACATTCTTATTTGTGCATGTTTTTCCCAACC ATGTAAAAATGTAAAGTGCATTCTTAGCTACTGGGGCAGGTTGAATTTGGCCCATGGGCT AGAGTTTGCCAACCCCTAACTTAAACCTTTGTACTAACTTTATGACCACTACTGGATTTT TGTTGTTGTTTGTTTTAGTTCTGGTGCCTGCTTTGTTTTTTTTTTTTTTTTTAATCCTCT TGCTGATGTTTCTTGGTGCAGTTACTGTGCCATTTGTATTGGTGCTTTTAATGTAATGCA AACTGGTAATAATATCTAAACTTGCTGGGGTTGTACATAAAATTATTGAAAAGATTGAAA AGATGCTGAGCATTGACTCTGTGGCATTCATTATGCCCTTTTGTGATTGCTGGATTTTAG CCATCTTTAGGACATTTGAGCTTTAGGAGAAGCCAAATTCTGTATAAATGACTTGAAGTG CTAATAGCACAGGTTTTGAAACCTCTGCCTGGGTTTGAGTCTCAGCTCTGCCTTTTACTA CCTGTGTGATCCTGAGCAAGTTACTTAGTATCCCTGTCCTCTAGTTTCCTCCTCTGTAGT GTGGGGATAATAACATAGACATAACCTGAGAGTTAGAGTGTAGAGAAGGCTCCCTGGCAG ATAGTGCTGTAGAAGTACTGGCCATTGCCATTACTCAGGTGCTTGTGTTTGCTGAACCTC ATAGTAAGGGCTCGGAGAGCACTAAGAGGAGGTGAGAAATGCTGCTAGATTGACAGCTTG TCCCCAGATAGCCCATTCCCGAGAGCACCTTAGGTTTATACCTGATTTGTGTTGTAGTTA GTAGTGTCTCTGGTAATTTGAACTAGTTTCAGGTTGGTCTTGAAAACCTGGGGAGGTTGG GGGTAAATGATTTGGTAGCAGTTCTCTTTTGTGATTTTATACATTATCTTTGTAGAACTG CAGTTTGCTAATTCTCTGAGCCCAACACAATGAAGTCTGGGCCTAAAATCATAGAATTTCTTCTTTGGAGTCTCACTCTGTCACCAGGCTGGAGTGCAGTGGCACGAACTTTCTTCAGAG TCTCACTTTGTCACCAGGCTGGAGTGCAGTGGCGCGAACTCAGCTCACTGCAACCTCCGT CTCCTGAGTTCAAGAGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTATAGGCATG TGCCACCATGCCCAGCTAATTTTCTTATTTTTAGTAGAGACGAGGTTTCACCATGTTGGC CAGGATGGTCTTGATCTCTTGACCTCGTGATCCACCTGCCTCAGCCTCCCAAAGTGCGGG GATTACAGGCGTGAGCTACCACGCCCAGCCTATTTTTTATTTTTTGAGGCAGAGTCTCAC TCTGTCACCCAGGCTGGAGTGCAGTGGTGCAATCTCAGCTCACTGCAACCTCCGCCTCCT GGGTTCAGGTGATTCTCCTGCCTTAGCCTCCTGAGCACCTGGGACTACAGGCGCCTGCCA CCACACCTGGCTAATTCTTATATTTTTAGTAGAGGCGGGGTTTCACCATGTTGGCCAGGC TGGTCTCGAACTCCTGATCTCAAGTGATCAACCTGCCTTGGCCTCCCAAAGTGCTGGAAT TACAGCCATGAGCCACCATGCCCAGCCAAATCATGAGATTTCAATACCGCTGAACTTTGA TTATGGCAAAGTGAACTTCTGCTTTGATTAAAGCTTGATGAGAGAGGTGGCTGGGGATAG TTTGAGATAAGGGCAAGGCAGGAAAATGCATAATCTTACGTGGGCTCATTGTCATTGTAC AATTCTTTTGGTCCATGTGGAATTTGATCCGTCCTATGACTTAAGTTATGTTTATTTTTG TTTTTATTTTTATTTATTTTGTGTCTTTTTGAGAGACATGATGTTGCTCTGTCACCTGGG CCAGAATACAGTGGCACAATCTTAGCTCCGTGTAGCCTTGAACTCCTGGGCTCAAGTGAT 13Evotec International GmbH EVO28777PCTCCTCCCACCTCAGCCCCTCAAACAGTTGAGATTATAGTATGAACCACTGTGCCTAGCCTT AAGTGATTTTTAAATTTGTACTGAACAGTTTGTCCTTTCCTTCCATTAAATCATATTAGA AGTACAGAACTTGATATTTCCTGTAGCAATACAGTTTTTCTTTGATGAAGTTTGATTTCA AGTACTTATTTTTCATAATTTAAAGCTATTTTTTATAGAGAGAATTTTAATCAAATATTT GGATGTCACTATTGCTATATATGGTATTAAGTATGGTGACCATAGTTTGTAAACTCCAAA CTGACAGCAAGACAGGAAATTTGTGTTAGCAAAGGCTTTTTTCTTACTGTTTGAATTTTT TAAAAATTAGATACAATACAGAGAGGAGCACACAAATCATTAAGAGTACAGCTCAGCGAA TTTTCACACAGTGAACATGTGTAAACAGCAAGTAACAAAAGATTTACCTGCATCCTATAA CCTCCCATTATTCCCTTTTCTAGGTACTGTCTCTCCACTGCATTCCCACCAAATATAACC ACTATGCTGAATTCTGACATCATAAATGAGTTTTGCCTGATTTTGAGCTTTTGTGACTGG AAGTGTACAGTGTATATACCCTTTCGATTCTGTCCTCTTTAGTTTACCATTGTTTGAGAA ATTTATCCATACTGTTCCAGAATTAACTACTGTTAATTATTGTTAATTAACTACTGTTGT AGTTAATTCATCCTCATTGTTATCTAGTATTCTTTTGTGAGTAAACACAATTTCCATTCT ACTGTGATCCCAGCTATCCATTTGGGTCGTTTCCAGTTTGGGGTCCATTACAAATAGTAA TGCTATCTGTAATGCTATTTTGTATTACTACAAATAGTAATGCTATTTGTGGCACAAAAA TACTGCTTTTGTGAACATTCTTATACATGTCTTTTGATGAATGTATGTTTGCATTGCTGT TGTTTACATTATGTACCTAGTAATGGAATTGCTAGATCATAGGAGATGTATATATTAAGC TTTAGTGGATGCATTACATAATTATTAGTTATTATTGGTTATACCAATTTATCCTCTCAT CAGTAGTATACAACAGTTTCTGTATCTCTAATCTCCAACATTTTAGCCATTTTAGAGTTT GTGTACTAACACATTGTGGTTTTAATTTACATTTCCCTGATGACTAATAAAGTTGAGTAC CTCTTTTGTGTTCTTTATAGCCATTTGACTGTCTTGTGAAGTGCTTGTTTGTCTTGCCTATGGTCTTGCCCTGTCACCCATGCTGGAGTGCAGTGGTGCAGTCTCAGCTTACTGTAGCCT CGACCTTTTTGGGGCTCAAGTTATCCTCCTTTCTCAGCCTCCCAAGAAGCTGGACTACAA GCACGCACCACCATGCTCAGTTAATTTTTTATTTTTTGTAGAAATGGGGTTTCACCATGT TGTCCAGGCTGGTCTCAAACTTCTGGGCTCAAGTAATCCTCCTGCCTTGGCCTCCCAAAA TGCTGGGATTACAGGCATGAGCCACCGCAGCCAGCCTTGGCTATTTTTCAAAAGGATATA AGTAGAACATCTGTATATCCCTTCAATTTGCATATTATTCAGTAAGAGTTGCACTCTGGT AGTAGAAATATATAAGGAGGAGAAAGAAGTGGAAACAAAAAGTCTATTCTCATGAGAAGA CTTGGGGGATAGTGTTCTCTCTAGCTCCAAGCTACTTATTCCTTACGAAAAGTTGAAGAT AAACTTATCTCAGACTGAGGCTGTCTCAATGTTGTCTTCCTATTCCATTATACACATATA ACCCATATTTTTTTCACCAGCTGAATTTTGCTCCTAGAAAATTGATTCATCAGGAAAAAT ATCCGTCTTGCAAGGTGGTTCTCTTTAGAGTCTGCTGTGTGACATAGCTCAGGACAAATT GTGTGATGTCAGATAGGTTGGGTTAAGGAATAGACCTTATTGGGGAAAGAGAGAACTTGG AGGGCCAAGGTTAGCAGGAGAAGGAAATGTTCTCTCATCTGCCGTCAATTCAGGGAGGGG CAAACCTGGTGTCTGTGTTCACAGGGAGGGATCCATCCATCTGTGATTCTCCCTTCTTAT CAGGTAGCATGGGAAAGCTACACTGTTGCGGGGAGGAGGGTCACACGCAGGCTACTTAGT ACCAGGCACCCTGGACTTGGATTCAGGTTGCCAGTTGTGTGAGAAACTGCCCAGCACCTG AAGGCCCTGAACCCATGAGAAGTTGTACCTACCTCCCATGAGGAGGAATCCTGTCATCCC ATGGGAGCTGAGCTTGGGTGCAGTCCCTCTTGCTGGCTTGTCCAGGAGTGAGCTCCAGGG TTGTTTGGGACAGTTCTGCTCATTGCTTTACACTGTGTATACATTATCTGTAGAGTTCCA TGAAGAGAACTTCAGCACTGTAACTGCAAGTTTTAACATGGAACAGAATTTTTCTCACCT GTATTAATTCTTAAGATTTGAAGTTCTATCAACAAGCATTTAGATTGTGTGGAGATTTTT TTATTTTTATTTTTGGAGACAGAGTCTTGCTCTGTTACCCAGACTGGAGTGGCAGTGGCA TGGTCTTGGCTCACTGCAGGCTCTACTTCCTGGGTTCAAGCGATTCTCATGCCTCAGTGT CCTGATTAGCTAGGACTACAGGTACACACCACCATGCTGGCTAATTTTTGTATTTTTAGT AGAGACGAGGTTTCACCGTATTGGTCAGGCTGGTCTCGAACTCCCAGCCTCAAGCAGTCC ACCCACCTCGGCCTCCCAAACTGCTGGGATTACAGGTGTGAGCCACCATGCTTGACTGAC ATCATCATGTTAAAAGAATAAATGTTCTAGGGAGCTGGGCACAGTGTCATGTTTCTGTAG TTCTAGCTGCTCGGGAGGCTGAGGCAGGAAGATCCCTTGAGCCCTGGAGTTCAAGTCCAG CCTGGGCAACATAGTGAGATCTCTTTTTTTAAATAAATAAATAACTGTTCTAGGGACTAA AATTTCCTTTCACCATTAGTAATTTACTGTAGAATCTCCAAGAATGAACTTATTTTAGGT ACTGAAAATGAGGGAGACTAAATGTTTTATACAGTAGTTTTTAGTAAAATATGAGATTTG ATGCATTTGATAGATGATGTTTGTTTAAAATAATTCTTAAATTTTTGATCATGTAATTAT AGTTTCATTAATGGTAGATTTGTAAAATAAATGTTACCAAATGAAAATGCATGTACCTAT 14Evotec International GmbH EVO28777PCTGTTAATTATCCTTATCTAAAGCTGAAAGTTCAGTTCAACTATGTTAAAACATAGTAGGGG CCTGGCAGGGTGGCTCTTGCCTGTAATCCCAGAACTTAGGGAGGCCAAGGTGGGCAGATC ACGAGGTCAGGAGATCGAGACCATCCTGGCTAACATTGTGAAACCGTATCGCTACTAAAA ATACAAAAAATTAGCCGGGCATGGCGGTGGGCACCTGTAGTCGCAGCTACTTGGTAGGCT GAGGCAGGAGAATGGCGTGAACTCAGGAGGCAGAGCTTACAGTGAGCCGAGATCATGCCA CTGCACTCCAGGCTGGGTGACAGAGCAAGACTCCATCTCAAAAAAAAAAAAAAAGTTGGC CAGGTGTGGCGGCTCACACCTGTAATCCCAGCACTTTTGGAGGCCGAGGCAGGCGGATCA CAAGATCAGGAGTTTGAGACCAGCCTGGCTAACAGAGTGAAACCCTGTATATACTAAAAA TACAAAAATTAGCCAGGCATGGTGGTGCATGCCTGTAGTCCCAGCTACTTGAGAGGCTGA GGCAGGAGAATCACTTGAACCCGGGAGGCGGAGGTTGTGGTAAGCTGAGATTGCTCCACT GCACTCCAGCCTGGACAACAGAGCAAGACTCTGTCTCAAAAAAAAAAAAAATTAATGATT AAATTATTTAGGGGAGCCGGGCGCAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGG CCAAGGCGGGCGGATCACGAGGTCAGGAGATCAAGACCATCCTGGCTAACACAGGATGAA ACCCCGTCTCTACTAAAAATACAAAAATTTAGCCGGGCGTGGTGGCGGGTGCCTGTAGTA CCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCATGAACCCGGGTGGCGGAGCTTGCAG TGAGCCAAGATAGCGCCACTGCACTCCGGCCTGGGTGAAAGAGTGAGACTCCGTCTCAAA AAAAAAAAAAAATTATTTAGGGGAAGATACTATACAATTCTGTTTAACAAGTCACATTTT AATTTTTTCTTTTGGAAATATTAGCAAGAAGGCTCACTTTGTGCTCAACATTGCCTGAAT AACTTATTGCAAGGAGAATATTTTAGCCCTGTGGAATTATCCTCAATTGCACATCAGCTG GATGAGGAGGAGAGGATGAGAATGGCAGAAGGAGGAGTTACTAGTGAAGATTATCGCACG TTTTTACAGGTACTGATTTTAAACTCACTAAGTCACATTTCTTTTTTTTTTTTTTTTTTG AGACGGAGTCTCGCCCTGTTGCCCATGCTGGAGTGCAATGGCGCGATCTCGGCTCACTGC AACCTCTGCCTCCCGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGATT ACAGGCACACGGCACTATGCCCGGCTAATTTTTTGTATCTTTGTTAGAGATGGGGTTTCA CCATGTTGGTCAGGTTGGTCTCAAACTCCTGACCTTATGATCCACCTGTCTTGGCCTCCC AAAGTGCTGGGATTATAGGTGTGAGCCACCACACCCGGCTTACATTTCTTTTAAAAATGT GGATACCATTTAGAAAAGGATGGGCCATTCTTCCTATAGGGATCTGACTGGTGAATTATA ACTGTGCTGTTAACTTTGGAAATGGGAATGCACAAGATATTGTTTTAAATATGCACGCTA ATGACAGTTTGTATCCTTCTTTCCCCACCCCCACCCTTGCTTCAACTACCTGTCAAAATT AACAGCAGCCTTCTGGAAATATGGATGACAGTGGTTTTTTCTCTATTCAGGTAAGTAGTC ACAAGCATGTACTATGTGTTGCTTACATCCCAGGCACCGTTTCACAGCCTTTCAATAGTC ACTGTAACAAGGCGACCTTCGGAAGTTCTTCTGTCTACAGAGTATAGATTATACTCTAGA GTACTAGATTTTTTTTTTCTTGAGACAGAGTCTCGTTCTGTCACCTAGGCTGGAGTGCAG TGGCGTGATCTTGGCTCACTGTAGCCTCTGCCTCCCGGGTTCAAGCGATCCTCCTGCCTC AGCCTCCCAAGTAGCTGGGATTACAGGCACCCGCCACCACACCAGTTAATATTTGTATTT TTAGTAGAGATAGTGGGGTTTCACCGTGTTGGCCAGTCTGGTCTCCAACTCCTGACCTCA GCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACTGCACCTGGCCAACTAGAGTACTA GATTTTTATATAGATAAACATGAAAGGATTGTAGAATCTTCATATTAGAGTGGGGCATTT AAAAATTCCTTCTTGAGAAAGATTAATTTGCATCTGGATGCTAATAATAACCTTAATTCT GGCCGGGCGCGGTGGCTCACACCTGTAATCCCAGCACTTTGGGGAGGCCGAGGTGGGCGG ATCACGAGGTCAGGAGATTGAGACCATCCTGGCTAACATGGTGAAACCCCGTCTCTACTA AAAATACAAAAATTAGCTGGACGTGGTGACACGTGCCTGTAATCCCAGCTACTCGGGAGG CTGAGGCAGGAGAATCGCTTGAACCAGGGAGTCGTAGGTTGCAGTGAGCCAAGATCGCGC CACTGCACTCTAGCCTGGTGACAGAGCGAGACTCCATCTCAAAGAAAAAAAGAAATCCTT AATTCTAATAAGTCACAATGTCTCAAACTTACCATCTGTTGGGTAAATTTGAGAAAATGC AATACCTTGCTACCATCCTTTTAAATCAGCCTACCAGACTGGATTTCCTTATTATGGTTT GTGGCTTTTGATTTTTTTTTTTTAATGTATAGCTCTCTTTGAATTCTTTGGTGGTTATAT ATATATGTACTCGCAAGATTCTTTTATCTGTGGGTCTTTCATTCTTTTTCTAACACTGTG AGTTGTATCCAGAGTACTTTCGGAACCTCTCCTGAGCGACCTATCTCTGCAGATATCTTT GTTTATGTTTCCCTTGTACTGCCCTCCTGGACTCTTCCTCATCCACCAGCATTTCCATCT AGTGCTTTACCGTGCCACTGCTAACAGGTAATGGCTACTGCAGGGCTGAAATCAGAGGCC AGAGTAGGCCCAGCACTTGGCGTTTCCTATTTGTGCCTTGCTGCTCTTGGTGCCTGTTCA TGTGTGCCCACTACCTTGCACTCAATTTCTGTCTTTGCTGGTACCTGGCTCACTTGCTTC TTTGTTGGCTACCTTGGAGGGCAGATAGTGAATTTTCAGAAATTTCCCTTTTTTTGTCAG ACAGATTGAAATAAACAGGTTTGCATTTTGTTTTTTCTACAAGCGGCAAGCCCATGACCC TAGAAGTCTGACATCTATGGAACCTTCAGTTTAAATGCCCAGGGAGAACTTATTTTGGTA 15Evotec International GmbH EVO28777PCTGATATGATTTCTGACATTGCAGGTAGCAAGTTGAATATAATTTTTCTAAAGTAGCACCCA CAGCAGCCAAATTATCAGATGTATATAGTAGACTAGTTTTAAGAAAAGCACTTATGGGTA GAATATACATCTGGATTTTTGAGGCAGTTTTATTTAGGAATTGTGTGGTTTTCTGGAACA TCTCAGAGACCTGGTATGAAAAGCACTCTTCTAATATATATGTGTTTTTTTTTATGGATT TAGTGATATATCTATACACACACACTTTTTAAAACCTATAGCCGGCTGGGCGTGGTGGCT CATGCCTGTAATCCCAGTACTTTGGGAGGCCCAGGCGGGTGGATCACAAGGTCAGGAGAT TGAGACCAGCCTGGCCAACAAGGTGAAACCCTGTCTCTACTAAAAATACAAAAATAGCTG GGTGTGGTGGCGTGTGCTTGTAATCCCAGCTACTCGGGAGCCTCAGGAGGAGAATCGCTT GAACCTGGGAGGCGGAGGTTGCAGCGAGCCGAGATCGTGCCACTATACTCCAGCCTGGGC GACAGAGCAAGACTCTGTCACAAAAAAAAAAAAAAAAACCTATAGCCTTCTAGAGAAATT TATATATGAAGTACACAACTAACATAGCTACACTTCCTAAATTTGGAATGGAGTGGTTTA GCTTATGAAAAGTTGCTATTTTTCTTAACAGGTTATAAGCAATGCCTTGAAAGTTTGGGG TTTAGAACTAATCCTGTTCAACAGTCCAGAGTATCAGAGGCTCAGGATCGATCCTATGTA AGATTCTGTTTTGCATTTCATACATTTCTTTTCCCAAATTTGATTTTTAAAGTTGTAATT TCTTAAAGAAGAGAAATACATTTTGAATACTTTTGTTTTGATGTTCCCTGTTTCATTCAC TCAGACTTTCCTATTTCACCTTTGTGATGTCCATGAGCATCTGCCCTGTAGCCTTCCTGG CACCCCAGTGTCTGTGGCAGCACAGAGCTGACCCCATAAGTGGTGCATGAGGCCATCTTG TGGCACAGCATCACTAAGCTGCTGCAGAGACGTTCATATGGTTGTGTGATCTTTTAAAAA CATCAGTGACACTTAACTATAAATATAATCTTAAATTATCACAAATTTTATATAATATTT GCCAGTAGACAACATAAATATGAATTCAATATTTCAAGTTAATATTGTCTGTTTTCTTTT TTAGAAATGAAAGATCATTTATATGCAATTATAAGGAACACTGGTTTACAGTTAGAAAAT TAGGAAAACAGGTAACATTTCTTACCCTTCCTTGTCTTTTTTTCTTATATTGTACCCCAT TTAAAACTAAAATGTGGGCCAGGTGTGGTGGCTCATGCCAACAGTTTGGGAGGCTGAGGT GGGGGGATCACTTGAAGCCAGGAGTTTGAGACCAGCCTGGGCAACAAAGGGAGGTCCTGT CTCTTAAAAAAAAAATAAAAATAAAAATAAAAATAAATAAAAAAAAAAACAAAGAGCCAG GCATGGTGGCTCACATCTGTAATTCCAGCTTACTTGGAAGGCTGAGTCAGAAGGATCACT TGAGCTCAGGAGTTTGAGGCTGCAGTGAACTATGATTTTGTCACTGTACCCCAGCCTGGG TGACAGAGTAAGACTGTTCTATAAAACATAAAAATAAAAAAAATATATTTAAAAATTAAA AAAAAAAAAGGATTGCTGACTTTAAAATTAGGAAACTGACCAGTAATGTGTGTGTGTGTA GCATGGTTTATCCTTCTTGATAGATAGAAATTGTCATTTTAAAAGATAATATCAGTTTTC CTTATAAATTTATTTGTGACAAGTATATGCAATTTAACTATATCATAAGAAAAATTCTAT ATTAAAGATAATACAAATGTGGTTACTTTTAAGTGGGTTTTTATGTGATGACTATGTTCT GTCAGTTAATTATTACATTTATAGATTTGTATTTAGCATAGTGCTGTCACAAAGCCTGAA ATAGTGTCAAGCATGAATAAAGCATTCAATTATGTTTGCTTTAGTGTAAGATTATTCATT ATGATTCCAAAAGCCATGTAATACGTACGTCTACAGAAAATCACTTCTATTTTTTAAATA AAACATGAAATATGTCTTGAGCAAGCTATTTTAAGAAACAATCATTTAACGTCCTTGTTA TTAGAATTTTGAATCTTTGAAAGAGGGTTATTGAAAACCAGCTAGGACAGTAAAAAAGAA TAAACTAGTGATACATGCAGCAATATGGATGAATCTCAAAATAATTATGCTGAAAGAATA ACCCACAAACAAAATACTACCTGCTGTATGGTATCATTTATTAAAAGTCTAGAAAAGTGC AGATTCATCTGTAGTGATGGAAAGCAGATTGACCAGCGGTTGCCTGGGGACGAGAAGGCT ATGGAGGAGTGAGAGGGGAGGGTTACAGAGAGGCACGGGAAACATGGCAATGAGGAATGT GTTCACTATCTTGGTTGTAGTAATGGTTTCATGGGAGTACAGTATACAAATGTGAAAACA TTTCAGAGGCCAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTTGGAGGCCAAGGC AGGAGGATTGCTTGAGCTCAAGGAGTTCAGGACCAGCCTGGGCAATGGCACAAGACCCCA TCTCTAAAAAAAAAATGAAAGAAAAAAAAATTGGCTAGGCGTGGTGATGCATGGCCGTAG TCCCAGGTGCTAGGGAGGCTGAGGAGGGAGCACAGAGGTCAAGCCTGCAGTGAATCATGA TCGTGCTACTGCACTCCAGCTTGGGTGACAGAAGGAGATCCTGTCTCAAAAAAAAAGTTT CAAATTATACACTTTAAATATGTGCAGTTTATTATATGTCACTTATACCCCAATAAATCT GTTTTTTTTAAAATGTAAATACAAGCCAAAAAAGGTATAAGTCAAGAAAATATATTGAAT TAAATCTGTAAGAGATAATTCAAAAACAAAAACCCTATTGTTATCTTTTAAGTCACCCAA ATCAAATTTGGGAAAAGTCACCTACTTAGCTTCATCCTAAGTTGGTTCTTTCTTTCTTTC TTTCCTTCTTTTGAGACGGATTCTTGCTCTATCGCCCAGGCTGGATTGCAGTGGCGGGAT CTTGGCTCCCTGCAACCTCCGCCACCTGGGTTCAAGCAATTCTCTTGTCTCAGCCTCCCA AATAGCTGTGTCTACAGCCACGCACCACCACACCCAGCTAATTTTTGTATTTTTAGTAGA GACGGGGTTTCGCCATGTTGGTCAGGCTGGTCTTGAACTCCTGACCTCAGGTGATCCGTC CGTCTCTGCCTCTCAAAGTGCTGGGGTTACAGGCGTGAGCCACCATGCCGAGCCCTAAGT 16Evotec International GmbH EVO28777PCTTGGTTCTTTCTTAAAGTTCTTCCTGAGGAGCCAAGAGCAAGTTAAGGAGATGTAACCTAG AAGCTTACAGTGGAGGCTAGCTGGGTGCAGTGGTTCACGCCTGTAATCCCAGCACTTTAG GAGGCTGAGGCAGGGAGATCACTGAGGCCAGGAGCTTGAGAGCAGCTTGGCCCAACACAG TGACACCTTGTCTCTACAAAAAAAAAAAAAAAAAAAGGCAGCTTACAGCAGTAGAGGCTG ATGCGAGTGGGAATCACCTCTAGGTAAAAACCAGTGTAGCGTACTGCTGAGATTATTTAA CCTCTGGGTTTTATTTATGTGTTTTTAAAAATTATGATCCAGTATTTTTTACTTTTTTTT GTATAAAGTAAGCACTGAATTTTTAAGGTTGTATTAATTTGCAAATAAATGTCTATCTTA TTATTTTGAGAGATTTAAAAAATTTTAGTTCTTCAAAATTGCATTTTCACATTTTGAATT ACGTTATCTTTGACAAATACAGAAGATGTCAAATTTTGGTTTATTTTCTTTGGTTCTAAT TTATATTTTTGTTTAAAACTATATTTTTCACTATAGACTCTTTCTGTCTCTCGAGGTCCC TGTATAATGAAAAAGAAGGCTGGAAAAAGTATTAACATTGTCAAAATCCAGGAAAAGTAG TTGGTCATGATATTGATCGTTAACTTTAGAAACTTTTTGTATCTTGTGGGTTAAATTAGG ATTACTATGTGGTAGTGATAAATGATGTTAATTAGGGCCGAGTGCAGTGGCTAACACCTG TAATTCCAGCATGTAGGGAGGCTGAGGTGGGAGGATGTCTTGAATCCAGGAGTTTGAGAC CAGCCTGTACAACATAGTGTAAGACCCCTTCTCCACACAAAAAAATTAGAAAATTTGTCA AGCATCTTGGTGCACACCTGTAGTCCCAGCTGCTTGGGAGGATGAAGCGAGAGAATCACT TAAGCCCAGGTGTTCGAGGCTGCAGTGAGCTATGATTGCACCACTGCACTCCAGACTAGA TGACCATCTCTTTTAAAAAAATGTGTTTATATGTTATATGTGATAGTGCTTTTTAAAAAC ATTTTTAAATTATAGAGACAGGGTCTCACTATGTTACAGCCCAGGCTGGTCTCAAATTCC TGGGCTCAAGCAATCCTCCCACCTTAGCTAACCTCCCAAAGTGCTCGGATTATAGGCATG AGCTGCATGCCCAGCTAATTTAGTGATTTTTAAAAACTGAGCTGGTAATTATAAATTCTC TTCCTGGAACTTCTGACTTTCTCACAATTGGAATCTTTTGACAAAAATTATCAGTAATGG GAAAACTTTGTGTAGTTGTCATTTTTCCTCCCATCAGTGTGATAGATATGATTGGAGTTA TGTTGGACTGATATTTTGAAAAAAGATTTAATTATAGCTATTAATAAAGACATTTAAACT ACTGACTATGCATTTTTATTCTTTTGGGAGGGTTTAATGTTTATAGTTTAAAGCAAACTG TTGTTTTTAAAAAAGTATCTAACAGGGCCGGGCGCGGTGGCTCACACCTGTAATCCCAGC ACTTTGGGAGGCCTAGGCGGGCGGATCACAAGGTCAAGAGATCAAGACCATCCTGGCTAA CATGGTGAAACCCTGTCTCTACTAAAAATACAAAAAAATAGCTGGGTGTGGCGGCGTGCG CCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGGATGGCATGAACCCGGGAGGCGG AGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGGGCGACAGAGCAATACTC TGTCTAAAAAAAAAAAAAAAAAAAAAAAAAGAGTATTTAGCAGAGGCCAGGTGCAGTGGC TCATGTTTGTAATCCCAGAACTTTGGGAGGCTGAGGCGGGCGGATCATTTGAGGTCAGGA GTTTGAGACCAGCCTGGCCAATGTGGCAAATGTGCTGTCTCTAACTAAAAATACAAAAAT TAGCTGGGTGTGGTGGTGCAGACCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGA ATCACTTGAACCTGGGAGGCAGAGGTTGCAGTGATCCGAGATCATGCCACTGCACTCCAG CCTGGGTTACAGAGTGAGACTCTTCTCAAAAAAAAAAAAAAGTATTTAATAGTGATAAAT CTGCAGTATTCTCTTGTAGTTTTTAAGATCATATTATTCAGTCAAAGAAAAGAGCTCAAC TTGAAATATTTCCAGAGTTTAAACAATCTTACTAAGCTTTGATGGGTTGTATCTATTCTT AACATGTGAAACTTCCTTATTACCTATAATATACACTAACTTAAATATTGACAATTTTTT TCCAGTGGTTTAACTTGAATTCTCTCTTGACGGGTCCAGAATTAATATCAGATACATATC TTGCACTTTTCTTGGCTCAATTACAACAGGAAGGTAAGTAACGGCTGAACATTTTGTAAT GTTACCTTTCGAAGTAGTTAAATAACCAGGCACATTAGATGACAGTGTGATAAAACTGTT TTTCTGGCAGTGGCAGTGAAACAATCTTTAGTTTTGACGTGGTGATAGGCTGTGATTTGG GTGACGCTGTTCAGTTAGAGTTCTCACTGACACCTGGCCCTTCCTCTTCTGAGGATGCTG CTTTCTTTGCAGCCCTTCTAAGTAATGGCTTTTTCTTTTATACATCACATATCACACGGC TGAGAGGAGGGATAGATGTTTTTCTTCTTTGCCTCTTCTAGGCCACTGTTCTTCCTTATA AACTCCAGTTTCTTTGAAATACATGCCCCTAACGGCTGGGCACGGTGGCTCACGCCTGTA ATCCCAGCACTTTGGGAGGCTGAGGCAGGCGGATCACGATGTCAGGAGATCGAGACCATC CTGGCTAACACGGTGAAATCCTGTCTCTACTAAAAATAACAAAAAATTAGCCGGGGTGTG GTGGCGGACGCCTGTAGTCCGAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGTGAACC CAGGAGGCGGAGCTTGCAGTGAGCTGAGATCGCGCCACTGCCCTCCAGCCTGGGCGACAG AGCGAGACTCCGTCTCAAAAAAAAAAAGAAAAGAAAAAAAAAAGAAATACATGCCCCTAG ATTAAACTATCCCTTGTCCTTTTGCACTCATCCACAAGTCTCTTTTCATCAGTGATTTTA GGATCTGACTCGTTGTCTTTTTCTCTACTTCAACTACTTTTATCATTCTTAATTATTTCT GTATCGTCAATCAATCCAGTACCTGCCTCTTAGTTTCAAAATCACTTACTCTTGCTTAGC TATTACCAGTAATCATAACCACTGTCAAATCTCAATTGCAAGCATATTACTCTTTAACTA 17Evotec International GmbH EVO28777PCTCCACCTCCTATCTTTAAACCATGTTTTGTCTGTTTTTTTATTCCAGCCATTCTTTAAACC CTACTGTGGGGCCCAAGCATTTCCTTTATACGCATTCTTCCTTTCTTCTACTGCTTATTT TCTGTAATCCGTCATCATAATCACTCCATTGCATTCTTCAACGTGTTTCCCCTCTCTCCC TCCATCATACTTGAATGACAAAAATCTCAACCCTGGTTAAACCACATCTTGGCCTTGTCC ATTCCTGTACCAGAGTAGCTGGACGTGGCTAAAAAATAACATAAAACATGATGATTGGTT TTACTTTTTTCTTAAATGATCTATCCATCCATTCACCCATCCATCTATCAAAGTGACTAG GCCTATTTCTGAAGCCCAGGCTGGAGTGCAGCAGCATAATCACAGCTCATTGCAGCTCCA AACTCCTGGGCTCAAGTGATTCTCTTGCCTTAGCCTGTTGAGTAGCTGGGACTACAGGCT TGTGCTACCACACCTAGCTAAGGTTTTACTTTAAATTTATTATAATCACAAAATTCAGAT GAGCCTTTAGTGCTGTCTGATATTTCTACTATGTTTTCTTAGTGATGTACCACCCTCCAA GGTGTTTATAAAAAATTATGTACCACTCTCCAAGAAGTTTATAAAAAATAATGTGCCACC CTCCAAGGTGACTAATTTCACAGCTTATGTCTTTAAACCTTTAAGCACTTTCCTCTCCCT TACACACCTTCCTTGTGGCTTTCCGTTACATTCTGCTGAGAACATAGAAGCAATTAAAAT TATGTTCTTTCTACCAGCAAATTTATCAATTTGCTTATATCTTCACCTGTGCTTTGAGCC TATTTAAATAGATGAATGGTCCCCTACCTCTAACCAAAACCAGTCCCTCACTTGTGGGCT GGATCCCAGCTCTTCTCACCTACTCAAGATGTTCCTGCTTTCATCTCTCCACTCTCTTAT ATAATCAGTTCCCCCCCCCTTTTTTTGTAATATTCCTATAAGCAGTAAAATAAGCTTTTT ATTTCCATTGATTAAAAATAAAAATCCTCTCTTAATTCCATGAAACTCCAGCTGCCTCCC CATTTTTATTTTTTCCTTAGGATTGTCTCTAGTGTGCCTTCTCCTTTTCTTGAACTCTGC CTCCTGGGTTCAAGCGATTCTCCTGCCTCAACCTCCCGAGTAGCTGGGATTACAGGCGTG CACCACCATGACCGGCTAATTTTTTTTTTTTTTTTTTGAGATGGAGTTTCCCTCTTGTTG CTCCGGCTGGAGTGCAATGGCGTGATCTCGGCTCACCGTAACTTCTGCCTCCTGGGTTCA AGCGATTTTCTTGCCTCAGCCTCCCGAGTAGCTGGATTTACAGGCATGTGCCACCATGCC TGGCTAATTTTGTATTTTAGTAGAGATGGAAGGGGTTTCTCCATGTTTGTTAGGCTGGTC TCCAACTCCTGACCTCAGGTGAGCCGCCCACCTCGGCCCCCTAAAGTGCTGGGATTACAG GCATGAGCCACTGCGCCTGGCCCCGGCTAAATTTTTTTTTTTTTTTTTTGTATTTTTAGT AGAGACAGGGTTTCACCATATTGGCCAGGTTGGTCTCGAATTCCTGGCCTCGAGTGATCC ACCTGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGTCACCTTGCCTAGCCATC TTTTAGTAATGGTATTTGGAGATCACAATTTGAGTGCTGGCATGCTTATTGCTGCTGGGT TTGTTATGTAGTTATTGTGAATTCACATTTAGGAATATAGGGTTTTTAATTCTTTGATTT TAGATACTTGTATCTTTTTTCTTTTATATTTAAAACCTTGGTTCCTGATGATATCCCTTC TTAGAAACCCTGTCTACCTTTGGCCTTCAGCCCACCATGCTGTGGTTTTCCTAACTTGCT GCCTGCACTTTTCAGATTCCTTTCATGGATCTTAAATATCATCTGTAAATAAGATCTATG TGTCAATAATTACCAAACTTTTATCTTTAGTCTTGACATCTACCCTGAACACCTAGCTTT GACTAACTCCTAGCTTTGGCATCTCCACTTGGAAATCCAAAAAGTGTTTCAAACTGAACA TGTCTATGAAAGACTTATTTTTTTCTCTCTATCCATGCTATCCATCAGGTTTTCCATTTC CATAAGGGTGACTCTTGTACTCTGGTTCCTATATATTATACCGACAGAGCAGCCCAGAGT GCTTCTTAACCAGTGTAAGGCCTGTTATGTCCCACCCTCACTCTTTGTCCTTCAGTGGCT TCCCAGCACACTTAGAATAAAATCTGAAGTCTTAGGCCGGGCTTGGTGGCTCATGCCTGC AATCCCAGCACTTTGGGAGGATGAGGGGGCAGATCACTTGAGGTCAGGAGTTGATGAGAC CAGCCTGGCCAACATGGTGAAACCCTGTCTCTACCAAAAAATACAAAAATTAACTGGGTG TGGTGTTGTGCACCTGTAGTCCCAGCTACTCGGGAGGCTGAGATAGGAGAATCACTTGAA CCCGGGAGGCAGAGGTTACAGCGAGCCAAGATCATACCACTGCACTCCAGCCTGGGTGAC AGAACGAGACTCTCAAAAAAAAATTAAAAAAAAAAAATATGTGAAGTCTTGAATAAAACC CAAGATCTTTACCATGGCCCCTGAACAGGGCAGAGTATCCATTCTTCAGACACTCTTCAT AGAATACCATGGTGAGCTGGCATATTTATTATACAATACAGAAACAATTTTACTGGCAGA AAACACATTAAACCGTCTAAACTCTGAATACAGTTGTCCTCATAAAAAATGTTCAACATA CTATTTTGAGGTTTTCCATTAATAGTTCTTATAATCTTTGTCCCATTATGTGTTAATCCA ACAAAGGATATCCAATAACAAACACCAAAGTTTAAGAAAAATGTGCTAGGCGCGGTGGCT CACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGTGGGCAGATCACCTGAGGTCAGGAG TTCGAGACCAGCCCAGCCAACATGGTGAAACCCTGCCTCTCCTAAAAATACAAACATTAA CTGGGTGTGGTGGTGGGTGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATC GCTTGAACCTCCTGGGAGGCAGAGGTTGCAGTGAGCTAATATTGCACCACTGCACTCCAG CCTGGGTGACAGAGTGAGACTCCATCTCAAATTAAAAAAAAAAAAAAATTAATGATAGAG AAACTTAAATCAGTTAGATTGTTTTAGGTATAGCCCATCCTTGGTTTTTGTGTGTAGCAT CTAGCTTGGGGAAACCCTGGATTTCTGGAATCATATTTAGACACAGTCACACTAGACTAA 18Evotec International GmbH EVO28777PCTTGTAATTCTTTTGGGATGCAAACCACACGTTTGACACCTTAAATAGCTTTTAGGTATTTG GCTTCCCAGCCCCTATTTTTAGTTACAAGGGGTGTACATGTGTGGGTCAGGGTGGGGGTA GCTCTTTCCGCAGATGATTAGTTTTAGCCATGTTACTAGTTATTGCACACATTATCTGTG TCCTCACAGCAGCCCTGTGAGTAAGTGTATTAGGGTTCTCTAGAGGGACAGAACTAATAA GGTAGATGTATATATGAAGGGTAATGTATTAAGGAGTATCGACTCGTATGATCACAAGGT GAAGTCCCACAATAGGCTCTCTGCAGGCTGAGGAACCAGGAAGCCAGTCCAAGTCCCAAA ACCTCAAAAGTAGGGAAGCTGACAGTGCAGCCTTCAGTCTGTGGCAAAAGGCCTGAGAGC CCCTGGCAAACCACTGGTGTAAGTTCAAGAGTCCAAAAGATGAAGAACTTGGAGTCTGAT GTTTGAGGGCAGGAAGCATCCAGCATGGGAGAAAGATGAAGGCTCAGCAAGTCTAGTACT TCCACACTCTTATTTCTGCCTGCTTTATTCTAGCTGAGCTGGCAGCTGATTAGATGGTGA CCACCCAGTTTGAGGGTGGGTCTACCTCTCCCAGTTCACTGGCTTAAATGTTAATCTCCT TTGGCAACACCCTCGCAGACACACCCAGAAACAATAATTTGTAGCCTTCAATCCAATCAA GTTGATAATATTAACCATCACAGGAAGGTACTAGTATCATATGTTTAACAGTAGAAACCA AGACAAATGCAGCTAGGAAGTGGGAGAACTGGGATCAGATGCAGGCAGTCTGATTCTAAA TCAGTTGCTGTTACCCACTCTGACAACAGTAAGTGAGTAGCCTGCTCAGTCAAGTACTAT ATTAGTAGGGCCCTTTACAGACATATTTATTTCTCACAGTCACTCAATGAGACGGCTCTT CCAGTCTTACAATGGAGAAAGTGAGGCTCAGAGACTTTAAGTAACTTACCTTAGACGACT TTACTAGTAAGTATAAGAATCATTATTTGGACTAAAGTCTTTCTGAATCCTCAGCTTGTA TTTTTTTCCAGTGTTCTGTGCTGCCTTTTTATCTACTAGTGTTTTACATCAATTTTGAAT CTCTTTACTAACTGGTTAGGTTGATTTTTGCCTTTTTTTTTTAGGTTATTCTATATTTGT CGTTAAGGGTGATCTGCCAGATTGCGAAGCTGACCAACTCCTGCAGATGATTAGGGTCCA ACAGATGCATCGACCAAAACTTATTGGAGAAGAATTAGCACAACTAAAAGAGCAAAGGTA AAAATGAGGCCTGCAGTATGGAATATATGGTAGTATTTCATTATGAGAATTAAATTTTCA TGCTTAGATTGAATATGTGGTCCTTGTGTTGTTGGCGACTCTATTTTGGACCTTATATTT TAGTGAAGTTTATTAGTTTAAACTTGAATCAACTCTTTGAAATACTTAAATATATTAACT TAGTTAGCTGGTATGGTATATTCCTAGCACTTCGGGAGGCTGAGGCAGGCTGATTGCTTC AACCCAGGAGTTCGAGACCAGCCTGGGCAACATGGCAAAACCTCATCTCTACAAATAGTA CAAAAATTAGCCAGATGTGGTGGTGTATGCCTATAGTCCCAGCTACTTGGGAGGCAGAGG AAGAAGGATCACCTGAAACTGGGGAGGTAGAGACTACAGTGAGCCATAATCACACTACCG CACTCCAGCCTGGTCGAGAGAGTCAGACCCTGTCTCAAAAAAAAAAAAAAAAAGAAACGG AAAAAAAAAACTTAGTTGGATTCAAATTGCAACACAATCATTATATTACTAGAGCTTATT TGCCAGAAAACATTTTAAGTTTTGACTTACTTAAAGCCTTTACATTACAAATGCCTTTAT GTTATGTCTAAAATAGAAGATTGGTTGCAGTTATTACCAGTGCTTTTGTTCTTTAGAGTC CATAAAACAGACCTGGAACGAGTGTTAGAAGCAAATGATGGCTCAGGAATGTTAGACGAA GATGAGGAGGATTTGCAGAGGGCTCTGGCACTAAGTCGCCAAGAAATTGACATGGAAGAT GAGGAAGCAGATCTCCGCAGGGCTATTCAGCTAAGTATGCAAGGTAAAGACATTCTGATG TGTGTTGTATTCATTGCTGAAGAATTGATTCCAATTATTCTTAGATTTCATGGAAGTTAA TGTACTCTTAGAGGTGTTTTGACAATTACTGCAGAAGCAATAGCTATATAGTGGGCTTTC CCTTTAGATTTCTTATAATGGAAATCACTTTTTACAACCTATATTTTATTAGGAGTAGTT ATATTTTTACTCCTGGTTATTTTATTTGGTTTCAACACTGTACTAACACAATAGTAAATT GTGGTTTTAATCTTTGTGGGTATCAGTTGACCCTTATCCAAATCAGCTGTTACATAAATA TGTGCCATTAGACACTATGGAAGGGCCTGGACAGGGAATATAAACTGATTTTACAAAAAC CCAACATTTATTGGCTATGCAACTTAAACCGTAAGCCCACTTTGGTGGGCCCAGTTTTTT AGTGATATAAACTATCAATAGAGAAAAGCGAAAACATATCCCCTAGACAATCTAGGCAAA GAAAAATGTTAAGACATAGCTCAAAGTAGCTTAATTAAAAGTTTGAAGTGGGTTTTTTGT TTTATTTTTTTCTAACTCATATGTATTTGCTTCTACTTTCTAATGAAATTATTTATCAGT TGATTTCCTTAGATATCTAAATAAAATTGAAATTTCATTAATGGGAAGATTATTTTTATC CTGAACTTTTCTTGCCTCTATGCATGCCTCTGAGTACTCCATATGGTGTGCAATCCCATT TTTGATTAATAGAGTCCTGCTGGATTAGCAGGGACAGAAATCAGCTTTAGATTTCTTTCT TTTTTTTTTTTCTTTCTTTTTTTTTTTTTTTTTTTTTGAGTCAGAGTCTCACTGTCGCCC AGCCTGGAGTGCAGTGATCTTGGCTCACTGCAACCCCTGCCTCCGAGGTTCAAGCGATTC TCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGGCGCCTACCACCACGCCCAGCTAAT TTTTTGTACTTTTAGTAGAGATAGGGTTTTGCCCTTTTGGCCAGGCTGGTCTTGAACTCC TGACCTCAGGTGATCCACCTGCCTTGGCCTCCCAAAGTGCTGGGATTACATGTGTGAGCC ACCACGCCCAGCCAGAAGAGTAGAATATTCTTAAAGAGAAAACGTTTTAAAGGCTTACTC AAATGAGTATAAACAAACATATTGTTGCTTGAATTGGTAAATACAGTGATTGGTTTTTGT 19Evotec International GmbH EVO28777PCTTGTGTTGTGTTTTGTTTTCAGGTAGTTCCAGAAACATATCTCAAGATATGACACAGACAT CAGGTACAAATCTTACTTCAGAAGAGCTTCGGAAGAGACGAGAAGCCTACTTTGAAAAGT AAAGTAGTTGGTACAAGTTAAAGTAGCATGTTTAATATTTGCTTTGGCTATTTTGTCTAT TTGTAAATGGTTACTGCCTGAATCCTGTGAATATTTGAATGTATTTTTTAAAAATTTACA GCAAATAGGACGGGCACGGTGGCTTACGCCTGTGATGCTAGCAGTTTGGGAGGCCAAGGC GGGCAGATTGCCTGAGGTCAGGAGTTCGAGACCAGCCTGGGCAACACAGTGAAACCCCAT CTCTACTAAAAATACAAAAGAATCAGCTGGGCATGGAAGCGTGCGCCTGTAGTCCCAGCT GCTTGGGAGGCTGAGCCAGGAGAATTGCTTGAACCCGGGACGTGGAGGTTGCAGTGAGCC GAGATCGCACCACTGCCCTCCAGACTGGGTGACAGAGTGAGACTCCGTCTCCAAAAATAT ATGTATATATATATAAATAAAAATAAAAATTTACGGCAAATAACATGAAACAAAAAAACC TTGCCCCAATACTGGATAAATTTTTTAAACTGAGTGAAGGAAACCTTATAAAATTTCATT TATTAAAAGAAAAATGAAATTAGGACAAGACAAGAAGAATGCCAATTGATCCTTTGGATG TACTTCTTGCTTACCTGATTAACCCTGCAAAATTCCTCTACCAATCAGTACGAAAAACAG CTTTGGAGGTATGGGAGCGCATTCCCAAATAGACGTGGTAGTTCATTTAGCTGCTCATGG CCGCTTCAGGCAGTCCTGTAAGCCTGTTAGCATCAGGGGAATGGATGCAAACCATAAATC TGGATCAACTCCTAAAACCTTACCTTGTGCCCAGCCTTGTAAGTGCTTGCTAAATAGGAA TTCCACCATATGAAAATACATTCTTTTCAAGTAACTATCATTCAGACTTTTGTCCCCCAC TTTTTTTTTTTAAAGAAAAATAAAAGGCTGGGCACGGTGGCTTACGTCTGTAATCCCACC ATTTTAGGAGGCCAAGGCAGGTGGATCACCTGAGGTCAGGAATTCAAGACCAGCCTGACC AACATGGTGAAACCTCATCTCTACTAAAAATACAAAAATTAGCCGGGCATGGTGGTGGGT GCCTGTAATCCCAGCTACTTGGGAGGCTCAGACAGGAGAATCGCTTGAATCTGGGAGGCA GAAGTTGCAGTGAGCTGAGATAACGCCATTGCACTCCAGCCTGGGGGACAAGAGCGAGAC TTCGTCTCAAAAAAAAAGAGAAAGAAAACTTCATGTTAAAGATTACAAGATAAATAATCA GACCCACTGATCCTAGGTCAGAAAACAGAGTCATAGCTCAATCTGACTTACTATTTGCTG TATTTCATCCATTCTGAGATGCACATAGTTTCACATTTCAATGTCTCTGAAATTGAGAAG CATCTTACAGTCATAATTGACAGTATATTAGCAGCACCTATAAATATTGGCTCATTTTAC ATTTGATGGTATAATGAAGAAAATATTTACCTTTTTTTCTGTTTTGTTTTTAAGTCACAA CTCAGAAGTAGATGAAGGAAAATTCTGATCAGCTGACATCCTCTTAATGTGAGATATTTC TAGTCTTTATTCAGTATAGATTAATGGCTAATTATATGTTAAATTTCAAAGTAGTGCTTA TTAGTGCTTTTTACTTTTAAGTTTCAAAATTAACTTTTTTATTATAATAAACTCCAAATT TATACAAAAGTAGAAAAACTAGCATACTCCTGTTTATGACCCAGATTCAACAAATACTAG CACACGGCCAATCTTGCTTTTTTTTTTTTTTTTTTTTGAGATGGAGTCTTGCTCTGTTGC CCAGGCTGGAGTGCAATGGCACAATTTCTGCTCACTGCAACCTCTGCCTCCTGAGTTCAA GCGATTCTCCCACTTCAGCCTCCCAAGTAGCTGGGATTACAGGTACACACCACCATGCCT GGCTAATTCTTGTATTTTTAGTAGACACGGGATTTCACCATGTCGTCCAGGCTGGCCTTA AACTCCTGACCTCAAGTGATCCACCTGCCTCGGCCTCCCAGAGTGCTGGGATTACAGGCA TGAGCCACTGAGCCCGGCCCAATCTCGTTTTATAATACTCCCATCTCCCATTCTTTCCAC TGTCCCACCTGCAAGTTTGGATTATTTTGTAACAAATCTCAATCATCATATTATTCTATA ACCATTTTAATATGTGTCTCTAAAATATATTAGCTTTATTTTTAACATAGTTAAATGCTA TTGTCATAAAATAATAATCATAATAATTAATTGTAATTCTATATCATCAATTATCTAGTT AATGTAAAAAATAAATCTAAGGCCAGGCGCGGTGGCTCACACCTGTAATCCCAGCACTTT GGGAGGCTGAGGTGGGCAGATCACCTGAGATCAGGAGTTCAAGACCAGCCTGACCAACAT GGAGAAACCCCATCTCTACTAAAAATACAAAAAATTAGCCAGGCGTGGTGGCGCATGCTT GTAATCCCAGCTACTTGAGAGGCTGAGGCAGGAGAATCACTTGAACCCGGGAGGCGAGGT TGCGGTGAGCCGAGATCGTGCCATTGCACTCTAGCCTGGGCAAAAAGAGTGAAACTCCAT CTCAAATAAATAAATAAATAAATAATAAAAAATAACTTAAATCTACTTAATTAGAAAAAC TAACATTCTAAAAATTTTATTTTAAGAAATATCAAAATTGGCTGGGCACGGTGGCTCACG CCTCTAATCCCTGCACTTTGGAAGGCTGAGGTGGGCGGATCACCTGAGGTCAGGAGGGTC AGGAGTACAAGACCAGCCTGGCCAACATGGCGAAACCCTGTCTCCACTAAAAATACAAAA ATTAGCCAGGCATGATGATGGGCACCTGTAATCCCAGCTACTCAGGAGGCTGAGACAGAA GAATCGCTTGAACCCAGGAGGTAGAGGTTGCAGTGAGCTGAGATCACCCCACTGCACTCC AGCCTGGGTGACAGAGTGAAACTCCGCCTCAAAAAAAAAAAAAAGAGAAAAGAAATATAG AAATTAAAGCATACATGGCCAGGCGTAGTGGCTCATGTCTGTAATCCCAGCACTTTGGGA GGCTGAGGCAGGCAGATCACTTGAGGCCATGAGTTCAAGACCAACCTGGCCAACATGGCG AAAGCCTGTCTCTACTAAAAATACAAAAAAATTAGTTGGGCATGGTGGTGCACACCTGTA ATCACAGCTACTTTGGAGGCTGAGGCAGGAGAATCGTTTGAACCCAGAGGTGGAGGTTGC 20Evotec International GmbH EVO28777PCTAGTGAGCCGAGATTGTGCCACTGCACTCTATCCTGGGTGACAGAGCGAGATACTGTCTCA AAAAGAAAAAAAAAAGGCTGGGCGCGGTAGTTCATGCCTGCAATCCCAGCACTTTGGGAG GCCGAGGCAGGCAGATTACGAAGTCAGGAGATGGAGACCATCCTGGCTAATACAGTGAAA CCCCGTCTCTACTAAAAAATACACAAAAATTAGCTGGGTGTGGTGGCAGGCACCTGTAGT CCCAGCTACTCTGGAGGCTGAGGCAGGAGAATGGCATGAACCCGGGAGGTGGAGCTTGCA GTGAGCAGAGATCACACCACTGCACTCCAGTCTGGGCGACAGAGCGAGGCTCTGTCTCAA AAAAAAAAAAGAAAGCATACTCTCACCTCCTTCAGTGACTGATGTTAGTATTTTGGCACA TTCTTTTTCTGTGACATATACACACTTACCTTGTAAGTGTTGTACTCATTTCCTATGACA GTAAATAGTCTTTGTAACAGGCTGCATGATATTTCATAAAATGAATGGATGTGGCATAAT TTATATGTGAGCCTTTTGAATTCTGCTATTATAATTAATATTGCAATGAACAATTCTTAT ATTGCCTCTACACCTCAAATGTCTTATCATTTCTTCTAGTTTTTCTGAGGATGTCAGATT ATTGGGTTAAAGGATATGAACATTTTTAAGGCCTTGGAACAGATTTCTAAATTGCTTTCC AGAATAATTCCCATGTGATACTTTCACCATGTTTATTTCAGACTTTTTTTTTTTTTTTTT TTTGAGACGAAATCTCACTCTGTCACCCAGGCTGGAGTGTAGTGGCATGATCTCGGCTCA CTGCAACCTCCGCCTCCTGAGTTTAAGCGATTATTCTGCCTCAGCCTCCCAAGTAGCTGC GGTTACAGGCAAGTGCCTCCATGCCTGGCTAATTTTTGTGTCTTTTGTAGACATGGGGTT TCACCATGTTGCCCAGGCTGGTTTCGAACTCCTGAGCTCAGGCAATCTGCCTACCTCGGC CTCCCAAAGTTCTGGGATTACAGGCGTGCACCACCGCGCCCAGCCATCAGAGTCTTTTTT GTCAAAATAAAATGGTCTAAAGACATACATCATAGAGAAACTATAATACAAAATTTACAG GTATATCTAAGAAAAGAAAAGTATATTTAAAGCATAAAAATAAACTGCTCTTTTACTTAA AATTTTTTAAAAACTGGATTAAAAATATGAAACTTCCAACAAATTGAGCTTTTTTTTTTT TTTTTTTCTTTTTTGAGACGAGGTCTCGCTTTTGTCACCCAGTCTGGAGTGCAGTGGCGC GATCTCGGCTCACTGCAACCTCCACCTCCCTGGTTCAAGCAATTCCCCTGCCTCAGCCTC CCAAGTAGCTGGGATTACAGGCGCATGCCACCACGTCGGGCTAATTTTTTTGTATTTTTA GTAGAGAGGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGATCTCAGGCAAT CTGCCAGCCTGGGTCTCCCAACATGCTGGGATTACAGGCATGAGCCACTGCACTCGGCCT GAACTTTTTATAGTAGTAACGATAATTCAGTAATGTCCAATAATGACTAAGTAAGTTATA ACAAGTACAATGTCAGCAATAACTAGTGCTTTTTAGTAAACAGGGTCAGGCAACCTTGTA CCCTTTTAAAAATGTTCGAATATCGATATACCTCCTTCCTACTTGGTGGAGGATTGATTG AGGAGGAAAGTGTGCAGTGATGGTTACCAGCTTCAGCCTCTTGGCTTGACTTTGCAAATA CTGGTGAGAATTTGGAAAGAGCTTGAGAATATCTTACATAGTCACATGTTGCTGAGAAGA GTTAAGAACTAACTTCTTGATGTTCATTTTTAACAATGGCTTGCATTCAAAACCTTGTAG AGCTCATTAGTAGGAGCTAAGAAGCTAATATTTGCCTTTCACTAAAATTCCTGATTACTT AGCCTAGGTAGTTCGTTGTCTCTCTAGGTTCTGTCTTTGGGAGCTTGGGTCTAAGGTTAT CAAGCTAACTCTTTCTTCCCTCTCACCCTTCCCAAATTGACCCTGGTGCTGATTTGTTAT TCATACGATTTTCTAGTTTTTCTTTTCCCTTTTTGAGTATTTGAAGCTTCATACTGAATA TAGTAATCATAGTATTCATGCATAAAGAAAATCATAAAGTAATTGCATAAATGCATAAAG TAATCATAGTTTTCATGCATTAAAAAAACTAGTTTTGGCTGGGCGCTATGGCTCACGCTT GTAATCCCAGCACTTTCGGAGGCCAAGGCAGGCGAATCATCTGAGGTCAGGAGTTCGAGA CTAGCCTGGCCAACATGGCGAAACCTCTTCTCTACTAAAAATACAAAAAAATTAGCCGAG TATGGTGGCGGGCGCCTGTAATCCTAGCTATTTGGCAGGCTGAGGCAGGAGAATCACTTG AACCTGGGAGGCAGAGGTTGCAGTGAGCCGAGGTTGTGCCATTGCACTACAGCCTAGGCG ACAAGAGCAAGACTCCATCTCAAAAAAAAAAAAAAAAAAAAAAAAACTCCCTATTACAGA TTCATAATTTATGAGTCATTAAATAATATTTTCAAGCCATGACATTTTTTCCAGCAGTAG TCTCTAAATCTGTTTTACCATCATAAAACCCCAAGCAAAACTCTACTACATCAGCTGTGT CACTGTAAAACCTGCCTTAACTCACAGAAGCATGAAATTAAGCAATGTGTGTGAAACTAT TTTATAAACTGTAAAGTATTCCATACATACATGTTGGCAGTTATTAATGTCTTCTCTAGG TGTGGCTTTGAAATGGATGCAGATGCTTTCTGTTACAAAAAACATAAGTTGCAAATGTTC TATAACAAGGAGAGACACAAATATCTTCATGGACATGGATTGCTATGAGTGTTTGATTGC CTAATACTTGAGCCACCACTTCAGTGATATGGTATAATTTATCAAACAGTGTTGAGAAAC AGAAACTACTGGGGATGTTTTAAAGAGGAAAATACTTAATATAGAAATTAGGGGTTTACA TAATCTTAAGAAAGGATGAAGGTGCAGCTCTTAGCCAGGCCTCCACAGTACCACAAACCA ACTTGCAGGAAGAGCTGTAACCACTGCCCCAGTTGGGACAATGGGTAATGAGGATATTAA ATTTAAGAACATACTGCTATAGCAATGATCCTTGGCATAGAAAGCTGCCACCACAATTGC CTAGAGATGGGAACATGAAGTCTGGCCCCCATTGCAACAGCAGTGAAGCAGAATTTTGGG ACTGGCATCTCCCAAATGGCTTTGCTTGCCACCAGAGAACAACCAAAGTGGAGGGAGATG 21Evotec International GmbH EVO28777PCTGCTAGGCCTCATTTCTGCCTATTTTATTTTATTTTTTGAGACGGAGTCTTGTCTGTCGCC CAGGCTGGAGTGCAGTAGTGTGATCTCGGCTCACTGCAGCCTCCGCCTCCCAGCTTCAAA CAATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGCACCCGCCACTGTGCCCA GCCAATTTTCTTATTTTTAGTAGAGGTGGGGTTTTGCCACGTTGGCCAGGCTGGTCTTGA ACTCCTGACCTCAGGTGATCTGCCCGCCTCAGCCTCCCAAAGTGTTGTGATTACAGGTAT GAGCCACCATGCCTGGCCCATTTCTCCCTTTTTTTTTTTTTTTTTTTTTTGAGGTGGAGT CTCACTCTGTTGCCCAGACTGGAGTGCAGTGGTGCAATCTTGGCGCATTGCAACCTCTGC CTCCCAGTTTCAAGCAATTCTTCTGCTTCAGCCTCCTGAGTAGCTGGGACTACAGGTGTG TAGCACCACACCTGGCTAATTTTTGTTTTTGTTTTGTTTTTTTTGAGACAGAGTCTCACT CTGTCACCCAGGCTGGAGTGTAGTGGCATGATCTGGGCTCACTACAACCTCCGCCTCCCG GGTTCAAGCAATTCTCCTGCCTCAGCCTCCAGAGTAGCTGGGATTACAGGTGTGCGCCAA CACACCTGGCTAATTTTTTTGTATTTTTAATAGAGATGGGGTTTCACCATGTTGGCCAGG CTGGTCTCGAACTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATT ACAGGCATGAGCCACCGTGCCCAGACAAGGTTTGTATTTTTAGTAGAGACAGTTTTGCCA TGTTGGCCAGGCTGGTCTTGAACTCCTCACCTCAGGTGATCCGCCTGCCTTGGCCTCCCA AAGTGCTGGGATTACAGGCGCAAGCCACTGTGCCTGACCCGTTTCTGCTTTTTAAAGCTC ATGTGAGCACTTAATTTGTAACCAGAATCCTACTTGTAAAATAATCTAAGACATGTAGCT TTTAGCTTTGTAACCTCTATAATATTGATGGCACAGTGGGAGTGGATGCTGAGTACCACT TGAACATGTTCCACCTCAGTGTCTTCACAGCTGGAAGGTGTCTACATTGTTTCAAGGTGG ACAATTGATTTACTTCTCATTTTTCATAAACTAAAAGTAGAATAAAGGCTATTCCTCTAA AATTGCTATCTCACCTGTCACTCCCTTGCATTCTCACATACCTTCTTGAGTGGAGGGGCA GAGGGCATGGAGTGATAGCAGATGTGCCAGGAATTCTCCATAACTCAGTCCGTCCCTCTT GTGCTATGTTGCAGCATCAGGATTTGCTAATGGGAGGATACTGCCCTTACGTGCATCATT AGCCATGCACACTAAGGTCTTACACCTACACACAGGTCAGTATTCTGGCTCAGAGACCAA CAGGGAGAAATTGCAGTTCTCATTAGTTGAACTTTCTTTATTGTTCACAGTTTTAAAACA CAAAATTGAGAGGAACTCTATAAAAAATGTGCCATTCTATTAATAATTGTTGCTGGTAAT TTAAAAATCCTTGTTCCTTTTCAAATTCTTATATACCTTTTTTTTTTAAACACTTGATCT TAGCCAAAAGACCGAGAAGCAATCTTTTTTTTTTTTTTTTTTTTTTTTAACCTATAGCTT CTCACTGAGATTGTCAGCTGTTTGTAAGTTTTGGTTTTTGGTTTTCTGTGTTTGTATTTA CATATATGAAATACAGATTGAGTATCCCTTATCCAAAATGCTTAAGACTGGAAGTGTTTT AGATTTGGGGTTTTTTAGGATTTGTGAATATTTGCACTATACTTACCAGTTAAGCATTCC AAATCCAAAATTTCAAATCTGAAGTGTTCCACTGAGCACCTCTTTTGAGTATCATGTTGG TGCTCAAAAAGTTTCTGATTTTGGAGCATTTGGATTTCTGATTCTCGGATTTAGGATGCT TGACCTGTAATTTCAGATTTACATAAAAGCAGAAATAGTACACAGAGCTCCTTATATCCT TCACCCAGATTCCCCAATTATTGGCCTTTCTGAACCATTTGGGAATAATATGCAGATATG ATTTTCCATTATGTCTCAGTTGTTCAGTGTATATTTTCTAAGTACAAGAATATATTCCTA CATATTTACATGATAACCGTCATGTTTAAACATTTTAAAATGGGGATTTGTATTACATTG TTTCTCTTTTTGAAAAAATTACAGAGGAGCTTAATGCAATCAGTATTACTTAAAATCTGA TAATGTGTGTTAAATAGTAGTTTTCATTTATTTCATTTATCAGGTGTTCAGTGAATGCTT ACTATGTAACAGCACAGTTATCAGCACTGGGGAAATAGATGAGTAAGATAAGATTTGCAC TTTCATTAGCTTACATGCCATAAAGAGGGAAATAAAGAGAACACCAGATGATGATAAGTT TATGCTGAGAATTAAAATGAAGTGATGAAATAATGGGAATGTCAGGTGGCTACTTTTGGT GGGATGGTCAGGAAAGGCATCTCTGGGGAGATAAATTTTAAGCTCAGACCTGAGTGAAAA GAATGAGCCAGCCATGGAAACATTATGTTAACTCACATGGTAGTTTGAAATGCTTTATCT GATCAAAGGTACTTATTTTTGGTGACTTTCAACAATATTAAGGGTCTATAAACCAACACT CATTTGCATAAGAATAACTACCAGTGAATCTTTTTGTATGATAGGTTTTTTGTTTGTTGT TTTTTTGAGACAGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGCGATCTTGGC TCACTGCAACCTCTACCTCCCCGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAAAGTAG CTGGGATTACAGGTGCCTGCCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATGG GGTTTCACCGTGTTGTCCAGGCTCGTGTCAAACTTCTGACCTCAAGCCATCCACCCGCCT CGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACTCCTGGCCATGATAGGTTA TTTTGTGATGAAAATACCTACCTCTTAATTTGTCTGATAAATTTAAATTTTATGTCTAGA TTTCCTAAGATCAGCACTTCCATATTTTAAAGTAATCTGTATCAGACTAACTGCTCTTGC ATTCTTTTAATACCAGTGACTACTTTGATTCGTGAAACAATGTATTTTCCTTATGAATAG TTTTTCTCATGGTGTATTTATTCTTTTAAGTTTTGTTTTTTAAATATACTTCACTTTTGA ATGTTTCAGACAGCAGCAAAAGCAGCAACAGCAGCAGCAGCAGCAGCAGCAGGGGGACCT 22Evotec International GmbH EVO28777PCTATCAGGACAGAGTTCACATCCATGTGAAAGGCCAGCCACCAGTTCAGGAGCACTTGGGAG TGATCTAGGTAAGGCCTGCTCACCATTCATCATGTTCGCTACCTTCACACTTTATCTGAC ATACGAGCTCCATGTGATTTTTGCTTTACATTATTCTTCATTCCCTCTTTAATCATATTA AGAATCTTAAGTAAATTTGTAATCTACTAAATTTCCCTGGATTAAGGAGCAGTTACCAAA AGAAAAAAAAAAAAAAAAGCTAGATGTGGTGGCTCACATCTGTAATCCCAGCACTTTGGG AAACCAAGGCAGGAGAGGATTGCTAGAACATTTAATGAATACTTTAACATAATAATTTAA ACTTCACAGTAATTTGTACAGTCTCCAAAAATTCCTTAGACATCATGGATATTTTTCTTT TTTTGAGATGGAGTCTTGCTCTGTCACCCAGGCTGGAGTGCAGTGTCGCGATCTCGGCTC ACTGCAAGCTCTGCTTCCTGGGTTCATGGCATTCTCCTGCCTCAGCCTCCTGAGTAGCTG GGACTACAGGCGCCCGCCACATCGCCTGGCTAATTTTTTGTATTTTTAGTAGAGACAGGG TTTCACCATGTTAGCCAGGATGGTCTCAATCTCCTGACCTCATGATCCGCCCGCCTCGGC CTCCCAAAGTGCTGGGATTACAGGCGTGAGCCATCACGTCCGGCCAGAAATCATGAATAT TAGTAGGTGAAAAATAAACACATTTTACCACCTGGAAAATGAAAAATACTTGAGTATAAT CTAAATAACAATGGGAAGTGCAGAGTTACTTTCCAGGTCTCGGTTTAAATATGTCTTAAA CTTTGGCCAATTAGTAGTAGAAGTTGAGAGAAAAAGTAACTATCTGACAAAGAAATTATA AGCAGAATATATAAAGAACTCTTAAAACTGAATAATCAGAAAACAACTCAATAAAAAGGT GAAGGATTTGAAAAGATATTTCACCAAATAAGACATAGGGATGACAAATAAGCACATGAA AAGACTCTCAGCATCACTAGTCACAGGGAAATGCACGATAAAACCACAGTGAGACACCAT GGCACCCCTGTAGGTATGGCTTTAATGAAGAAATAAAACTGACAATACCAAGTGTTGGCA AGGATCCAAGCAGCTGAGACTCATATACTGTTAATGGGAATGTAAAAGTGTACAGCTTTG GAAAACAGTTTGGCATTTTTTTGATAAATGTATACTTAGCCATGTGATCCAGCAGTCCCA ATCATGTATATATAACCAAAAGAAAAGAAAACTTAGGTTCACATAAAAACTTATATCAAA TGCTTATAGCTGACCAGGCATGGTGGCCCATGCCTATAATCCCAGCACTTTGGGAGGCCG AGGTTGGCAGATACCTGAAGTCAAGTGTTCGAGACCAGCCTGGCCAACATGGCAAAACCC TGTCTCTACTTAAAATACAAAAATTAGCCAGGCGTGATGGCAGGCACCTGTAGTCCAGCT ATTCAGGAGGCTGAGGCAGGAGAATCACGTGAACCCGGGAGGCAGAGGTTGCAGTGAGCC GAGATCGTGCCACTATACTCCAGCCTGGGTGACAGAGCAAAACTCTGTCTCAAAAAAAAA AAAAAAAAAAAGGGCTGGACACGGTGGCTTACGCCTGTTATCCCGGCACTTTGGGAGGCC AAGGCTGATGGATCACCTGAGGTCAGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAAC CCCATCTCTACTAAAAATACAAAAATTTGCTGGGCATGGTGGTGGGCACCTGTAATCCCA GGAGGCTGAGGCAGGAGAATCACTTGAACCCGGGAGGCGGAGATTGCAGTGAGCCAAGAT TGTGCCATTGAACTCCAGCCTGGGTGACAAGACCAAAACTCCTTCTCAAAAAAAAAAAAG ATTATAGCATCTTTATTCATCATTGCCCAAAATTACAAACTGCCTAAATGTAGACCTTCA TTTAGTTAATGAATGCACAAACTGTGGTATATCCAAACAATTGAATAAAAAAAGGAATGA ACTGGTACTTTTTTCTATTCCTCCTGTTTAAGTACAGCCAAAACACCTCAACATTTGTAT AAAACATGAGCTGGGCTGGGTGCGGTGGCTCACACGTGTAATCCCAGCACTTTGGGAGGC TGAGGCGGGTGGATCACCTAAGGTTGGGAGTTCAAGACCGGTCTGACCAACATGGAGAAA CCCTGTCTCAACTAAAAATACAAGATTAGTCGGGCATGGTGGCGCATGCCTGTAATCCCA GCTTCTTGGGAGGCTGAGGCAGGAGAATTGCTTGATCCCGGGAAGCGAAGGTTGCAGTAA GCTGAGATTGCACCATTGCACTCCAGCCTGGGCAACAAGAGCAAAACTCTGTCTCAAAAA GAAAAAAAAAACCATTCAGCTGAATCTCAAAGGCAGAGAGAAGACAGACTGGCTAGGGAC CTTGGAACCAGAGGAGCAGTGTGGTGGGGAGTGGACTGGATTTTCTTTTTGCCTCATTTA TCCTGGACTTGGTGCTGGAGAAGCTATGGGTTCAGACCAAGAGAAAACCCCATGAAAAGC CTGCTCTCTCTAGCCAAAAGAGGCAACCTAGCAAGATAAAAACCTTTAGATAATAAGCAC TTGACTCCAGTCAAACAAAACAGAATAAACTGGCCCCATTCACCCCTGTCAGCAAAGGCC AAGTGGGAGCCAAGATATGTACCCCAACCTGGAAGTCATAAGGTACACTTCTCCCCTTTC CCAGCCAAGGTGGTGTTAGAGAAGGCTGACTGGGGAGCTGGGATTCTCATTCCCTCCAGG AGGTGATAACACTCCTTTCACATGGTGTCAGTGGTCACAGGGAGGCTGAACTTCCACCCA GTAATACATAGGCATCTCTCTGGCTCCTATATGGGTGATGTTGGAGAAGAGGCCGAGTAG AGAATCCAGACTGTTGCTGACACCCAGCAGTAACAAGGACACCTCCACAATGTCCGTGGA GGCCATGTGGAGATCAGTAACAAGGCACTGCTCTCCCTCCCAGTCAGAGAGATGTCAGTG GAGGACTAGGGGGCTAGAACTCCCATGTGCGTTCAGCAGTAATCCCCATGACCGCCACTC CTTGACATCACAGGCCTTGAAGAAACCTGGACTTTCACTCCCCTCTGGTTGTAGCGAGGT GGCACTCCCTTTTCCCTGTTGCCAGTGCTGTGTCAGTGGAGGCTTGCTAAATTGGAAGAT GTAAATAAGATTCACATTCTCATAACATAATACCCCAAATTTTCAGGATTTAATTGAAAA TCACTAAGCTGGGCATGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCAAGGTG 23Evotec International GmbH EVO28777PCTGGCCAAACACTTAAGGTCAGGAATTCAAGACCAGCCTGGCCAGCATGGTGAAACCCTGTC TCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGGCACATGCCTGTAATCCCAGCTACT GGGAAGGCTAAGGCAGGAAAATCACTGGAACCTGGGAGACGGAGGTTGCAGTGATCCAAG ATCGCACTAGTGTACTGCAGCCTGGGCAACAGAGCAAGACTCCATCTAAATTTGTGTCAG GATTCCCAGAAGGAGATGAGAAAGGGTGGGGCTGAAAAAAATTGAGGAAGAAGTCATGGC TGAAAATTTCCCAAATTTGGCAAAAGTCAGAAACCTACAGATTGAAAAAGCTGAATGAAG CTCAAATATGATAAACTCAAAGAAGTTCACACAGAGACACATCACAGTCAGATTTCTGAA CACTGCAGACAAAAAATGAAGATCTCGAAATTAGCAAGAAATGACCTTACCTAAGCAATT TGAATGACAGCAGATTTCCCATCAGAGATCATAAAGGCCAGAAGGAAGGGGTACATACAA CATTTTTTCTAGTGCTGAAAGACAAAAACTCTAGGCTGGGCACGGTGGCACACACCTGTA ATCCCAGCACTTTTGGAGGCTGAGGCAGGCAGATCACCTGAAGTCAGGAGTTCGAGACCA GCCTGGCCAACATGGGGAAACCCTGTCTCTACTAAAAATACAAAAATTAGCCAGGTGTGG TGGCACGCACCTATAATCCTAGCTACTTGGGAGGCTGAGGCAGGGGAATCGCTTGAACCT GGGAGGCGACGGTTGCAGTGAGCCAAGGTCGCGCCACTGCACTCCAGCCTGGGCAGTTGA GCGAGACTCCATCTCAAAAAAAAAAAAATTATCCAGGCTTGGTGGTGGGCGCCTATAGTC CCAGCTACTTGGGAGGCTGAGGCAAGAGAATTGGTTGAACCCAGGAGGTGGAGGTTGCAG TGAGCCAAGCTCATGCCACTGTACTCCAGCCTGGGTGACAGAGCGAGACCTTGTCTCAAA AAAAAAAAAAAAAAAAAAAAACAAGAAAAAAACTCTAAACCCAGAGTTACATATCCAGTG AAATATCCTTCAGGAGTGAAGGGAAAATTAACGATTTGTCTTCAGGAGACCTACCCTAAA AGAATGGCTAAAGGAATTTCTCTAAACAGAAAAGAAATGATAAAAGAAGTAATTTTGGAA CATCAGGAAGGAAGAAAGAACAATAAAAAGAGTAAAATATGGGTAAACACAATAGACTTT CCCCTCCTTTTGAATTTTCTAAATTGTATGATGGTTGAAGCAAGAATTATAGCACTGATT TGGTTTTCAGTATATATATTGGAAATATTTAAGGCATTATGTTACAGATGAAGGAGGGTC AAAGGATATAAAGGGAGGTAACCTTTCTATATTTCTTTTGTACTGATGCAGGCACTTTGG AAAATAATTTCACTATTTGTTTAAAAACTGAACATACCCTGACCATATGACATAGCATCT ATACTCCTGGGCATTTATCCCAGAGAAACAGAAATTTATTTATTTTTTTTTTAGTATTAC ACTCCGTAAGTGCTGTAATACTAGCACTTAGGGAGGCTGAGGCAAGCAGATTGCTTGAGC CCAGGAGTTCAAGACCAGCCTGGGCAATGCTGCACAGTCAAAAAAGAAAAACAAACATTT AGAAAACTATTTTAAAAGTCTTTAATTGCTGAATGCCTCTTTGGCTAATATTTGGAAGAT CATTATTATTATTTTTCTTTTTTAGGCAGAGTCTTGCTCTGTCACTGAGGCTGGAGTGCA GTGGCGCCATCTCGGCTTACTGCAACCTCTGCCTCCCGGGTTCACGCCATTCTCCTGCCT CAGCCTCCCGAGTAGCTGGGACTACAGGCGTGTGCCACCATGCCCGGCTAATTTTTTGTG TTTTTAGTAGAGATGGGGTTTCACTATGTTAGTCAGGATGGTCTCCATCTCCTAACCTCG TGATCCGCCCACCTCGGCTTCCCAAAATGCTGGGATTACAGGCGTGAGCCACTGTGCCCA GCCTGGAAGATCATTATTTAGTCCTACAACTGACACATTGTTCCACTGACGCAATTGCCC AGGCTGGTCTTGAACTCCTGGGCTCAAGCAATCTGCCTGCCTCGGCCTCCCTAAGTGCTA GTATTACAGGCTTGAGCCACTGTGCCCAGCCAAAAATAGAAATTTATATTCTCACAAAAA CATGTACATGAATGTTTATAGCAGCTTTACTTGTCATAATCAAAAACTGGAAACAACCAA AATGTCCTACAGTGAAACAAACTGTAGTACATCCATAGCATGTAATACTCTACTGTCAGG ATTAAAAAGAAACCCACTGTTGGCACAGGCAGCACCGTGGCTGGATCTCAGGGGCATTAT GCTGAGTGCAAAAAAGCCTCAAAGGGTCTTACACTGTATGATTCCACTTGTTCAACTAAA AATGACAGCTGTATAGAGATAGAGAACATATTAGTGGTTTCCACTAGTTAGAGAAAGTGG GTAAAAGATAGGTGGGTGGGAATATAAATCGATAGCAGGGAGATCTTTGTGGTATTATAA CACTTCTATGTCTTGATTGTAGTGGTGGTGGTTACATGAATACACGTGTGATAAAATGCC ATGTAGAACTACATATAACGTTGTGCCAATGTCAATATCTAGGTTTTAGTTTGATCTTTA GTTACATAAGATGTAACTATTGGGTGAAATTGGGCAAAAGAGTACACGAAACCTCTCTTA AATATCTTTACAACTTCCTTTGAATTGACAGTTTTTCAAAATAGAAAGTTGGGTTTTTGT AAATACATGAATTGTTGATATACACAACAAATCTCAAATGCATTATGCTACGTGAAAGAA GCCATATTCAAAAGGCTACATACCTACTGATGCCTTTTATATGACGTGCAGGAAAAGATA AAACTGTAGGACAGAGAATATACTGGTGGCTATCTGGGATTAGGAAATGGGGATCGACCA CAAAGGGGCAGCATGGGGGAATTTTCTGGGGCAATGGAATGGTTGTGTATCTTGATGGTG TATTTGTCAAAATATATAGAACTATAAAAGTAAATTTTGCTTTATATGTATTAAATCAAA AAAAGAAACTCGTGCTCAAATAGAAATACATTTTCTGAGAACTTGCCTTTTGATGACTTT GAGAATTTTCTGGAAATTTTAAAGAAATGTGGTTTTGTTTCCCAACAGGTGATGCTATGA GTGAAGAAGACATGCTTCAGGCAGCTGTGACCATGTCTTTAGAAACTGTCAGAAATGATT TGAAAACAGAAGGAAAAAAATAATACCTTTAAAAAATAATTTAGATATTCATACTTTCCA 24Evotec International GmbH EVO28777PCTACATTATCCTGTGTGATTACAGCATAGGGTCCACTTTGGTAATGTGTCAAAGAGATGAGG AAATAAGACTTTTAGCGGTTTGCAAACAAAATGATGGGAAAGTGGAACAATGCGTCGGTT GTAGGACTAAATAATGATCTTCCAAATATTAGCCAAAGAGGCATTCAGCAATTAAAGACA TTTAAAATAGTTTTCTAAATGTTTCTTTTTCTTTTTTGAGTGTGCAATATGTAACATGTC TAAAGTTAGGGCATTTTTCTTGGATCTTTTTGCAGACTAGCTAATTAGCTCTCGCCTCAG GCTTTTTCCATATAGTTTGTTTTCTTTTTCTGTCTTGTAGGTAAGTTGGCTCACATCATG TAATAGTGGCTTTCATTTCTTATTAACCAAATTAACCTTTCAGGAAAGTATCTCTACTTT CCTGATGTTGATAATAGTAATGGTTCTAGAAGGATGAACAGTTCTCCCTTCAACTGTATA CCGTGTGCTCCAGTGTTTTCTTGTGTTGTTTTCTCTGATCACAACTTTTCTGCTACCTGG TTTTCATTATTTTCCCACAATTCTTTTGAAAGATGGTAATCTTTTCTGAGGTTTAGCGTT TTAAGCCCTACGATGGGATCATTATTTCATGACTGGTGCGTTCCTAAACTCTGAAATCAG CCTTGCACAAGTACTTGAGAATAAATGAGCATTTTTTAAAATGTGTGAGCATGTGCTTTC CCAGATGCTTTATGAATGTCTTTTCACTTATATCAAAACCTTACAGCTTTGTTGCAACCC CTTCTTCCTGCGCCTTATTTTTTCCTTTCTTCTCCAATTGAGAAAACTAGGAGAAGCATA GTATGCAGGCAAGTCTCCTTCTGTTAGAAGACTAAACATACGTACCCACCATGAATGTAT GATACATGAAATTTGGCCTTCAATTTTAATAGCAGTTTTATTTTATTTTTTCTCCTATGA CTGGAGCTTTGTGTTCTCTTTACAGTTGAGTCATGGAATGTAGGTGTCTGCTTCACATCT TTTAGTAGGTATAGCTTGTCAAAGATGGTGATCTGGAACATGAAAATAATTTACTAATGA AAATATGTTTAAATTTATACTGTGATTTGACACTTGCATCATGTTTAGATAGCTTAAGAA CAATGGAAGTCACAGTACTTAGTGGATCTATAAATAAGAAAGTCCATAGTTTTGATAAAT ATTCTCTTTAATTGAGATGTACAGAGAGTTTCTTGCTGGGTCAATAGGATAGTATCATTT TGGTGAAAACCATGTCTCTGAAATTGATGTTTTAGTTTCAGTGTTCCCTATCCCTCATTC TCCATCTCCTTTTGAAGCTCTTTTGAATGTTGAATTGTTCATAAGCTAAAATCCAAGAAA TTTCAGCTGACAACTTCGAAAATTATAATATGGTATATTGCCCTCCTGGTGTGTGGCTGC ACACATTTTATCAGGGAAAGTTTTTTGATCTAGGATTTATTGCTAACTAACTGAAAAGAG AAGAAAAAATATCTTTTATTTATGATTATAAAATAGCTTTTTCTTCGATATAACAGATTT TTTAAGTCATTATTTTGTGCCAATCAGTTTTCTGAAGTTTCCCTTACACAAAAGGATAGC TTTATTTTAAAATCTAAAGTTTCTTTTAATAGTTAAAAATGTTTCAGAAGAATTATAAAA CTTTAAAACTGCAAGGGATGTTGGAGTTTAGTACTACTCCCTCAAGATTTAAAAAGCTAA ATATTTTAAGACTGAACATTTATGTTAATTATTACCAGTGTGTTTGTCATATTTTCCATG GATATTTGTTCATTACCTTTTTCCATTGAAAAGTTACATTAAACTTTTCATACACTTGAA TTGATGAGCTACCTAATATAAAAATGAGAAAACCAATATGCATTTTAAAGTTTTAACTTT AGAGTTTATAAAGTTCATATATACCCTAGTTAAAGCACTTAAGAAAATATGGCATGTTTG ACTTTTAGTTCCTAGAGAGTTTTTGTTTTTGTTTTTGTTTTTTTTTGAGACGGAGTCTTG CTATGTCTCCCAGGCTGGAGGGCAGTGGCATGATCTCGGCTCACTACAACTTCCACCTCC CGGGTTCAAGCAATTCTCCTGCCTCAGCCTCCAGAGTAGCTGGGATTACAGGCGCCCACC ACCACACCCGGCAGATTTTTGTATTTTTGGTAGAGACGCGGTTTCATCATGTTTGGCCAG GCTGGTCTCGAACTCCTGACCTCAGGTGATCCGCCTGCCTTGGCCTCCCAAAGTGTTGGG ATTACAGGCATGAGCCACTGCGCCTGGCCAGCTAGAGAGTTTTTAAAGCAGAGCTGAGCA CACACTGGATGCGTTTGAATGTGTTTGTGTAGTTTGTTGTGAAATTGTTACATTTAGCAG GCAGATCCAGAAGCACTAGTGAACTGTCATCTTGGTGGGGTTGGCTTAAATTTAATTGAC TGTTTAGATTCCATTTCTTAATTGATTGGCCAGTATGAAAAGATGCCAGTGCAAGTAACC ATAGTATCAAAAAAGTTAAAAATTATTCAAAGCTATAGTTTATACATCAGGTACTGCCAT TTACTGTAAACCACCTGCAAGAAAGTCAGGAACAACTAAATTCACAAGAACTGTCCTGCT AAGAAGTGTATTAAAGATTTCCATTTTGTTTTACTAATTGGGAACATCTTAATGTTTAAT ATTTAAACTATTGGTATCATTTTTCTAATGTATAATTTGTATTACTGGGATCAAGTATGT ACAGTGGTGATGCTAGTAGAAGTTTAAGCCTTGGAAATACCACTTTCATATTTTCAGATG TCATGGATTTAATGAGTAATTTATGTTTTTAAAATTCAGAATAGTTAATCTCTGATCTAA AACCATCAATCTATGTTTTTTACGGTAATCATGTAAATATTTCAGTAATATAAACTGTTT GAAAAGGCTGCTGCAGGTAAACTCTATACTAGGATCTTGGCCAAATAATTTACAATTCAC AGAATATTTTATTTAAGGTGGTGCTTTTTTTTTTTGTCCTTAAAACTTGATTTTTCTTAA CTTTATTCATGATGCCAAAGTAAATGAGGAAAAAAACTCAAAACCAGTTGAGTATCATTG CAGACAAAACTACCAGTAGTCCATATTGTTTAATATTAAGTTGAATAAAATAAATTTTAT TTCAGTCAGAGCCTAAATCACATTTTGATTGTCTGAATTTTTGATACTATTTTTAAAATC ATGCTAGTGGCGGCTGGGCGTGGTAGCTCACGCCTGTAATCCCAGCATTTTGGGAGGCCG AAGTGGGTGGATCACGAGGTCGGGAGTTCGAGACCAGCTTGGCCAAAATGGTGAAACCCC 25Evotec International GmbH EVO28777PCTATCTGTACTAAAAACTACAAAAATTAGCTGGGCGCGGTGGCAGGTGCCTGTAATCCCAGC TACCTGGGAGTCTGAGGCAGGAGAATTGCTTGAACCCTGGCGACAGAGGATGCAGTGAGC CAAGATGGTGCCACTGTACTCCAGACTGGGCGACAGAGTGAGACTCTGTCTCAAAAAAAA AAAAAAAATCATGCTAGTGCCAAGAGCTACTAAATTCTTAAAACCGGCCCATTGGACCTG TACAGATAAAAAATAGATTCAGTGCATAATCAAAATATGATAATTTTAAAATCTTAAGTA GAAAAATAAATCTTGATGTTTTAAATTCTTACGAGGATTCAATAGTTAATATTGATGATC TCCCGGCTGGGTGCAGTGGCTCACGCCTGTAATCCCAGCAGTTCTGGAGGCTGAGGTGGG CGAATCACTTCAGGCCAGGAGTTCAAGACCAGTCTGGGCAACATGGTGAAACCTCGTTTC TACTAAAAATACAAAAATTAGCCGGGCGTGGTTGCACACACTTGTAATCCCAGCTACTCA GGAGGCTAAGAATCGCATGAGCCTAGGAGGCAGAGGTTGCAGAGTGCCAAGGGCTCACCA CTGCATTCCAGCCTGCCCAACAGAGTGAGACACTGTTTCTGAAAAAAAAAAATATATATA TATATATATATATGTGTGTATATATATATGTATATATATATGACTTCCTATTAAAAACTT TATCCCAGTCGGGGGCAGTGGCTCACGCCTGTAATCCCAACACTTTGGGAGGCTGAGGCA GGTGGATCACCTGAAGTCCGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCCATC TCTACTAAAAATACAAAACTTAAGCCAGGTATGGTGGCGGGCACCTGTAATCCCAGTTAC TTGGGAGGCTGAGGCAGGAGAATCGTTTAAACCCAGGAGGTGGAGGTTGCAGTGAGCTGA GATCGTGCCATTGCACTCTAGCCTGGGCAACAAGAGTAAAACTCCATCTTAAAGGTTTGT TTGTTTTTTTTTAATCCGGAAACGAAGAGGCGTTGGGCCGCTATTTTCTTTTTCTTTCTT TCTTTCTTTCTTTTTTTTTTTTTCTGAGACGGAGTCTAGCTCTGCTGCCCAGGCTGGAGT ACAATGACACGATGTTGGCTCACTGCAACCTCCACCTCCTGGGTTCAAGCGATTCTCCTG CCTCAGCCTCCCAAGTACCTGGGATTACAGGCACCTGCCACTACACCTGGCGAATATTTG TTTTTTTTAGTAGAGACGGGCTTTTACCATGTTAGGCTGGTCTCAAACTCCTGACCTCAG GTGATCTGCCTGCCTTGGCCTCCCAAAGTGCTGGGATTACAGGTGCAGGCCACCACACCC GGCCTTGGGCCACTGTTTTCAAAGTGAATTGTTTGTTGTATCGAGTCCTTAAGTATGGAT ATATATGTGACCCTAATTAAGAACTACCAGATTGGATCAACTAATCATGTCAGCAATGTA AATAACTTTATTTTTCATATTCAAAATAAAAACTTTCTTTTATTTCTGGCCCCTTTATAA CCAGCATCTTTTTGCTTTAAAAAATGACCTGGCTTTGTATTTTTTTAGTCTTAAACATAA TAAAAATATTTTTGTTCTAATTTGCTTTCATGAGTGAAGATTATTGACATCGTTGGTAAA TTCTAGAATTTTGATTTTGTTTTTTAATTTGAAGAAAATCTTTGCTATTATTATTTTTTC CAAGTGGTCTGGCATTTTAAGAATTAGTGCTAATAACGTAACTTCTAAATTTGTCGTAAT TGGCATGTTTAATAGCATATCAAAAAACATTTTAAGCCTGTGGATTCATAGACAAAGCAA TGAGAAACATTAGTAAAATATAAATGGATATTCCTGATGCATTTAGGAAGCTCTCAATTG TCTCTTGCATAGTTCAAGGAATGTTTTCTGAATTTTTTTAATGCTTTTTTTTTTTTTGAA AGAGGAAAACATACATTTTTAAATGTGATTATCTAATTTTTACAACACTGGGCTATTAGG AATAACTTTTTAAAAATTACTGTTCTGTATAAATATTTGAAATTCAAGTACAGAAAATAT CTGAAACAAAAAGCATTGTTGTTTGGCCATGATACAAGTGCACTGTGGCAGTGCCGCTTG CTCAGGACCCAGCCCTGCAGCCCTTCTGTGTGTGCTCCCTCGTTAAGTTCATTTGCTGTT ATTACACACACAGGCCTTCCTGTCTGGTCGTTAGAAAAGCCGGGCTTCCAAAGCACTGTT GAACACAGGATTCTGTTGTTAGTGTGGATGTTCAATGAGTTGTATTTTAAATATCAAAGA TTATTAAATAAAGATAATGTTTGCTTTTCTA.

[0050] The term “target sequence” as used herein refers to a sequence of nucleotides presentin the target nucleic acid which comprises the nucleobase sequence which is complementary to the modified oligonucleotide of the invention. Herein provided is exemplarily the target sequence GAAAGGATTGTAGAATCT (as SEQ ID NO: 5) which is comprised in SEQ ID NO: 4 and which may be targeted by the modified oligonucleotides of the invention. SEQ ID NO: 5 is a DNA sequence – it will be understood that target RNA sequences have uracil (U) bases in place of the thymine bases (T). The modified oligonucleotide of the invention comprises a contiguous nucleotide sequence which is complementary to or hybridizes to the 26Evotec International GmbH EVO28777PCTtarget nucleic acid, such as a sub-sequence of the target nucleic acid, such as a target sequence described herein.

[0051] The term a “target cell” as used herein refers to a cell which is expressing the targetnucleic acid. In some embodiments the target cell may be provided or present in vivo or in vitro.In some embodiments the target cell is a mammalian cell such as a rodent cell, such as a mouse cell or a rat cell, or a primate cell such as a monkey cell (e.g. a cynomolgus monkey cell) or ahuman cell. In preferred embodiments the target cell expresses human ATXN3 RNA, such asthe human ATXN3 pre-mRNA or partial or incomplete variants thereof. In some embodimentsthe target cell expresses monkey (e.g., Macaca fascicularis aurea) ATXN3 RNA, such asmonkey pre-mRNA. In some embodiments the target cell expresses mouse or rat ATXN3 RNA, such as mouse or rat pre-mRNA.

[0052] The term “naturally occurring variant” refers to variants of ATXN 3 gene ortranscripts which originate from the same genetic loci as the target nucleic acid, but may differ for example, by virtue of degeneracy of the genetic code causing a multiplicity of codons encoding the same amino acid, or the presence of polymorphisms, such as single nucleotide polymorphisms (SNPs), and allelic variants. Based on the presence of the sufficient complementary sequence to the oligonucleotide, the modified oligonucleotide of the inventionmay therefore target the target nucleic acid and naturally occurring variants thereof. The homosapiens ATXN3 gene is located at chromosome 14, 92058552…92106621, complement (NC_000014.9, Gene ID 4287). In some embodiments, the naturally occurring variants have at least 95% such as at least 98% or at least 99% homology to a mammalian (such as the human) ATXN3 target nucleic acid, such as a target nucleic acid SEQ ID NO: 4.

[0053] The term “modulation of expression” as used herein is to be understood as an overallterm for an oligonucleotide’s ability to alter the amount of ATXN3 protein or ATXN3 mRNAwhen compared to the amount of ATXN3 protein or ATXN3 mRNA prior to administration ofthe modified oligonucleotide of the invention. Alternatively, modulation of expression may be determined by reference to a control experiment. It is generally understood that the control is an individual or target cell treated with e.g. a saline composition or with a non-targeting oligonucleotide (mock). One type of modulation is an oligonucleotide’s ability to inhibit, down- regulate, reduce, suppress, remove, stop, block, prevent, lessen, lower, avoid or terminate expression of ATXN3, e.g. by degradation of ATXN3 RNA, in particular ATXN3 pre-mRNA. 27Evotec International GmbH EVO28777PCT

[0054] The modified oligonucleotide of the invention comprises nucleosides which have amodified sugar moiety, i.e. a modification of the sugar moiety when compared to the (deoxy)ribose sugar moiety found in DNA and RNA.

[0055] Such modifications include those where the (deoxy)ribose ring structure is modifiedby a substituent linking the C2’ and C4’ of the (deoxy)ribose sugar ring (also referred to as locked nucleic acids; LNA; (2’ - 4’ bridged) nucleosides).

[0056] A “LNA nucleoside” is a 2’- modified nucleoside which comprises a substituentlinking the C2’ and C4’ of the (deoxy)ribose sugar ring of said nucleoside (also referred to as a “2’- 4’ bridge”), which restricts or locks the conformation of the ribose ring. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature. The locking of the conformation of the pentose is associated with an enhanced affinity of hybridization (duplex stabilization) when the LNA is incorporated into an oligonucleotide for a complementary RNA or DNA molecule. This can be routinely determined by measuring the melting temperature of the oligonucleotide / complement duplex. Non limiting, exemplary LNA nucleosides are disclosed in WO 99 / 014226, WO 00 / 66604, WO 98 / 039352, WO 2004 / 046160, WO 00 / 047599, WO 2007 / 134181, WO 2010 / 077578, WO 2010 / 036698, WO 2007 / 090071, WO 2009 / 006478, WO 2011 / 156202, WO 2008 / 154401, WO 2009 / 067647, WO 2008 / 150729, Morita et al., Bioorganic & Med.Chem. Lett. 12, 73-76, Seth et al. J. Org. Chem. 2010, Vol 75(5) pp. 1569-81, and Mitsuoka et al., Nucleic Acids Research 2009, 37(4), 1225-1238, and Wan and Seth, J. Medical Chemistry 2016, 59, 9645-9667. Further non limiting, exemplary LNA nucleosides are disclosed in Scheme 1 (in which “B” denotes a nucleobase).

[0057] Scheme 1:28Evotec International GmbH EVO28777PCT

[0058] Particular LNA nucleosides are beta- D-oxy- LNA nucleoside or 6’-methyl-beta-D-oxy LNA nucleoside. More particularly the LNA nucleoside is beta- D-oxy- LNA nucleoside.

[0059] The RNase H activity of an antisense oligonucleotide refers to its ability to recruitRNase H when in a duplex with a complementary RNA molecule. WO01 / 23613 provides invitro methods for determining RNase H activity, which may be used to determine the ability torecruit RNase H.

[0060] Preferably, the modified oligonucleotide of the invention is a gapmer. A gapmeroligonucleotide comprises at least three distinct structural regions a 5’-flank, a gap and a 3’- flank, in the 5’ to 3’ orientation. The gap region comprises a stretch of contiguous DNA nucleotides which enable the oligonucleotide to recruit RNase H. The gap region is flanked by a 5’-flanking region comprising one or more sugar modified nucleosides and by a 3’-flanking 29Evotec International GmbH EVO28777PCTregion comprising one or more sugar modified nucleosides. Antisense gapmers are commonly used to inhibit a target nucleic acid via RNase H mediated degradation.

[0061] As used herein “pharmaceutical composition” means a mixture of substancessuitable for administering to a subject. For example, a pharmaceutical composition may comprise a modified oligonucleotide or a pharmaceutically acceptable salt thereof according to the invention and a sterile aqueous solution.

[0062] As used herein, "sugar moiety” means an unmodified sugar moiety or a modifiedsugar moiety. As used herein, "unmodified sugar moiety” means a 2’-OH(H) ribosyl moiety, as found in RNA (an "unmodified RNA sugar moiety”), or a 2’-H(H) moiety, as found in DNA (an "unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1’, 3’, and 4’ positions, an oxygen at the 3’ position, and two hydrogens at the 5’ position. An “unmodified DNA sugar moiety” may be denoted herein as 2’-H(H) deoxyribosyl sugar moiety or 2'-deoxy-ribosyl moiety. In particular, the unmodified DNA sugar moiety is 2'-deoxy- D-ribosyl moiety.

[0063] As used herein, "therapeutically effective amount” means an amount of apharmaceutical agent that provides a therapeutic benefit to an animal such as a mammal. For example, a therapeutically effective amount improves a symptom of a disease.

[0064] As used herein, "prophylactically effective amount” means an amount of apharmaceutical agent that provides a prophylactic benefit to an animal such as a mammal. For example, a prophylactically effective amount reduces the risk of developing a symptom of a disease.

[0065] The term ’treatment’ as used herein refers to both treatment of an existing disease(e.g. a disease or disorder as herein referred to), or prevention of a disease, i.e. prophylaxis. It will therefore be recognized that treatment as referred to herein may, in some embodiments, be prophylactic.

[0066] The term ‘conjugate’ as used herein refers to a modified oligonucleotide or apharmaceutically acceptable salt thereof which is covalently linked to a non-nucleotide moiety. Conjugation of the modified oligonucleotide of the invention to one or more non-nucleotide moieties may improve the pharmacology of the modified oligonucleotide of the invention, e.g. by affecting the activity, cellular distribution, cellular uptake or stability of the modified oligonucleotide of the invention. In particular, the conjugate may target the modified oligonucleotide of the invention to a specific organ, tissue or cell type and thereby enhance the 30Evotec International GmbH EVO28777PCTeffectiveness of the modified oligonucleotide of the invention in that organ, tissue or cell type. The non-nucleotide moiety (conjugate moiety) may e.g. be selected from the group consisting of carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides or combinations thereof. Conjugate moieties can be attached to the oligonucleotide directly or through a linking moiety.II. Exemplary modified oligonucleotides of the Disclosure

[0067] Exemplary modified oligonucleotides of the invention are those modifiedoligonucleotides in which one or more of the moieties contained therein have the meanings given above or below, with all combinations of preferred embodiments definitions being a subject of the present invention.

[0068] The present invention relates in a first aspect to a modified oligonucleotide or apharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT(SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non-modified nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides, wherein a non-modifiednucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and 31Evotec International GmbH EVO28777PCTiii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are non-modified nucleosides linked by phosphorothioate internucleoside linkages, and wherein (me)C denotes cytosine or 5-methyl cytosine.

[0069] In the following, specific embodiments of the present invention such as regardingthe moieties are described in further details. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments.

[0070] According to some embodiments of the present invention, the modifiedoligonucleotide is in the form of a pharmaceutically acceptable salt thereof, preferably having cationic counterions. Suitably, the cationic counterions are ions of alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4- alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. According to some embodiments of the present invention, the modified oligonucleotide is in the form of an alkali salt thereof, preferably the lithium salt, sodium salt or potassium salt, more preferably the sodium salt.

[0071] According to some embodiments of the present invention, the non-modifiednucleoside is a nucleoside comprising an unmodified sugar moiety and a nucleobase selectedfrom the group consisting of A, G, T, and (me)C, preferably comprising an unmodified sugarmoiety and a nucleobase selected from the group consisting of A, G, T, and C. 32Evotec International GmbH EVO28777PCT

[0072] According to some embodiments of the present invention, the core sequence asdefined in i) partially overlaps with the 5’ stretch as defined in ii), and / or the core sequence as defined in i) partially overlaps with the 3’ stretch as defined in iii). It is to be understood that the core sequence as defined in i) corresponds to the nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT; i.e. SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1.

[0073] According to another embodiment of the present invention, the core sequence asdefined in i) does not overlap with the 5’ stretch as defined in ii), preferably the core sequence is linked to the 5’ stretch by phosphorothioate internucleoside linkage, and / or the core sequence as defined in i) does not overlap with the 3’ stretch as defined in iii), preferably the core sequence is linked to the 3’ stretch by phosphorothioate internucleoside linkage. It is to be understood that the core sequence as defined in i) corresponds to the nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT; i.e. SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1. Preferably, the nucleoside comprising the 5’-terminal nucleobase of the core sequence is linked to the 5’ stretch by phosphorothioate internucleoside linkage and / or the nucleoside comprising the 3’-terminal nucleobase of the core sequence is linked to the 3’ stretch by phosphorothioate internucleoside linkage.

[0074] According to some embodiments of the present invention, the coresequence is linked to the 5’ stretch and to the 3’ stretch by phosphorothioate internucleoside linkages. The nucleoside comprising the 5’-terminal nucleobase of the core sequence is linked to the 5’ stretch by phosphorothioate internucleoside linkage and the nucleoside comprising the 3’-terminal nucleobase of the core sequence is linked to the 3’ stretch by phosphorothioate internucleoside linkage.

[0075] In some embodiments of the present invention, at least nine nucleosides, preferablyat least ten nucleosides, more preferably at least eleven nucleosides, of said core nucleosides are consecutive non-modified nucleosides, and the internucleoside linkages of all of said non- modified nucleosides are phosphorothioate internucleoside linkages.

[0076] In some embodiments of the present invention, nucleosides of the 5’ stretch definedunder ii) a) are linked by 0, 1, 2, 3 or 4, preferably linked by 1, 2, or 3, more preferably linked by 2 or 3, phosphorothioate internucleoside linkages, wherein the remaining (if any) internucleoside linkages of the 5’ stretch are phosphodiester internucleoside linkages. For example only, if the 5’-stretch has five consecutive nucleosides linked by phosphorothioate 33Evotec International GmbH EVO28777PCTinternucleoside linkages, the number of the phosphorothioate linkages would be 4 and no internucleoside linkage of the phosphodiester type would be present in such 5’-stretch.

[0077] In some embodiments of the present invention, nucleosides of the 3’ stretch definedunder iii) a) are linked by 0, 1, 2, 3 or 4, preferably linked by 0, 1, 2, or 3, more preferably linked by 2 or 3 or linked by 0 or 1, phosphorothioate internucleoside linkages, wherein the remaining (if any) internucleoside linkages of the 3’ stretch are phosphodiester internucleoside linkages. For example only, if the 3’-stretch has five consecutive nucleosides linked by phosphorothioate internucleoside linkages, the number of the phosphorothioate linkages would be 4 and no internucleoside linkage of the phosphodiester type would be present in such 3’- stretch.

[0078] In some embodiments of the present invention, nucleosides of the 5’ stretch definedunder ii) a) are linked by 0, 1, 2, 3 or 4, preferably linked by 1, 2, or 3, more preferably linked by 2 or 3, phosphorothioate internucleoside linkages, and nucleosides of the 3’ stretch defined under iii) a) are linked by 0, 1, 2, 3 or 4, preferably linked by 0, 1, 2, or 3, more preferably linked by 2 or 3, phosphorothioate internucleoside linkages, wherein the remaining (if any) internucleoside linkages of the 5’ stretch and of the 3’ stretch are phosphodiester internucleoside linkages.

[0079] In some embodiments of the present invention, all nucleosides of the 5’ stretch arelinked by phosphorothioate internucleoside linkages.

[0080] In some embodiments of the present invention, all nucleosides of the 3’ stretch arelinked by phosphorothioate internucleoside linkages.

[0081] In some embodiments of the present invention, all nucleosides of the modifiedoligonucleotide or pharmaceutically acceptable salt thereof are linked by phosphorothioate internucleoside linkages.

[0082] In some embodiments of the present invention, the C at position 18 of the nucleobasesequence SEQ ID No. 1 is 5-methyl cytosine (i.e. meC), preferably wherein the nucleobasesequence (SEQ ID NO: 1) has the nucleobase sequence of AGATTCTACAATC(me)CTTTmeC (SEQ ID NO: 2), more preferably has the nucleobase sequence ofAGATTCTACAATCCTTTmeC (SEQ ID NO: 3), wherein meC denotes 5-methyl cytosine.

[0083] In some embodiments of the present invention, all (me)C are meC.

[0084] In some embodiments of the present invention, if (me)C is comprised in an LNAnucleoside, then (me)C is 5-methyl cytosine (meC). 34Evotec International GmbH EVO28777PCT

[0085] In some embodiments of the present invention, if (me)C is comprised in a2’-deoxynucleoside, then (me)C is cytosine (C).

[0086] In some embodiments of the present invention, all (me)C in the 3’stretch are 5-methylcytosine (meC).

[0087] In some embodiments of the present invention, all (me)C in the core nucleosides arecytosine (C).

[0088] In some embodiments of the present invention, all non-modified nucleosidescomprise unmodified DNA sugar moiety. In some embodiments, all non-modified nucleosides comprise 2’-H(H) deoxyribosyl sugar moiety. In some embodiments, all non-modified nucleosides comprise 2'-deoxy-ribosyl moiety, in particular 2'-deoxy-D-ribosyl moiety.

[0089] The LNA nucleoside may be any suitable LNA nucleoside known in the art (suchas disclosed above, e.g. in Scheme 1). In some embodiments, the LNA nucleoside is independently selected from the group consisting of beta-D-oxy LNA nucleoside and 6’- methyl-beta-D-oxy LNA nucleoside, preferably the LNA nucleoside is beta-D-oxy LNA nucleoside.

[0090] In some embodiments of the present invention, the 5’end of the modifiedoligonucleotide of the invention (i.e. the A-containing nucleoside) is an LNA nucleoside such as beta-D-oxy LNA nucleoside. In some embodiments, the 3’ most nucleoside of the 5’ stretch is an LNA nucleoside such as beta-D-oxy LNA nucleoside.

[0091] In some embodiments of the present invention, the 3’end of the modifiedoligonucleotide of the invention (i.e. the (me)C-containing nucleoside) is an LNA nucleoside such as beta-D-oxy LNA nucleoside. In this context, the LNA nucleoside preferably comprisesmeC. In some embodiments, the 5’ most nucleoside of the 3’ stretch is an LNA nucleoside such as beta-D-oxy LNA nucleoside.

[0092] In some embodiments of the present invention, the 3’end and the 5’end of themodified oligonucleotide of the invention is an LNA nucleoside, preferably a beta-D-oxy LNA nucleoside.

[0093] In some embodiments of the present invention, the modified oligonucleotide isselected from the group consisting of the following compounds 35ASO2,ASO19,ASO21, andEvotec International GmbH EVO28777PCTASO22 or a pharmaceutically acceptable salt thereof. In some embodiments the pharmaceutically acceptable salt is a sodium salt.

[0094] In some embodiments of the present invention, the modified oligonucleotide isselected from the group consisting of ASO2, ASO3, ASO5, ASO6, ASO7, ASO8, ASO9, ASO10, ASO11, ASO12, and ASO18, or a pharmaceutically acceptable salt thereof, preferably the modified oligonucleotide is selected from the group consisting of ASO2, ASO3, ASO6, ASO7, ASO8, ASO9, ASO11, ASO12, and ASO18, or a pharmaceutically acceptable salt thereof, more preferably the modified oligonucleotide is selected from the group consisting of ASO3, ASO6, ASO7, ASO11, ASO12, and ASO18, or a pharmaceutically acceptable salt thereof, even more preferably the modified oligonucleotide is ASO7, ASO11, ASO12 or 55Evotec International GmbH EVO28777PCTASO18, or a pharmaceutically acceptable salt thereof. In this context, it is to be understood that the respective ASOs’ chemical structures are depicted above.

[0095] In a preferred embodiment of the present invention, the modified oligonucleotide isselected from the group consisting of ASO7, ASO11, ASO12, and ASO18, or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of ASO11 and ASO12, or a pharmaceutically acceptable salt thereof. In this context, it is to be understood that the respective ASOs’ chemical structures are depicted above.

[0096] In some embodiments of the present invention, the modified oligonucleotide isselected from the group consisting of ASO2, ASO3, ASO6, ASO7, ASO8, ASO9, ASO11, and ASO12, or a pharmaceutically acceptable salt thereof, such as ASO2, ASO3, ASO6, ASO7, ASO11, or ASO12, or a pharmaceutically acceptable salt thereof, or such as ASO3, ASO6, ASO11, or ASO12, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments of the present invention, the modified oligonucleotide isselected from the group consisting of ASO5, ASO11, ASO12, ASO14, ASO16, ASO17, ASO18, ASO19, ASO20, ASO21, and ASO22, or a pharmaceutically acceptable salt thereof, such as ASO5, ASO11, ASO12, ASO14, ASO16, ASO18, ASO19, or ASO21, or a pharmaceutically acceptable salt thereof, or such as ASO5, ASO11, ASO12, ASO18, or ASO19, or a pharmaceutically acceptable salt thereof.

[0098] The present invention relates in a further aspect to a modified oligonucleotidehaving the chemical structure 56Evotec International GmbH EVO28777PCTASO7 or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments the pharmaceutically acceptable salt of ASO7 is a sodium saltas depicted below 57Evotec International GmbH EVO28777PCT.

[0100] The present invention relates in a further aspect to a modified oligonucleotidehaving the chemical structure 58Evotec International GmbH EVO28777PCTASO11 or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments the pharmaceutically acceptable salt of ASO11 is a sodiumsalt as depicted below 59Evotec International GmbH EVO28777PCT.

[0102] The present invention relates in a further aspect to a modified oligonucleotidehaving the chemical structure 60Evotec International GmbH EVO28777PCTASO12 or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments the pharmaceutically acceptable salt of ASO12 is a sodiumsalt as depicted below 61Evotec International GmbH EVO28777PCT.

[0104] The present invention relates in a further aspect to a modified oligonucleotidehaving the chemical structure 62Evotec International GmbH EVO28777PCTASO18 or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments the pharmaceutically acceptable salt of ASO18 is a sodiumsalt as depicted below 63Evotec International GmbH EVO28777PCT.

[0106] The modified oligonucleotide or pharmaceutically acceptable salt thereof aregenerally accessible by known in the art methods such as reacting nucleotide units and thereby forming covalently linked contiguous nucleotide units comprised in the modified oligonucleotide. These methods generally apply phosphoramidite chemistry.III. Conjugate

[0107] The present invention relates according to a further aspect to a conjugate comprisingthe modified oligonucleotide or a pharmaceutically acceptable salt thereof according to the present invention, and at least one conjugate moiety covalently attached to said modified oligonucleotide, or said pharmaceutically acceptable salt thereof. 64Evotec International GmbH EVO28777PCTIV. Pharmaceutical Compositions

[0108] The present invention relates according to a further aspect to a pharmaceuticalcomposition comprising the modified oligonucleotide or pharmaceutically acceptable salt thereof as above-outlined in more detail and a pharmaceutically acceptable excipient.

[0109] The present invention relates according to a further aspect to a pharmaceuticalcomposition comprising the conjugate according to the present invention and a pharmaceutically acceptable excipient.

[0110] Particular embodiments (e.g. regarding the modified oligonucleotide of theinvention) are already above-outlined and shall hold for the pharmaceutical composition as well. In the following, particular embodiments of the pharmaceutical composition are described in further detail. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments.

[0111] In some embodiments of the present invention, the pharmaceutically acceptableexcipient is selected from the group consisting of water, salt solutions (e.g. saline), alcohol, buffer solution (e.g. artificial cerebrospinal fluid), buffered saline (e.g. phosphate buffered saline - PBS), surfactants (such as polysorbate 80, polysorbate 20, poloxamer 188; and the like) polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone. Preferably, the pharmaceutically acceptable excipient is sterile. In certain embodiments, the pharmaceutically acceptable excipient is sterile water, sterile saline, sterile buffer solution, or sterile artificial cerebrospinal fluid.

[0112] In some embodiments of the present invention, the pharmaceutical compositioncomprises an additional active agent that is different to the modified oligonucleotide or pharmaceutically acceptable salt thereof according to the present invention.

[0113] Pharmaceutical compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered. The active pharmaceutical ingredient (in the present case the modified oligonucleotide or pharmaceutically acceptable salt thereof) and the further substances are typically combined in a manner that mammalian subject safety and treatment efficacy is ensured. A pharmaceutical composition for injectables can be an aqueous solution, a suspension, a frozen aqueous solution or a lyophilizate (a lyophilized powder), wherein the lyophilizate is reconstitutable to an aqueous solution. A pharmaceutical 65Evotec International GmbH EVO28777PCTcomposition that is a lyophilizate has gone through the process of lyophilization (freeze- drying), wherein a solution with the pharmaceutical composition is first frozen, then water and other volatile substances are removed under vacuum through the process of sublimation.

[0114] These pharmaceutical compositions may be sterilized by conventional sterilizationtechniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 7 and 8, such as 7 to 7.5. The resulting pharmaceutical compositions in solid form may be packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules. The pharmaceutical composition in solid form can also be packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.

[0115] The pharmaceutical composition may be in form of tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspension and lozenges e.g. for the oral ingestion by a subject. The pharmaceutical composition may also be in form of a solution for the parenteral administration such as for intrathecal, intravenous, intramuscular, subcutaneous, intraperitoneal, or intraocular administration and the like.

[0116] Sterile injectable solutions can be prepared by incorporating the activepharmaceutical ingredient in the required amount in the appropriate solvent with any of the other ingredients enumerated above, as required, followed by sterile filtration. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0117] In certain embodiments, modified oligonucleotides of the invention are in aqueoussolution with an alkali such as sodium or potassium. In certain embodiments, modified oligonucleotides of the invention are in PBS. In certain embodiments, modified oligonucleotides of the invention are in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and / or HCl to achieve a desired pH. In certain embodiments, modified oligonucleotides of the invention are formulated in a lipid solution.V. Applications66Evotec International GmbH EVO28777PCT

[0118] The modified oligonucleotide or pharmaceutically acceptable salt thereof or thepharmaceutical composition of the present invention may be utilized as research reagents for, for example, diagnostics, therapeutics and prophylaxis.

[0119] In research, such modified oligonucleotides of the invention may be used tospecifically modulate the synthesis of ATXN3 protein in cells (e.g. in vitro cell cultures) andexperimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention. Typically, the target modulation is achieved by degrading or inhibiting the (pre)mRNA producing the protein, thereby preventing protein formation or by degrading or inhibiting a modulator of the gene or (pre)mRNA producing the protein.

[0120] If employing the modified oligonucleotide of the invention in research ordiagnostics the target nucleic acid may be a (synthetic) nucleic acid derived from DNA or RNA.

[0121] The present invention relates in a further aspect to an in vitro method for reducingATXN3 expression in a target cell expressing ATXN3, said method comprising administering a modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined herein, or the pharmaceutical composition as defined herein in an effective amount to said cell.

[0122] The present invention relates in a further aspect to a modified oligonucleotide or apharmaceutically acceptable salt thereof as defined herein or the pharmaceutical composition as defined herein for use in reducing ATXN3 expression in a target cell expressing ATXN3 in vivo.

[0123] The present invention relates in a further aspect to a modified oligonucleotide or apharmaceutically acceptable salt thereof as defined herein or to the pharmaceutical compositionas defined herein for reducing ATXN3 expression in a target cell expressing ATXN3 in vitro.

[0124] In some embodiments of the present invention, the target cell is a mammalian cell,in particular a human cell. The target cell may be present in an in vitro cell culture or may bean in vivo cell forming part of a tissue in a mammal.

[0125] In diagnostics, the modified oligonucleotide or pharmaceutically acceptable saltthereof may be used to detect and quantitate ATXN3 expression in cell and tissues by northernblotting, in-situ hybridization or similar techniques.

[0126] The present invention relates in a further aspect to a modified oligonucleotide or apharmaceutically acceptable salt thereof as defined herein or the pharmaceutical composition as defined herein for use in medicine. 67Evotec International GmbH EVO28777PCTThe present invention relates in a further aspect to a modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined herein or the pharmaceutical composition as defined herein for use in a method of treating or preventing a neurodegenerative disease, preferably spinocerebellar ataxia, more preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. The present invention also relates to the use in a method of treating or preventing ALS.

[0127] In some embodiments of the present invention, the subject is a mammal, preferablya human.

[0128] The disease or disorder, as referred to herein, is associated with expression ofATXN3. In some embodiments the disease or disorder may be associated with a mutation in the ATXN3 gene. Therefore, in some embodiments, the target nucleic acid is a mutated form of the ATXN3 sequence.

[0129] The methods of the invention are preferably employed for treatment or prophylaxisagainst diseases caused by abnormal levels and / or activity of ATXN3. The invention furtherrelates to use of a modified oligonucleotide as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for the manufacture of amedicament for the treatment of abnormal levels and / or activity of ATXN3.

[0130] In some embodiments, the invention relates to a modified oligonucleotide as definedherein or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions as defined herein for use in the treatment of a neurodegenerative disease, preferably spinocerebellar ataxia, more preferably spinocerebellar ataxia 3 (Machado-Joseph disease).

[0131] In some embodiments of the present invention, the modified oligonucleotide definedherein or a pharmaceutically acceptable salt thereof or the pharmaceutical composition defined herein may be administered oral. In further embodiments of the present invention, the modified oligonucleotide defined herein or a pharmaceutically acceptable salt thereof or the pharmaceutical composition defined herein may be administered topical, enteral, or parenteral (such as, intravenous, intramuscular, subcutaneous, intradermal intracerebral, intracerebroventricular, or intrathecal). 68Evotec International GmbH EVO28777PCT

[0132] In a preferred embodiment the modified oligonucleotide defined herein or apharmaceutically acceptable salt thereof or the pharmaceutical composition as defined herein are administered by a parenteral route including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, intrathecal or intracranial, e.g. intracerebral or intraventricular, intravitreal administration. In some embodiments of the present invention, the modified oligonucleotide defined herein or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as defined herein is administered intravenously. In another embodiment of the present invention, the modified oligonucleotide defined herein or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as defined herein is administered subcutaneously.

[0133] In some embodiments the modified oligonucleotide as defined herein or apharmaceutically acceptable salt thereof or pharmaceutical composition as defined herein is for use in a combination treatment with another therapeutic agent (i.e. an additional active agent that is different to the modified oligonucleotide or a pharmaceutically acceptable salt thereof according to the present invention). Said therapeutic agent can for example be the standard of care for the diseases or disorders described above.

[0134] The modified oligonucleotide or a pharmaceutically acceptable salt thereof asdefined herein may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).

[0135] As shown below in the Examples, the modified oligonucleotide of the presentinvention is suitable for reduction of ATXN3 expression.

[0136] The conjugate according to the present invention may also be suitable for the aboveapplications.VI. Methods of Treatment

[0137] The present invention provides a modified oligonucleotide or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the present invention, for use in the treatment or prevention of one or more diseases or disorders associated with ATXN3 expression.

[0138] The therapeutic method described may be applied to mammals such as dogs, cats,cows, horses, rabbits, monkeys and humans. Preferably, the mammalian subject in need of the treatment is a human. 69Evotec International GmbH EVO28777PCT

[0139] Yet another aspect of the present invention is a method for treating, controlling,delaying and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with ATXN3 expression, wherein the method comprises administering to the subject a therapeutically effective amount of a modified oligonucleotide or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[0140] Yet another aspect of the present invention is a method of treating, controlling,delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with mutations in the ATXN3 gene including CAG repeat expansion, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention.

[0141] Yet another aspect of the present invention is a method of treating, controlling,delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with overexpression of ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention.

[0142] Yet another aspect of the present invention is a method for treating, controlling,delaying and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions mentioned herein, wherein the method comprises administering to the subject a therapeutically effective amount of a modified oligonucleotide or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[0143] Diseases or disorders amenable to treatment using the compounds and compositionsof the invention include but are not limited to diseases associated with spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease). Further diseases or disorders amenable to treatment using the compounds and compositions of the invention include but are not limited to ALS.

[0144] Any suitable route of administration may be employed for providing a mammal,especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, 70Evotec International GmbH EVO28777PCTaerosols, and the like. Suitably, the modified oligonucleotide or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention are administered parenteral. Preferably, the modified oligonucleotide or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention are administered intravenous, subcutaneous, intravitreal, or intrathecal.

[0145] The effective dosage of active ingredient employed may vary depending on theparticular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

[0146] The conjugate according to the present invention may also be suitablefor the above methods of treatment. EXAMPLES

[0147] Where the context allows, the term “ASO” is used interchangeably withthe term “compound(s)”. The following Abbreviations and Acronyms are used (Table 1):71Evotec International GmbH EVO28777PCTI Chemical synthesisSynthesis

[0148] All modified oligonucleotides (named ASO1 to ASO22 as disclosed in Table 3) weresynthesized with the classical way of phosphoramidites. Synthesis were performed on Universal Support Column, DMT off (N-iPr), 1000 Å, 1 μmol scale on a MerMade 48X synthesizer with solutions of phosphoramidites at 0.1 M and BTT in Acetonitrile (0.3 M) as activator. The time coupling was 1 min for DNA and 3 min for LNA. At the end of the synthesis, a first deprotection step was performed with 20% of diethylamine to remove the cyanoethyl group of all phosphate / phosphorothioate backbone. After the synthesis, oligonucleotides were cleaved from the solid support using aqueous ammonia following by heating for 4 hours at 55 °C to deprotect all nucleobases.

[0149] All ASOs were purified by AEX chromatography and characterized by UPLC / MS.

[0150] Crude ASOs were purified by preparative Anion Exchange HPLC on a TosohTSKgel® SuperQ-5PW column (13 µm, 150 x 21.5 mm). Sodium phosphate dibasic (20 mM) and sodium chloride or bromide (1 M) were used as buffers at a flow rate of 8 mL / min. The 72Evotec International GmbH EVO28777PCTcollected fractions were desalted on an AKTA system with Cytiva HiPrep™ 26 / 10 desalting column in a water / ethanol (80 / 20) isocratic system. ASO titrations were performed with a nanodrop, and the endotoxin threshold was checked with a Nexgen PTS to ensure an endotoxin level of less than 0.1 EU / mg. All compounds were freeze-dried to give the purified oligonucleotide as a white solid. Compound preparation and formulation

[0151] For in vitro characterization compounds were dissolved either in WFI or NaCl 0.9%(100%; v).

[0152] For in vivo testing compounds were dissolved in NaCl 0.9% (100%; v). Theformulations were prepared ahead of time and stored at -20 °C (protected from light) for up to 3 weeks. Before each administration, the corresponding formulation is brought to room temperature and vortexed prior to use. Sequences

[0153] Table 2: Unmodified oligonucleotide sequence

[0154] Table 3: List of modified oligonucleotides73Evotec International GmbH EVO28777PCT74Evotec International GmbH EVO28777PCTActivity Assessment in iPSC neurons Cell Culture and Compound treatment

[0155] Several LNA modified oligonucleotides targeting human ATXN3 and non-targetingcontrols were tested in iPSC-derived cortical neurons. iPS cells from an apparently healthy individual (CENSOi016-A; wild type (wt)) as well as from an individual suffering from Machado-Joseph disease (CENSOi071-A; mutation in ATXN3 gene; mutated (mut)) were purchased from Censo Biotechnologies. iPS cells were differentiated into cortical neurons according to Tchieu et al. (A Modular Platform for Differentiation of Human PSCs into AllMajor Ectodermal Lineages. 2017, Cell Stem Cell, 21(3), 399-410.e7.https: / / doi.org / 10.1016 / j.stem.2017.08.015) with minor adaptations. For the assay cells were seeded in 384 multiwell plates in neuronal maturation medium (DMEM / F12, Glutamax, N2, B21, Pen / Strep, 20 ng / ml GDNF, 20 ng / ml BDNF, 200 µM cAMP, 200 µM ascorbic acid, 10 µM DAPT, 10 µM ROCKi). ROCKi was removed from the medium 1 day after seeding. Cells were grown for 7 days before treatment with titrated amounts of respective antisense oligonucleotides (top concentration of 5 µM). Seven days post-treatment, cells were harvested and lysed for different assays. RNA Quantification via QuantiGene assay 75Evotec International GmbH EVO28777PCT

[0156] For RNA Quantification, cells were lyzed using QuantiGene lysis mixture(Component of the QuantiGene Singleplex assay kit (Thermofisher QS0016)) according to the manufacturer’s instructions. QuantiGene Singleplex assay kit was used to determine expression of human HPRT1 and human ATXN3 according to the manufacturer’s instructions. ATXN3 expression values were normalized for expression values of HPRT1. HPRT1 normalized ATXN3 expression values of ASO-treated samples were divided by HPRT1 normalized ATXN3 expression values of mock-treated samples and multiplied by 100 to obtain “Remaining % ATXN3 RNA at X concentration”.

[00157] Table 4: QuantiGene reagents

[00158] Table 5: Results from single concentration screen in wt iPSC-derived cortical neurons76Evotec International GmbH EVO28777PCT

[0159] Table 6: mRNA expression analysis in iPSC-derived cortical neuronsATXN3 protein quantification (total and mutant ATXN3 protein) Method

[0160] MSD 384-well plates (MA6000; Meso Scale Discovery) were coated overnight at4 °C with 10 μL of coating antibody in a carbonate-bicarbonate coating buffer (15 mM Na2CO3 / 35 mM NaHCO3, pH 9.6) per well. Plates were then washed three times with 35 μL of wash buffer (0.2% Tween-20 in PBS) per well and blocked with 10 μL of blocking buffer (2% probumin / 0.2% Tween-20 in PBS) per well for 1 h at RT with horizontal shaking. In the 77Evotec International GmbH EVO28777PCTmeantime, samples were thawed on ice. After four additional washing steps, 10 μL per sample were transferred to each well of the antibody-coated MSD plate and incubated over night at 4 °C. After disposal of samples and four wash cycles with 35 μL of wash buffer, 10 μL of the primary detection antibody was added to each well and incubated with shaking for 1 h at RT. Prior to adding 10 μL anti-mouse SULFO-TAG labeled secondary detection antibodies, additional washing steps and an incubation for 1 h at RT was conducted. After washing three times with wash buffer, 35 μL of read buffer were added to each well and the plate was imaged on a Sector Imager 6000 (Meso Scale Discovery) according to manufacturers’ instructions. The following antibody combinations were used (Table 7):

[0161] Optimal antibody concentrations may vary with each new SULFO-TAG-labelledantibody batch.

[0162] Table 8: hATXN3 protein quantification via MSD assay in wt iPSC-derived corticalneurons78Evotec International GmbH EVO28777PCT

[0163] Table 9: hATXN3 protein quantification via MSD assay in ATXN3 mut iPSC-derivedcortical neuronsTranscriptomic analysis in iPSCs to assess target knock-down and off-targets Differential Gene Expression Analysis

[0164] To obtain differentially expressed genes, and assess on and off target effects, pairwisecomparisons of each combination of ASO / Concentration against the Water control (WFI) were performed with the package DEseq2 (Love MI et al., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. 2014, Genome Biology, 15(12). https: / / doi.org / 10.1186 / s13059-014-0550-8). These comparisons were done grouping samples by Plate / cell line yielding a total of 400 comparisons.

[0165] After multiple comparison correction, gene changes with an False Discovery Rate(FDR) < 0.05 were considered as significant, no logFC threshold was applied to be as sensitive as possible to off target effects. logFC is Fold Change expressed on log2 units, where Fold Change is (Expression on Numerator[treated] samples) / (Expression on Control samples). 79Evotec International GmbH EVO28777PCT

[0166] Knockdown efficiency of ATXN3 was calculated percentagewise, as well by logFCvalues through the experiment.

[00167] Table 10a: ATXN3 Target Knockdown – LogFC for ATXN3 (significant results arehighlighted in bold); wt

[00168] Table 10b: ATXN3 Target Knockdown – LogFC for ATXN3 (significant results arehighlighted in bold); mut

[00169] Table 11a: Off-target effects – Comparative numbers of Differentially ExpressedGenes triggered by ASO treatment: Dose response in wt iPSC-derived cortical neurons80Evotec International GmbH EVO28777PCT

[0170] Table 11b: Off-target effects – Comparative numbers of Differentially ExpressedGenes triggered by ASO treatment: Dose response in ATXN3 mut iPSC-derived cortical neurons

[0171] Conclusion: For comparable on-target (Atxn3) potency, the number of differentiallyexpressed genes (DEG) indicative of dose dependent unwanted off target effects occurring upon ASO treatment is very high for comparator ASO_1122_67. ASO2 as well as variants ASO11 and ASO12 lead to a concentration dependent reduction of ATXN3 levels in both wt and mut ATXN3 iPSC-derived cortical neurons. At the same time, they exhibit an improved selectivity profile as it is indicated by the limited number of DEGs with increasing ASO concentration and significantly reduced ATXN3 level. In this context, it is noted that while ASO 1122_67 exhibits a comparable activity as the above ASOs of the present invention, the comparator ASO 1122_67 leads to a very high number of off-target effects, indicating promiscuous binding and non-specific activity on other human genes. ASO 1100673 and ASO 1101915 are less potent than indicated ASOs of the present invention (see Tables 6, 8, 9, 10a and 10b). MEA assay

[0172] To investigate compound effects on neuronal activity in vitro a multielectrode arrayassay was conducted on the MEA platform Maestro (Axion Biosystems). Initially, a MEA 48- well plate (M768-KAP-48) was first coated with freshly prepared 0.07% PEI in borate buffer solution, followed by a laminin coating the next day. On the same day, mouse primary cortical neurons were seeded (75k cells / well) and on DIV3 mouse primary astrocytes were added to the well (25k cells / well), accompanied by a half-medium change. On DIV13, basal activity was 81Evotec International GmbH EVO28777PCTrecorded before compounds were added at a concentration of 50 µM to the well. Spontaneous network activity from cortical cultures was recorded with the Axion multiwell MaestroTMMEA system 2 h after the compound application and analysis was performed using the Axion Integrated Studio software. Multiple parameters were measured (up to 50) and were taken into account for the classification of the test substances including the impact of the ASO treatment on neuronal firing rate. Test substances that did not change selected parameters by more than 50% in comparison to vehicle treated wells were assigned to class 1. Oligonucleotides that altered parameters between 51-70% were placed in class 2. Compounds that caused greater changes were classified as class 3 and considered to be neurotoxic and not suitable for progression in vivo.

[0173] Table 12: Results from MEA assay82Evotec International GmbH EVO28777PCTTarget engagement study Animal care

[0174] Hemizygous YAC84Q mice (B6;CBA-Tg(ATXN3*)84.2Cce / IbezJ; Jax Strain#:012705) were obtained from the Jackson Laboratory, USA. Before starting the experiments, the animals were kept in the facility for at least 1 week to ensure their acclimatization. The animal testing rooms were subject to constant conditions with a relative humidity of 55 ± 5 % and a temperature of 22 ± 2 °C with a 12h00 / 12h00 light / dark cycle. After delivery by the breeder, the animals were kept in groups in transparent polycarbonate cages (365 x 207 x 140 mm (L x W x H), 530 cm2; Eurostandard Type IIL L x W x H), 1820 cm2 Tecniplast, Germany). Standard aspen material was used as a base in the cages and paper towels were used for nest building and occupation. The animals were provided with food and received autoclaved water ad-libitum. The animal facility fulfils all conditions according to the guidelines for the keeping and care of laboratory animals and has been AAALAC accredited. Stereotaxic mouse ICV ASO Administration

[0175] Animals were given buprenorphine (0.05 mg / kg subcutaneously) for pre-operativeanalgesia at least 30 minutes before the start of surgery. The animal was then first anesthetized using isoflurane inhalation, then the head was fixed in a stereotactic frame. Anesthesia was maintained throughout the procedure using a mask. Body temperature was monitored by a rectal probe and maintained at a constant 36-37 °C by thermostatically controlled pad. The eyes were protected from dehydration by applying eye ointment and the surgical area was disinfected. After ensuring that the animal was successfully anesthetized, a drop of lidocaine (2%) was applied to the scalp before an approximately 1cm long central longitudinal incision was made above the scalp. Using a dental drill (~1 mm), a small hole was drilled into the skull at the defined coordinates (AP: +0.26 mm, ML: ±0.90 mm, DV: -2.18 mm) and 1.5 µl of ASO or vehicle solution (per ventricle; total 3 µl) was injected bilaterally into the ventricles using a 10 µL Hamilton syringe (flow rate: 0.5 µl / min). After the stereotactic injection, the skin was closed with tissue glue. Postoperatively, the mice were placed on a warming plate and closely monitored until they awaken from the anesthesia. After recovery, the animals were transferred to their home cages and provided with meshed food. For postoperative analgesia, the animals 83Evotec International GmbH EVO28777PCTwere given tramadol (1 mg / kg) in their drinking water and meshed food for 2 days. After the operation, the animals' complete recovery and body weight were monitored daily for at least 7 days. Thereafter, mice observed daily; bodyweight was assessed twice a week until the end of the experiment. Tissue preparation Euthanasia

[00176] The brain and relevant tissue were removed and analyzed for the effect of the testsubstances on the target structures and the human mutATXN3 level. RNA quantification

[00177] To a maximum of 30 mg of fresh or frozen tissue, 350 µL of Buffer RLT (Qiagen,Cat. No.79216) were added and homogenized using a FastPrep instrument. RNA was purified from 350 µL of supernatant using RNeady Mini Kit according to the manufacturer’s instructions (Qiagen, Cat. No. M6250-100mL). Purified RNA was stored at -80 °C until further use. For cDNA synthesis 1000 ng RNA was used. Initially, Mastermix I (oligo (dt) primer, random hexamers, dNTP mix) and purified RNA were added to a 96-well plate and incubated at 65 °C for 5 min before incubating the plate on ice for 1 min. Next Mastermix II (Buffer RT (Qiagen), MgCl2, DTT, RNAse Out, Superscript III (ThermoFisher, 18080-51)) was added to each well and the plate was subjected to the following protocol in a Thermal Cycler (10 min at 25 °C, 50 min at 50 °C, 5 min at 85 °C). cDNA was diluted to a final concentration of 12.5 ng / µL and stored at -80 °C until further use. For quantitative, real-time PCR, each sample was run in quadruplicates. To each reaction 2 µL cDNA and 8 µL Mastermix III (Taqman Gene Expression Assay, TaqMan Gene Expression Master Mix (ThermoFisher, 4369016)) was added. Plates were centrifuged before analyzing the samples using qPCR (Incubation at 50° C for 2 min and 95° C for 10 min followed by 45 cycles at 95° C for 15 sec and 60° C for 1 min). Assay probes are described below. Data was analyzed using the relative standard curve method where each is first normalized to the housekeeping gene (HPRT1) and then expressed as percent of untreated control animals.

[00178] Table 13: TaqMan Gene Expression Assays84Evotec International GmbH EVO28777PCT

[00179] Table 14: qPCR results - Remaining ATXN3 levels [%] 4 weeks after ASOadministration

[00180] Table 15: qPCR results - Remaining ATXN3 levels [%] 4 weeks after ASOadministration85Evotec International GmbH EVO28777PCTEfficacy Study: Materials and Methods Animals

[0181] Experiments were conducted using male and female homozygous YAC84Q mice(B6;CBA-Tg(ATXN3*)84.2Cce / IbezJ; Jax Strain #:012705) and wild type C57BL / 6 mice. The YAC84Q mice are a transgenic model expressing the full-length human ATXN3 gene with an expanded CAG repeat tract, used to study MJD (SCA3). The homozygous genotype confers a robust motor phenotype, facilitating efficient evaluation of therapeutic interventions.

[0182] Genotyping was conducted from tail biopsies collected prior to weaning. Animalswere sex- and age-matched for each study. Mice were acclimatized for at least one week before study initiation. Housing conditions included constant conditions with a relative humidity of 55 ± 5 % and a temperature of 22 ± 2 °C with a 12-hour light / dark cycle. After delivery by the breeder (Janvier Labs), the animals were housed in groups in transparent polycarbonate cages (365 x 207 x 140 mm (L x W x H), 530 cm2; Eurostandard Type IIL L x W x H), 1820 cm2Tecniplast, Germany). The animals were provided with food and received autoclaved water ad- libitum. The facility complies with the National Research Council guidelines for the care and use of laboratory animals (NRC 1996 and 2011) and has maintained AAALAC accreditation since March 2015. Study design

[0183] Ataxin3-targeting ASO11 (150 µg dose) or non-targeting ASO (NTC; 150 µg dose)or vehicle (i.e. saline) were administered to the mice via intracerebroventricular (ICV) route at 8 weeks of age. Ten weeks later, mice received a second ICV administration at 150 µg dose of same substance. Mice were tested for their rearing activity (i.e. vertical activity as upright standing on hind limbs) before the ICV administration at 7 weeks of age, and after ICV administration at 12, 16 and 23 weeks of age. The treatment regimen for each group of mice is shown in the Table 16 below. Mice were sacrificed at 24 weeks of age. Stereotaxic intracerebroventricular (ICV) administration of ASO in mice

[0184] Prior to ICV administration, the mice were given buprenorphine (0.05 mg / kg,subcutaneously) for pre-operative analgesia at least 30 minutes before the surgery. Mice were anesthetized via isoflurane inhalation, and the head was fixed in a stereotactic frame. Anesthesia 86Evotec International GmbH EVO28777PCTwas maintained throughout the procedure via a mask. Body temperature was monitored by a rectal probe and maintained at a constant 36-37°C by thermostatically controlled pad. The eyes were protected from dehydration by applying ophthalmic ointment and the surgical area was disinfected. Once anesthesia was confirmed, a drop of lidocaine (2%) was applied to the scalp and a 1 cm longitudinal incision was made at the midline of the scalp. Using a dental drill (~1 mm), two small holes were drilled into the skull at the defined coordinates (Anterior-Posterior (AP): +0.26 mm, Medial-Lateral (ML): ±0.90 mm, Dorsal-Ventral (DV): -2.18 mm) and 1.5 µl of ASO or vehicle solution per ventricle (total 3 µl volume) was injected bilaterally into the ventricles using a 10 µL Hamilton syringe (flow rate: 0.5 µl / min). After the stereotactic injection, the incision was closed with tissue glue. Postoperatively, the mice were placed on a warming plate and closely monitored until recovery from anesthesia. Upon recovery, the animals were transferred to their home cages and provided with meshed food. For postoperative analgesia, the animals were given tramadol (1 mg / kg) in their drinking water and meshed food for 2 days. Health status was monitored daily throughout the experimental period. Rearing assessment for motor behavior evaluation

[0185] Rearing time was evaluated in homozygous YAC84Q mice using an open fieldapparatus equipped with clear Plexiglas walls and a photobeam activity detection system (ActiMot2, TSE Systems). Each mouse was placed individually in the arena for a 30-minute session to monitor vertical activity, serving as an indicator of exploratory behavior and motor function deficit associated with the MJD phenotype. Data analysis was performed by two-way mixed ANOVA with Geisser-Greenhouse‘s correction; multiple comparison were performed by Tukey test. Statistical analysis demonstrated a significant main effect of treatment (F(3, 53) = 14.39, p < 0.001), indicating enhanced rearing behavior in ASO11 treated group. This effect was not observed in animals receiving the vehicle (i.e. saline) or NTC groups, confirming that the behavioral changes were specific to the ASO11 treatment. These results demonstrate potential use of ASO11 in therapeutic applications. Table 16: Treatment groups; WT denotes wild type mice and N denotes animal numbers87Evotec International GmbH EVO28777PCT

[0186] Homozygous YAC84Q mice, an animal model for SCA3, show reduced rearingactivity time compared to wild type animals at 7 weeks of age (p<0.005) resembling symptoms in SCA3 patients. ASO11 administration led to recovery in rearing time as measured after 4 weeks after the first ASO administration (150 µg dose) as ASO11 treated YAC84Q mice performed comparable to wild type controls (p=0.9747) which persisted throughout experimental timeline (cf. Figure 1). Difference between YAC84Q / ASO11 and YAC84Q / Saline groups were indicated in the graph. #p=0.067 *p<0.05, ** p≤0.005, ***p≤0.001, ****p≤0.0001. N=14-15 / group. Data is shown as Mean±SD. EQUIVALENTS

[0187] The present technology is not to be limited in terms of the particular embodimentsdescribed in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0188] In addition, where features or aspects of the disclosure are described in terms ofMarkush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. ITEMS

[0189] In view of the above, it will be appreciated that the present invention also relates tothe following items:88Evotec International GmbH EVO28777PCTItem 1. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGANN(me)CNA(me)CAAN(me)C(me)CNNN(me)C (SEQ ID NO: 6), wherein the modified oligonucleotide comprises at least one modification selected from the group consisting of a modified sugar, a modified internucleoside linkage, and combinations thereof, wherein (me)C denotes cytosine or 5-methyl cytosine, and wherein N denotes thymine or uracil. Item 2. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises at least one modification selected from the group consisting of a modified sugar, a modified internucleoside linkage, and combinations thereof, and wherein (me)C denotes cytosine or 5-methyl cytosine. Item 3. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to item 1 or 2, wherein the modified sugar comprises a (deoxy)ribose ring modified by a substituent linking the C2’ and C4’ of the (deoxy)ribose sugar ring. Item 4. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 1 to 3, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. Item 5. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGANN(me)CNA(me)CAAN(me)C(me)CNNN(me)C (SEQ ID NO: 6), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence ofANN(me)CNA(me)CAAN(me)C(me)CNN (SEQ ID NO: 8; nucleobases 3 to 16 of SEQ ID NO: 6), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non-modified nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are 89Evotec International GmbH EVO28777PCTindependently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a non- modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are are non-modified nucleosides linked by phosphorothioate internucleoside linkages, wherein (me)C denotes cytosine or 5-methyl cytosine, and wherein N denotes thymine or uracil. Item 6. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT (SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non-modified nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: 90Evotec International GmbH EVO28777PCTa) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a non- modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are non-modified nucleosides linked by phosphorothioate internucleoside linkages, and wherein (me)C denotes cytosine or 5-methyl cytosine. Item 7. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT (SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non-modified nucleosides are phosphorothioate internucleoside linkages, and 91Evotec International GmbH EVO28777PCTii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides, wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a non- modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are non-modified nucleosides linked by phosphorothioate internucleoside linkages; wherein non-modified nucleoside means a nucleoside comprising an unmodified sugar moiety and a nucleobase selected from the group consisting of A, G, T, and (me)C; andwherein (me)C denotes cytosine or 5-methyl cytosine. Item 8. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, the modified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: 92Evotec International GmbH EVO28777PCTi) core nucleosides of a nucleobase sequence of ATT(me)CTA(me)CAAT(me)C(me)CTT (SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive nucleosides each comprising an unmodified sugar moiety and a nucleobase selected from the group consisting of A, T,and (me)C, and internucleoside linkages, wherein the internucleoside linkages betweenall of said consecutive nucleosides of said core nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein:a) each consecutive nucleoside of said 5’ stretch comprises an LNA nucleoside, andwherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, orb) the 5’ stretch consists of three consecutive linked nucleosides, wherein anucleoside comprising an unmodified sugar moiety and a guanine nucleobase is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNA nucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 3’ stretch consists of three consecutive linked nucleosides, wherein a nucleoside comprising an unmodified sugar moiety and a thymine nucleobase is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are nucleosides comprising an unmodified sugar moiety and a nucleobase selected from 93Evotec International GmbH EVO28777PCTthe group consisting of A, G, T, and (me)C linked by phosphorothioate internucleosidelinkages, and wherein (me)C denotes cytosine or 5-methyl cytosine. Item 9. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 8, wherein the core sequence as defined in i) partially overlaps with the 5’ stretch as defined in ii), and / or wherein the core sequence as defined in i) partially overlaps with the 3’ stretch as defined in iii). Item 10. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 8, wherein the core sequence as defined in i) does not overlap with the 5’ stretch as defined in ii), preferably wherein the core sequence is linked to the 5’ stretch by phosphorothioate internucleoside linkage, and / or wherein the core sequence as defined in i) does not overlap with the 3’ stretch as defined in iii), preferably wherein the core sequence is linked to the 3’ stretch by phosphorothioate internucleoside linkage. Item 11. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 10, wherein at least nine nucleosides, preferably at least ten nucleosides, more preferably at least eleven nucleosides of said core nucleosides are consecutive non- modified nucleosides, and wherein the internucleoside linkages of all of said non-modified nucleosides are phosphorothioate internucleoside linkages. Item 12. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 11, wherein: A) the nucleosides of the 5’ stretch defined under ii) a) are linked by 0, 1, 2, 3 or 4 phosphorothioate internucleoside linkages, and B) the nucleosides of the 3’ stretch defined under iii) a) are linked by 0, 1, 2, 3 or 4 phosphorothioate internucleoside linkages, wherein the remaining internucleoside linkages of the 5’ stretch and of the 3’ stretch are phosphodiester internucleoside linkages. Item 13. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12, wherein the C at position 18 of the nucleobase sequence SEQ ID 94Evotec International GmbH EVO28777PCTNo.1 (or the nucleobase sequence SEQ ID No.6) is 5-methyl cytosine, preferably wherein the nucleobase sequence (SEQ ID NO: 1) has the nucleobase sequence of AGATTCTACAATC(me)CTTTmeC (SEQ ID NO: 2), more preferably has the nucleobasesequence of AGATTCTACAATCCTTTmeC (SEQ ID NO: 3), wherein meC denotes 5-methylcytosine. Item 14. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 13, wherein if (me)C is comprised in an LNA nucleoside, then (me)C ismeC. Item 15. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 5 to 14, wherein the LNA nucleoside is independently selected from the group consisting of beta-D-oxy LNA nucleoside and 6’-methyl-beta-D-oxy LNA nucleoside, preferably the LNA nucleoside is beta-D-oxy LNA nucleoside. Item 16. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 1 to 15, wherein the modified oligonucleotide is selected from the group consisting of the following compounds ASO1, ASO2, ASO3, ASO4, ASO5, ASO6, ASO7, ASO8, ASO9, ASO10, ASO11, ASO12, ASO13, ASO14, ASO15, ASO16, ASO17, ASO18, ASO19, ASO20, ASO21, and ASO22. Item 17. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 1 to 16, wherein the modified oligonucleotide is selected from the group consisting of the following compounds ASO2, ASO3, ASO4, ASO5, ASO6, ASO7, ASO8, ASO9, ASO10, ASO11, ASO12, ASO14, ASO15, ASO16, ASO17, ASO18, ASO19, ASO20, ASO21, and ASO22. Item 18. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of items 1 to 17, wherein the modified oligonucleotide is selected from the group consisting of ASO2, ASO3, ASO5, ASO6, ASO7, ASO8, ASO9, ASO10, ASO11, ASO12, and ASO18, preferably wherein the modified oligonucleotide is selected from the group consisting of ASO2, ASO3, ASO6, ASO7, ASO8, ASO9, ASO11, ASO12, and ASO18, more preferably wherein the modified oligonucleotide is selected from the group consisting of ASO3, ASO6, 95Evotec International GmbH EVO28777PCTASO7, ASO11, ASO12, and ASO18, even more preferably wherein the modified oligonucleotide is ASO7, ASO11, ASO 12 or ASO18. Item 19. A modified oligonucleotide or a pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structureASO7. Item 20. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 96Evotec International GmbH EVO28777PCTASO11. Item 21. A salt of a modified oligonucleotide having the chemical structure 97Evotec International GmbH EVO28777PCT(sodium salt of ASO11). Item 22. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 98Evotec International GmbH EVO28777PCTASO12. Item 23. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 99Evotec International GmbH EVO28777PCTASO18. Item 24. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 100Evotec International GmbH EVO28777PCTASO1. Item 25. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 101Evotec International GmbH EVO28777PCTASO13. Item 26. The pharmaceutical composition according to any one of items 5 to 7 and 11, wherein non-modified nucleoside means a nucleoside comprising an unmodified sugar moiety and a nucleobase selected from the group consisting of A, G, T, and C. Item 27. A pharmaceutical composition comprising the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 and a pharmaceutically acceptable excipient.Item 28. An in vitro method for reducing ATXN3 expression in a target cell expressingATXN3, said method comprising administering a modified oligonucleotide or a 102Evotec International GmbH EVO28777PCTpharmaceutically acceptable salt thereof as defined in any one of items 1 to 26, or the pharmaceutical composition as defined in item 27 in an effective amount to said cell. Item 29. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use in medicine. Item 30. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use inreducing ATXN3 expression in a target cell expressing ATXN3 in vivo.Item 31. Use of the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or of the pharmaceutical composition as defined in item 27for reducing ATXN3 expression in a target cell expressing ATXN3 in vitro.Item 32. A method of treating, controlling, delaying, or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders associated with ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27. Item 33. A method of treating, controlling, delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with mutations in the ATXN3 gene including CAG repeat expansion, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27. Item 34. A method of treating, controlling, delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with overexpression of ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27. 103Evotec International GmbH EVO28777PCTItem 35. The method according to any one of items 32 to 34, wherein the disease or disorder is a neurodegenerative disease or disorder, preferably spinocerebellar ataxia, more preferably spinocerebellar ataxia 3 (Machado-Joseph disease). Item 36. The method according to item 35, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS). Item 37. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use in a method of treating or preventing of one or more diseases or disorders associated with ATXN3 in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. Item 38. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use in a method of treating or preventing spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. Item 39. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use in a method of treating or preventing amyotrophic lateral sclerosis (ALS), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. Item 40. The modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the pharmaceutical composition as defined in item 27 for use according to any one of items 37 to 39, wherein the subject is a human. 104Evotec International GmbH EVO28777PCTItem 41. A conjugate comprising the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26, and at least one conjugate moiety covalently attached to said modified oligonucleotide, or said pharmaceutically acceptable salt thereof. Item 42. A pharmaceutical composition comprising the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 26 or the conjugate of item 41 and a pharmaceutically acceptable diluent, solvent, carrier, salt and / or adjuvant. Item 43. A pharmaceutical composition comprising the conjugate of item 41 and a pharmaceutically acceptable excipient. Item 44. The conjugate as defined in item 41 or the pharmaceutical composition as defined in item 2 or 43 for use in medicine. Item 45. The conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43 for use in a method of treating or preventing of one or more diseases or disorders associated with ATXN3 in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. Item 46. The conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43 for use in a method of treating or preventing spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. Item 47. The conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43 for use in a method of treating or preventing amyotrophic lateral sclerosis (ALS), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said pharmaceutical composition to said subject. 105Evotec International GmbH EVO28777PCTItem 48. An in vitro method for reducing ATXN3 expression in a target cell expressingATXN3, said method comprising administering a conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43 in an effective amount to said cell. Item 49. The conjugate as defined in item 41 or the pharmaceutical composition as defined initem 42 or 43 for use in reducing ATXN3 expression in a target cell expressing ATXN3 in vivo.Item 50. Use of the conjugate as defined in item 41 or of the pharmaceutical composition asdefined in item 42 or 43 for reducing ATXN3 expression in a target cell expressing ATXN3 invitro. Item 51. The conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43 for use according to any one of items 45 to 47, wherein the subject is a human. Item 52. A method of treating, controlling, delaying, or preventing in a mammalian subject in need of the treatment of one or more diseases or disorders associated with ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43. Item 53. A method of treating, controlling, delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with mutations in the ATXN3 gene including CAG repeat expansion, wherein the method comprises administering to the subject a therapeutically effective amount of the conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43. Item 54. A method of treating, controlling, delaying, and / or preventing in a mammalian subject in need of the treatment of one or more diseases, disorders or conditions associated with overexpression of ATXN3, wherein the method comprises administering to the subject a therapeutically effective amount of the conjugate as defined in item 41 or the pharmaceutical composition as defined in item 42 or 43. 106Evotec International GmbH EVO28777PCTINCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or item of information was specifically and individually indicated to be incorporated by reference. To the extent publications, patents, patent applications, and items of information incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. 107

Claims

Evotec International GmbH EVO28777PCTClaims 1. A modified oligonucleotide or a pharmaceutically acceptable salt thereof, themodified oligonucleotide having a length of 18 nucleosides linked by internucleoside linkages and having a nucleobase sequence of AGATT(me)CTA(me)CAAT(me)C(me)CTTT(me)C (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: i) core nucleosides of a nucleobase sequence ofATT(me)CTA(me)CAAT(me)C(me)CTT (SEQ ID NO: 7; nucleobases 3 to 16 of SEQ ID NO: 1), wherein at least eight nucleosides of said core nucleosides are consecutive non-modified nucleosides, and internucleoside linkages, wherein the internucleoside linkages between all of said consecutive non-modified nucleosides are phosphorothioate internucleoside linkages, and ii) a 5’ stretch of at least two and at most five consecutive linked nucleosides at the 5’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 5’ stretch comprises an LNAnucleoside, and wherein the internucleoside linkages between all nucleosides of said 5’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or b) the 5’ stretch consists of three consecutive linked nucleosides,wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, and iii) a 3’ stretch of at least two and at most five consecutive linked nucleosides at the 3’ end of the modified oligonucleotide, wherein: a) each consecutive nucleoside of said 3’ stretch comprises an LNAnucleoside, and wherein the internucleoside linkages between all nucleosides of said 3’ stretch are independently selected from phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages, or 108Evotec International GmbH EVO28777PCTb) the 3’ stretch consists of three consecutive linked nucleosides,wherein a non-modified nucleoside is positioned between and linked to two LNA nucleosides by phosphorothioate internucleoside linkages, wherein if nucleosides of the modified oligonucleotide which are not part of the 5’ stretch as defined in ii), or not part of the 3’ stretch as defined in iii) remain, these are non-modified nucleosides linked by phosphorothioate internucleoside linkages, wherein non-modified nucleoside means a nucleoside comprising an unmodified sugar moiety and a nucleobase selected from the group consisting of A, G, T, and (me)C, and wherein (me)C denotes cytosine or 5-methyl cytosine.

2. The modified oligonucleotide or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein the core sequence as defined in i) partially overlaps with the 5’ stretch as defined in ii), and / or wherein the core sequence as defined in i) partially overlaps with the 3’ stretch as defined in iii).

3. The modified oligonucleotide or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein the core sequence as defined in i) does not overlap with the 5’ stretch as defined in ii), preferably wherein the core sequence is linked to the 5’ stretch by phosphorothioate internucleoside linkage, and / or wherein the core sequence as defined in i) does not overlap with the 3’ stretch as defined in iii), preferably wherein the core sequence is linked to the 3’ stretch by phosphorothioate internucleoside linkage.

4. The modified oligonucleotide or a pharmaceutically acceptable salt thereofaccording to any one of claims 1 to 3, wherein at least nine nucleosides, preferably at least ten nucleosides, more preferably at least eleven nucleosides of said core nucleosides are consecutive non-modified nucleosides, and wherein the internucleoside linkages of all of said non-modified nucleosides are phosphorothioate internucleoside linkages.

5. The modified oligonucleotide or a pharmaceutically acceptable salt thereofaccording to any one of claims 1 to 4, wherein: A) the nucleosides of the 5’ stretch defined under ii) a) are linked by 0, 1, 2, 3 or 4 phosphorothioate internucleoside linkages, and 109Evotec International GmbH EVO28777PCTB) the nucleosides of the 3’ stretch defined under iii) a) are linked by 0, 1, 2, 3 or 4 phosphorothioate internucleoside linkages, wherein the remaining internucleoside linkages of the 5’ stretch and of the 3’ stretch are phosphodiester internucleoside linkages.

6. The modified oligonucleotide or a pharmaceutically acceptable salt thereof accordingto any one of claims 1 to 5, wherein the C at position 18 of the nucleobase sequence SEQ ID No.1 is 5-methyl cytosine, preferably wherein the nucleobase sequence (SEQ ID NO: 1) has the nucleobase sequence of AGATTCTACAATC(me)CTTTmeC (SEQ ID NO: 2), more preferably has the nucleobase sequence of AGATTCTACAATCCTTTmeC (SEQ ID NO: 3), wherein meC denotes 5-methylcytosine.

7. The modified oligonucleotide or a pharmaceutically acceptable salt thereof accordingto any one of claims 1 to 6, wherein if (me)C is comprised in an LNA nucleoside, then (me)C is meC.

8. The modified oligonucleotide or a pharmaceutically acceptable salt thereof accordingto any one of claims 1 to 7, wherein the LNA nucleoside is independently selected from the group consisting of beta-D-oxy LNA nucleoside and 6’-methyl-beta-D-oxy LNA nucleoside, preferably the LNA nucleoside is beta-D-oxy LNA nucleoside.

9. The modified oligonucleotide or a pharmaceutically acceptable salt thereof accordingto any one of claims 1 to 8, wherein the modified oligonucleotide is selected from the group consisting of the following compounds 110ASO2,ASO21, andEvotec International GmbH EVO28777PCT.

10. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the modified oligonucleotide is selected from the group consisting of ASO2, ASO3, ASO5, ASO6, ASO7, ASO8, ASO9, ASO10, ASO11, ASO12, and ASO18, preferably wherein the modified oligonucleotide is selected from the group consisting of ASO2, ASO3, ASO6, ASO7, ASO8, ASO9, ASO11, ASO12, and ASO18, more preferably wherein the modified oligonucleotide is selected from the group consisting of ASO3, ASO6, ASO7, ASO11, ASO12, and ASO18, even more preferably wherein the modified oligonucleotide is ASO7, ASO11, ASO12 or ASO18.

11. The modified oligonucleotide or a pharmaceutically acceptable salt thereof according to claim 1, wherein the modified oligonucleotide is ASO7 having the chemical structure: 130Evotec International GmbH EVO28777PCT, or ASO11 having the chemical structure: 131Evotec International GmbH EVO28777PCT, or ASO12 having the chemical structure: 132Evotec International GmbH EVO28777PCT, or ASO18 having the chemical structure: 133Evotec International GmbH EVO28777PCT.

12. A modified oligonucleotide or pharmaceutically acceptable salt thereof wherein the modified oligonucleotide has the chemical structure 134Evotec International GmbH EVO28777PCTASO11.

13. A conjugate comprising the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, and at least one conjugate moiety covalently attached to said modified oligonucleotide, or said pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the modified oligonucleotide or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12 or a conjugate as defined in claim 13 and a pharmaceutically acceptable excipient.

15. An in vitro method for reducing ATXN3 expression in a target cell expressing ATXN3,said method comprising administering a modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or the conjugate as 135Evotec International GmbH EVO28777PCTdefined in claim 13, or the pharmaceutical composition as defined in claim 14 in an effective amount to said cell.

16. The modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or the conjugate as defined in claim 13, or the pharmaceutical composition as defined in claim 14 for use in medicine.

17. The modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or the conjugate as defined in claim 13, or the pharmaceutical composition as defined in claim 14 for use in reducing ATXN3 expression in a target cell expressing ATXN3 in vivo.

18. Use of the modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or of the conjugate as defined in claim 13, or of the pharmaceutical composition as defined in claim 14 for reducing ATXN3 expression in a target cell expressing ATXN3 in vitro.

19. The modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or the conjugate as defined in claim 13, or the pharmaceutical composition as defined in claim 14 for use in a method of treating or preventing spinocerebellar ataxia, preferably spinocerebellar ataxia 3 (Machado-Joseph disease), in a subject suffering from or being susceptible to such disease, comprising administering a therapeutically or prophylactically effective amount of said modified oligonucleotide or said pharmaceutically acceptable salt thereof or said conjugate or said pharmaceutical composition to said subject.

20. The modified oligonucleotide or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 12, or the conjugate as defined in claim 13, or the pharmaceutical composition as defined in claim 14 for use according to claim 19, wherein the subject is a human. 136

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