MAPK8IP3 / JIP3-targeted oligomeric compounds, compositions and uses

Abstract

The technology relates in part to oligomeric compounds that can reduce MAPK8IP3 / JIP3 expression. The technology also relates in part to methods, and uses of the oligomeric compounds, for reducing MAPK8IP3 / JIP3 expression, and in certain instances treating a MAPK8IP3 / JIP3-associated medical condition such as a neurological medical condition for example.

Description

[0001] PATENT

[0002] 7328.158159PCT / NLM-1002-PC

[0003] MAPK8IP3 / JIP3-TARGETED OLIGOMERIC COMPOUNDS, COMPOSITIONS AND USES

[0004] RELATED APPLICATIONS

[0005] This Patent Convention Treaty (PCT) International Application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. (USSN) 63 / 693,069, Sept. 10, 2024. The aforementioned application is expressly incorporated herein by reference in its entirety and for all purposes. All publications, patents, patent applications cited herein are hereby expressly incorporated byreference for all purposes.

[0006] REFERENCE TO ELECTRONIC SEQUENCE LISTING The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on September 10, 2025, is named “7328-158159PCT.xml” and is 215,140 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety.

[0007] TECHNICAL FIELD

[0008] This invention generally relates to oligomeric compounds that can reduce MAPK8IP3 / JIP3 expression. In alternative embodiments, provided are methods and uses of oligomeric compounds for reducing MAPK8IP3 / JIP3 expression, and in certain instances treating a MAPK8IP3 / JIP3-associated medical condition such as a neurological medical condition.

[0009] BACKGROUND

[0010] Less than 10% of rare diseases have approved treatments (Kaufmann et al., Orphanet J. Rare Dis. 13: 1-8 (2018)). Within rare diseases there are ultra-rare diseases with only 1-30 patients with the same pathogenic genetic variant worldwide (Crooke et al., Nat. Biotechnol. 39: 671-677 (2021)). The rarity of these diseases often excludes them from drug development programs. While individually rare, these diseases collectively affect more than 263 million individuals worldwide, and developing strategies to meet the needs of these patients is challenging (Vockley et al., Genet. Med. 25: 100022 (2023)).

[0011] The mitogen-activated protein kinase 8 interacting protein 3 gene (MAPK8IP3) encodes the c-Jun N-terminal kinase (JNK)-interacting protein 3 (JIP3). MAPK8IP3 PATENT 7328.158159PCT / NLM-1002-PC genomic nucleic acid is located on chromosome 16. MAPK8IP3 nucleic acid and encoded JIP3 protein collectively are referred to as “MAPK8IP3 / JIP3.’' MAPK8IP3 / JIP3 is a member of the kinesin family playing a role in cellular processes, including axonal transport of cargo. MAPK8IP3 / JIP3 is known to play a role in lysosomal and JNK trafficking along the axonal cytoskeleton. The absence of MAPK8IP3 / JIP3 in neuronal cells results in the accumulation of these cargoes, leading to the disruption of the axonal cytoskeleton. MAPK8IP3 / JIP3 participates in regulation of dynein, kinesin, and TrkB.

[0012] Mutations in MAPK8IP3 / JIP3 have been linked to severe neurodevelopmental disorders, resulting in progressive neurodegeneration and multiple severe symptoms. Rare mutations in MAPK8IP3 / JIP3, exemplified by the missense mutation C.1735OT (p.Arg579Cys) (R579C) (OMIM #618443), can activate the JNK pathway, culminating in cell death and apoptosis, and can manifest as dystonia, gross motor delay and developmental delay.

[0013] SUMMARY

[0014] In alternative embodiments, provided are oligomeric compounds comprising a modified oligonucleotide that can reduce MAPK8IP3 / JIP3 expression. Also provided in certain aspects are compositions containing the oligomeric compounds. Provided also in certain aspects are methods, and uses of the oligomeric compounds, for reducing MAPK8IP3 / JIP3 expression, and in certain instances treating a medical condition such as a MAPK8IP3 / JIP3-associated medical condition, which can be a neurological medical condition for example. In certain aspects, provided are compositions, including products of manufacture and kits, and methods, for treating, preventing, reducing the symptoms or side effects of, or ameliorating a MAPK8IP3 / JIP3-associated medical condition, such as a neurological medical condition, for example. This Summary section is not limiting and certain aspects and embodiments of the technology7are described in the following description, claim(s) and drawings.

[0015] The details of one or more exemplary7embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. PATENT

[0016] 7328.158159PCT / NLM-1002-PC

[0017] All publications, patents, patent applications, American Type Culture Collection (ATCC) deposits and NCBI reference sequences cited herein are hereby expressly incorporated by reference in their entireties for all purposes.

[0018] DESCRIPTION OF DRAWINGS

[0019] The drawings illustrate certain embodiments of the technology7and are not limiting. For clarity and ease of illustration, the drawings are not made to scale and, in some instances, various aspects can be shown exaggerated or enlarged to facilitate an understanding of particular embodiments.

[0020] Fig. lAto Fig. 1G show that MT-MAPK8IP3 / JIP3 induces JNK signaling and disrupts (decreases) cargo-laden late endosome mobility, thereby inhibiting cell growth in Hela cells.

[0021] Fig. 2Ato Fig. 2F show observations that MT-MAPK8IP3 / JIP3 induces JNK signaling and disrupts (decreases) cargo endosome mobility7, thereby inhibiting cell growth in patient derived fibroblasts.

[0022] Fig. 3 A to Fig. 3G show MT-MAPK8IP3 / JIP3 induces JNK signaling, disrupts (decreases) cargo endosome mobility and accumulates varicosities, thereby gaining a high risk of death in patient iPSC derived neurons.

[0023] Fig. 4Ato Fig. 4H show dopamine signaling was impaired in patient fibroblasts.

[0024] Fig. 5 A to Fig. 5D show dopamine signaling was uncoupled in patient iPSC derived neurons.

[0025] Fig. 6Ato Fig. 6G show non-allele selective PS-ASOs rescue of patient fibroblasts from MT-MAPK8IP3 / JIP3 induced cell toxicity.

[0026] Fig. 7Ato Fig. 7H show non-allele selective PS-ASOs rescue of patient iPSC derived neurons from MT-MAPK8IP3 / JIP3 induced cell toxicity.

[0027] Fig. 8Ato Fig. 8C show Hela cells that were transfected with siRNAs (siLuc or siJIP4) and then transfected with expression plasmids encoding either Flag tagged WT-MAPK8IP3 / JIP3 or MT-MAPK8IP3 / JIP3.

[0028] Fig. 9Ato Fig. 9E, and Fig. lOAto Fig. IOC, show studies of Rab5, Rab7, transferrin and MAPK8IP3 / JIP3.

[0029] Fig. HA and Fig. 11B show NLRP2 and cAMP levels in cells. PATENT 7328.158159PCT / NLM-1002-PC

[0030] Fig. 12A to Fig. 12C show non-allele selective PS-ASOs rescue of patient derived fibroblasts from MT-MAPK8IP3 / JIP3 induced cell toxicity.

[0031] Fig. 13 A and Fig. 13B show non-allele selective PS-ASOs rescue of patient iPSC derived neurons from MT-MAPK8IP3 / JIP3 induced cell death.

[0032] Like reference symbols in the various drawings indicate like elements.

[0033] DETAILED DESCRIPTION

[0034] In alternative embodiments, provided are oligomeric compounds comprising a modified oligonucleotide that can reduce MAPK8IP3 / JIP3 expression and related methods of use. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0035] Definitions

[0036] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used. Unless otherwise indicated, the following terms have the following meanings.

[0037] In alternative embodiments, '‘2 ’-deoxynucleoside” means a nucleoside including a 2’- H(H) deoxyribosyl sugar moiety. In certain embodiments, a 2’-dcoxynuclcoside is a 2’-beta-D-deoxynucleoside and includes a 2’ -beta-D-deoxy ribosyl sugar moiety, which has the beta-D ribosyl configuration as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2’ -deoxynucleoside or a nucleoside including an unmodified 2’-deoxyribosyl sugar moiety may include a modified nucleobase or may include an RNA nucleobase (uracil).

[0038] In alternative embodiments, “2’ -MOE” means a 2’-OCH2CH2OCH3 group in place of the 2’-OH group of a ribosyl sugar moiety. A “2’-M0E sugar moiety” or a “2 -0- methoxy ethyl sugar moiety” or “2’ -MOE ribosyl sugar moiety” means a sugar moiety with a 2’-OCH2CH2OCH3 group in place of the 2’-OH group of a ribosyl sugar moiety. Unless otherwise indicated, a 2’-M0E sugar moiety is in the beta-D configuration. “‘MOE” means O-methoxyethyl. “2’-M0E nucleoside” or “2’- O(CH2)2OCH3 nucleoside” means a nucleoside including a 2’- MOE sugar moiety (or 2’-O(CH2)2OCH3 ribosyl sugar moiety ). PATENT

[0039] 7328.158159PCT / NLM-1002-PC

[0040] In alternative embodiments, “2’-OMe” means a 2 -OCH3 group in place of the 2’-OH group of a ribosyl sugar moiety. A “2’-O-methyl sugar moiety" means a sugar moiety' with a 2’-OCH3 group in place of the 2’-OH group of a ribosyl sugar moiety. Unless otherwise indicated, a 2’-OMe has the beta-D ribosyl stereochemical configuration. ■‘2’-OMe nucleoside” means a nucleoside including a 2’-OMe sugar moiety'.

[0041] In alternative embodiments, “2’-F” means a 2‘-fluoro group in place of the 2 -OH group of a ribosyl sugar moiety. A “2’-F sugar moiety” or “2’ -fluororibosyl sugar moiety” means a sugar moiety7with a 2’-F group in place of the 2’-OH group of a ribosyl sugar moiety. Unless otherwise indicated, a 2’-F has the beta-D ribosyl stereochemical configuration. “2 -F nucleoside” means a nucleoside including a 2’-F sugar moiety .

[0042] In alternative embodiments, “2 ’-substituted nucleoside” means a nucleoside including a 2’-substituted furanosyl sugar moiety, “2’ -substituted” in reference to a sugar moiety means a sugar moiety' including at least one 2'- substituent group other than H or OH.

[0043] In alternative embodiments, “5 -methylcytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5 -methylcytosine is a modified nucleobase.

[0044] In alternative embodiments, “abasic sugar moiety” means a sugar moiety of a nucleoside that is not attached to a nucleobase. Such abasic sugar moieties are sometimes referred to as ’‘abasic nucleosides.”

[0045] In alternative embodiments, ’‘administration” or “administering” means providing a pharmaceutical agent or composition to cells. “Administration” or “administering” can be providing a pharmaceutical agent or composition to cells of a subject, and can be providing a pharmaceutical agent or composition to a subject.

[0046] In alternative embodiments, “antisense activity ” means any detectable and / or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound. PATENT

[0047] 7328.158159PCT / NLM-1002-PC

[0048] In alternative embodiments, ’‘antisense agent” means an antisense compound and optionally one or more additional features, such as a sense compound.

[0049] In alternative embodiments, “antisense compound” means an antisense oligonucleotide and optionally one or more additional features, such as a conjugate group.

[0050] In alternative embodiments, “sense compound” means a sense oligonucleotide and optionally one or more additional features, such as a conjugate group.

[0051] In alternative embodiments, “antisense oligonucleotide” means an oligonucleotide, including the oligonucleotide portion of an antisense compound, that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. Antisense oligonucleotides include but are not limited to antisense RNase H oligonucleotides and antisense RNAi oligonucleotides.

[0052] In alternative embodiments, “sense oligonucleotide” means an oligonucleotide, including the oligonucleotide portion of a sense compound, that is capable of hybridizing to an antisense oligonucleotide. Sense oligonucleotides include, but are not limited to, sense RNAi oligonucleotides.

[0053] In alternative embodiments, “bicyclic nucleoside” or “BNA” means a nucleoside including a bicyclic sugar moiety.

[0054] In alternative embodiments, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety including two rings, where the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl sugar moiety. In certain embodiments, the furanosyl sugar moiety is a ribosyl sugar moiety. In certain embodiments, the bicyclic sugar moiety does not include a furanosyl sugar moiety.

[0055] In alternative embodiments, “blunt” or “blunt ended” in reference to an oligomeric duplex formed by two oligonucleotides means that there are no terminal unpaired nucleotides (i.e. , no overhanging nucleotides). One or both ends of a double-stranded RNAi agent can be blunt. PATENT

[0056] 7328.158159PCT / NLM-1002-PC

[0057] In alternative embodiments, ’‘cell-targeting moiety ” means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.

[0058] In alternative embodiments, “cerebrospinal fluid” or “CSF” means the fluid fdling the space around the brain and spinal cord. “Artificial cerebrospinal fluid” or “aCSF” means a prepared or manufactured fluid that has certain properties (for example, osmolarity, pH, and / or electrolytes) similar to cerebrospinal fluid and is biocompatible with CSF.

[0059] In alternative embodiments, “chirally enriched” in reference to a population means a plurality of molecules of identical molecular formula, where the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereo-random. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereo-random chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are oligomeric compounds including modified oligonucleotides. In certain embodiments, the chiral center is at the phosphorous atom of a phosphorothioate intemucleoside linkage. In certain embodiments, the chiral center is at the phosphorous atom of a mesyl phosphoramidate intemucleoside linkage.

[0060] In alternative embodiments, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

[0061] In alternative embodiments, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more portions thereof and the nucleobases of another nucleic acid or one or more portions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. “Complementary nucleobases” means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include PATENT

[0062] 7328.158159PCT / NLM-1002-PC adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methylcytosine (mC) and guanine (G). Certain modified nucleobases that pair with unmodified nucleobases or with other modified nucleobases are known. For example, inosine can pair with adenosine, cytosine, or uracil. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. “Fully complementary ” or “100% complementary ” in reference to an oligonucleotide, or a portion thereof, means that the oligonucleotide, or portion thereof, is complementary to another oligonucleotide or nucleic acid at each nucleobase of the shorter of the two oligonucleotides, or at each nucleoside if the oligonucleotides are the same length. “Complementary' region” in reference to a region of an oligonucleotide means that at least 70% of the nucleobases of that region and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions.

[0063] In alternative embodiments, “conjugate group” means a group of atoms that is directly attached to an oligonucleotide and confers at least one property7to the resulting conjugated oligonucleotide. Conjugate groups include a conjugate moiety7and a conjugate linker that attaches the conjugate moiety to the oligonucleotide. “Conjugate linker” means a single bond or a group of atoms including at least one bond that connects a conjugate moiety to an oligonucleotide. “Conjugate moiety7” means a group of atoms covalently bound to an oligonucleotide via a conjugate linker.

[0064] In alternative embodiments, "contiguous" in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or intemucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence and “contiguous nucleosides” means nucleosides that are immediately adjacent to each other in a sequence.

[0065] In alternative embodiments, “constrained ethy l” or “cEt” or “cEt sugar moiety7” means a beta-D ribosyl bicyclic sugar moiety where the second ring of the bicyclic sugar is formed via a bridge connecting the 4 ’-carbon and the 2 ’-carbon of the beta-D ribosyl sugar moiety, where the bridge has the formula 4'-CH(CH3)-O-2', and where the PATENT

[0066] 7328.158159PCT / NLM-1002-PC methyl group of the bridge is in the S configuration. The term “cEt nucleoside" means a nucleoside including a cEt sugar moiety.

[0067] In alternative embodiments, ‘‘deoxy region” means a region of 5-12 contiguous nucleosides, where at least 70% of the nucleosides are 2’-beta-D-deoxynucleosides. In certain embodiments, each nucleoside is selected from a 2’-beta-D-deoxynucleoside, a bicyclic nucleoside, and a 2 ’-substituted nucleoside. In certain embodiments, a deoxy region supports RNase H activity. In certain embodiments, a deoxy region is the gap or internal region of a gapmer.

[0068] In alternative embodiments, “diluent” means an ingredient in a composition that lacks pharmacological activity but is pharmaceutically necessary7or desirable. For example, a diluent in an injected composition can be a liquid, for example, aCSF. phosphate buffered saline (PBS), or saline solution.

[0069] In alternative embodiments, “double-stranded” in reference to a region or an oligonucleotide means a duplex formed by complementary strands of nucleic acids (including, but not limited to, oligonucleotides) hybridized to one another. In certain embodiments, the two strands of a double-stranded region are separate molecules. In certain embodiments, the two strands are regions of the same molecule that has folded onto itself (for example, a hairpin structure).

[0070] In alternative embodiments, “duplex” or “duplex region” means the structure formed by two oligonucleotides or portions thereof that are hybridized to one another.

[0071] In alternative embodiments, “gapmer” means a modified oligonucleotide including an internal region having a plurality7of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, where the nucleosides in the internal region are chemically distinct from the nucleoside or nucleosides in the external regions. The internal region can be referred to as the “gap” and the external regions can be referred to as the “wings” or “wing segments.” In certain embodiments, the internal region is a deoxy region. The positions of the internal region or gap refer to the order of the nucleosides of the internal region and are counted starting from the 5 ’-end of the internal region. Unless otherwise indicated, “gapmer’ refers to a sugar motif. In certain embodiments, each nucleoside of the gap is a 2’-beta-D-deoxynucleoside. In certain embodiments, the gap includes one 2’ -substituted nucleoside at position 1, 2, 3, 4, or 5 of the gap, and the remainder PATENT

[0072] 7328.158159PCT / NLM-1002-PC of the nucleosides of the gap are 2’ -beta-D-deoxynucleosides. the term '‘MOE gapmer” indicates a gapmer having a gap including 2’-beta-D-deoxynucleosides and wings including 2’-M0E nucleosides, the term “mixed wing gapmer’ indicates a gapmer having wings including modified nucleosides including at least two different sugar modifications. Unless otherwise indicated, a gapmer may include one or more modified intemucleoside linkages and / or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications.

[0073] In alternative embodiments, “hybridization” means the annealing of oligonucleotides and / or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which can be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an oligonucleotide and a nucleic acid target.

[0074] In alternative embodiments, “intemucleoside linkage” means the covalent linkage between contiguous nucleosides in an oligonucleotide. “Modified intemucleoside linkage” means any intemucleoside linkage other than a phosphodiester intemucleoside linkage. “Phosphorothioate intemucleoside linkage” or “PS intemucleoside linkage” is a modified intemucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester intemucleoside linkage is replaced with a sulfur atom. “Inverted nucleoside” means a nucleotide having a 3’ to 3’ and / or 5 ’ to 5 ’ intemucleoside linkage, as shown herein.

[0075] In alternative embodiments, “inverted sugar moiety” means the sugar moiety of an inverted nucleoside or an abasic sugar moiety having a 3’ to 3’ and / or 5’ to 5‘ intemucleoside linkage.

[0076] In alternative embodiments, “linked nucleosides” are nucleosides that are connected in a contiguous sequence, where no additional nucleosides are presented between those that are linked.

[0077] In alternative embodiments, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides PATENT

[0078] 7328.158159PCT / NLM-1002-PC are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

[0079] In alternative embodiments, ‘‘mismatch’’ or “non-complementary” means a nucleobase of a first nucleobase sequence that is not complementary with the corresponding nucleobase of a second nucleobase acid sequence or target nucleic acid when the first and second nucleobase sequences are aligned in opposing directions.

[0080] In alternative embodiments, “motif’ means a pattern of unmodified and / or modified sugar moieties, nucleobases, and / or intemucleoside linkages, in an oligonucleotide.

[0081] In alternative embodiments, “non-bicyclic modified sugar moiety” means a modified sugar moiety that includes a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

[0082] In alternative embodiments, "nucleobase" means an unmodified nucleobase or a modified nucleobase. An “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). A “modified nucleobase” is a group of atoms other than unmodified A, T, C. U, or G capable of pairing with at least one unmodified nucleobase. A “5 -methylcytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide, including such nucleobases that are each optionally independently modified or unmodified, and independent of any sugar or intemucleoside linkage modification. “Nucleobase sequence of’ a reference SEQ ID NO, refers only to the nucleobase sequence provided in such SEQ ID NO and therefore, does not limit sugar or intemucleoside linkage modifications. Unless otherwise specified, each nucleobase can be an unmodified nucleobase. or a modified nucleobase as defined herein. For example, “A” represents unmodified or modified adenine; “C” represents unmodified or modified cytosine, “T” represents unmodified or modified thymidine, “U” represents unmodified or modified uracil, and “G” represents unmodified or modified guanine. Modified nucleobases that fall outside of these definitions are represented in the sequence by a different symbol, such as an “X”. “Nucleoside” means a compound, or fragment of a compound, including a nucleobase and a sugar moiety. The nucleobase and sugar moiety each independently are unmodified or modified. PATENT

[0083] 7328.158159PCT / NLM-1002-PC

[0084] In alternative embodiments, ’‘modified nucleoside” means a nucleoside including a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence, where no additional nucleosides are presented between those that are linked. “Oligomeric agent” means an oligomeric compound and optionally one or more additional features, such as a second oligomeric compound. An oligomeric agent can be a single-stranded oligomeric compound or can be an oligomeric duplex formed by two complementary’ oligomeric compounds.

[0085] In alternative embodiments, “oligomeric compound” means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound can be paired with a second oligomeric compound that is complementary to the first oligomeric compound or can be unpaired. A “singled-stranded oligomeric compound” is an unpaired oligomeric compound.

[0086] In alternative embodiments, “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex can be referred to as a “duplexed oligomeric compound.”

[0087] In alternative embodiments, “oligonucleotide” means a strand of linked nucleosides connected via intemucleoside linkages, where each nucleoside and intemucleoside linkage can be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. “Modified oligonucleotide” means an oligonucleotide, where at least one nucleoside or intemucleoside linkage is modified. “Unmodified oligonucleotide” means an oligonucleotide that does not include any nucleoside modifications or intemucleoside modifications. An oligonucleotide can be paired with a second oligonucleotide that is complementary to the oligonucleotide or it can be unpaired. A “single-stranded oligonucleotide” is an unpaired oligonucleotide. A “double-stranded oligonucleotide” is an oligonucleotide that is paired with a second oligonucleotide.

[0088] In alternative embodiments, “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” means any substance suitable for use in administering to a subject. Certain carriers and diluents enable pharmaceutical PATENT

[0089] 7328.158159PCT / NLM-1002-PC compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.

[0090] In alternative embodiments, "pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts Ty pically retain a desired biological activity' of the parent compound and do not impart undesired toxicological effects thereto.

[0091] In alternative embodiments, “pharmaceutical composition” means a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may include an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

[0092] In alternative embodiments, “population” with respect to molecules means a plurality' of molecules of identical molecular formula. “Population” with respect to genetic variations refers to a plurality of individuals of the same species (humans for example).

[0093] In alternative embodiments, “prodrug” means a therapeutic agent in a first form outside the body that is converted to a second form within a subject or cells thereof. Typically, conversion of a prodrug within the subject is facilitated by the action of an enzy me (for example, endogenous or viral enzyme) or chemicals present in cells or tissues and / or by physiologic conditions. In certain embodiments, the first form of the prodrug is less active than the second form.

[0094] In alternative embodiments, “reducing” or “inhibiting” an amount or activity refers to a reduction or blockade of the transcriptional expression or activity relative to the transcriptional expression or activity7in an untreated or control sample. “Reducing” and “inhibiting” do not necessarily indicate a total elimination of transcriptional expression or activity7.

[0095] In alternative embodiments, “selectively reducing” or “selectively inhibiting” an amount or activity refers to relative reduction or blockade of gene expression or activity of one species relative to another species. The different species can be PATENT

[0096] 7328.158159PCT / NLM-1002-PC different alleles or allelic variants, and can be a mutant allele relative to a wild-type allele in certain embodiments. A compound that selectively reduces expression of a first allele relative to a second allele reduces expression of the first allele 2-fold or more relative to expression of the second allele. Stated another way, an expression level of a first allele is at least 2-fold lower than the expression level of a second allele in the presence of an allele-selective compound. A compound that does not selectively reduce expression of a first allele relative to a second allele reduces expression of the first allele less than 2-fold relative to expression of the second allele. Stated another way, an expression level of a first allele is less than 2-fold lower than the expression level of a second allele in the presence of a non-allele-selective compound. In certain embodiments a first allele is a mutant allele (a mutant MAPK8IP3 / JIP3 allele for example) and a second allele is a wild-type allele (a wild-type MAPK8IP3 / JIP3 allele for example). In certain embodiments, allele selectivity of an oligomeric compound is assessed by a selectivity ratio.

[0097] In alternative embodiments, “RNA” means an RNA transcript and includes pre- mRNA and mature mRNA unless otherwise specified. “RNAi agent” means an antisense agent that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. RNAi agents include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNAi), and microRNA, including microRNA mimics. RNAi agents may include conjugate groups and / or terminal groups. In certain embodiments, an RNAi agent modulates the amount, activity', and / or splicing of a target nucleic acid. The term RNAi agent excludes antisense agents that act through RNase H.

[0098] In alternative embodiments, “RNase H agent” means an antisense agent that acts through RNase H to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. In certain embodiments, RNase H agents are single-stranded. In certain embodiments, RNase H agents are double-stranded. RNase H agents may include conjugate groups and / or terminal groups. In certain embodiments, an RNase H agent modulates the amount and / or activity of a target nucleic acid. The term “RNase H agent” excludes antisense agents that act principally through RISC / Ago2.

[0099] In alternative embodiments, “antisense RNase H oligonucleotide” means an oligonucleotide including a region that is complementary to a target sequence, and PATENT

[0100] 7328.158159PCT / NLM-1002-PC which includes at least one chemical modification suitable for RNase H-mediated nucleic acid reduction.

[0101] In alternative embodiments, ‘‘antisense RNAi oligonucleotide” means an oligonucleotide including a region that is complementary to a target sequence, and which includes at least one chemical modification suitable for RNAi-mediated nucleic acid reduction.

[0102] In alternative embodiments, “self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.

[0103] In alternative embodiments, “single-stranded” means a nucleic acid, including but not limited to an oligonucleotide, that is unpaired and is not part of a duplex. Singlestranded compounds are capable of hybridizing with complementary nucleic acids to form duplexes, at which point they are no longer single-stranded.

[0104] In alternative embodiments, “stabilized phosphate group” means a 5 ’-phosphate analog that is metabolically more stable than a 5 ’-phosphate as naturally occurs on DNA or RNA.

[0105] In alternative embodiments, “stereo-random” and “stereo-random chiral center” in the context of a population of molecules of identical molecular formula refer to a chiral center that is not controlled during synthesis, or enriched following synthesis, for a particular absolute stereochemical configuration. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. For example, in a population of molecules including a stereo-random chiral center, the number of molecules having the (S) configuration of the stereo-random chiral center can be but is not necessarily the same as the number of molecules having (R) configuration of the stereo-random chiral center (“racemic”). In certain embodiments, the stereo-random chiral center is not racemic because one absolute configuration predominates following synthesis, for example, due to the action of non-chiral reagents near the enriched stereochemistry of an adjacent sugar moiety. In certain embodiments, a stereo-random chiral center is a stereo-random phosphorothioate intemucleoside linkage or a mesyl phosphoramidate intemucleoside linkage. PATENT

[0106] 7328.158159PCT / NLM-1002-PC

[0107] In alternative embodiments, "‘subject” means a human or non-human animal. In certain embodiments, the subject is a human. “Animal” means a human or non-human animal.

[0108] In alternative embodiments, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. “Unmodified sugar moiety” means a 2’-OH(H) beta-D-ribosyl sugar moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2’-H(H) beta-D-deoxyribosyl sugar 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. “Modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

[0109] In alternative embodiments, "sugar surrogate" means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an intemucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides including sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.

[0110] In alternative embodiments, “treating” means improving a subject’s medical condition by administering a pharmaceutical agent or composition, such as a pharmaceutical agent or composition comprising an oligomeric compound described herein for example. In certain embodiments, treating a subject improves a symptom or hallmark relative to the same symptom or hallmark in the absence of the treatment. In certain embodiments, treatment reduces in the severity or frequency of a symptom or hallmark, or delays the onset of a symptom or hallmark, slows the progression of a symptom or hallmark, or slows the severity or frequency of a symptom or hallmark.

[0111] In alternative embodiments, “therapeutically effective amount” means an amount of a pharmaceutical agent or composition that provides a therapeutic benefit to a subj ect. For example, a therapeutically effective amount improves a symptom of a disease.

[0112] In alternative embodiments, “medical condition” means a disease, disorder or other condition for which a subject receives medical attention, medical service, treatment, diagnosis, consultation or a drug prescription. A medical condition can be a MAPK8IP3 / JIP3-associated medical condition, which typically is a medical condition PATENT

[0113] 7328.158159PCT / NLM-1002-PC associated with a modified MAPK8IP3 nucleic acid and / or J1P3 protein (e.g., a mutant MAPK8IP3 nucleic acid and / or mutant JIP3 protein) or dysregulation of a MAPK8IP3 nucleic acid and / or JIP3 protein. A MAPK8IP3 / JIP3-associated medical condition can be a neurological medical condition, a neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease or microencephaly.

[0114] In alternative embodiments, "symptom or hallmark” means a physical feature or test result that indicates the existence or extent of a medical condition. In certain embodiments, a symptom is apparent to a subject or to a medical professional examining or testing the subject. In certain embodiments, a hallmark is a particular indicator, such as a molecular indicator for example. In certain embodiments, a hallmark is an indicator that can be identified by testing. In certain embodiments, a hallmark is identified by diagnostic testing. In certain embodiments, a hallmark is identified by invasive testing, such as a post-mortem test for example. In certain embodiments, a symptom or hallmark is one or more of: neurodevelopment impairment, intellectual disability, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality', physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity, walking difficulties, visual impairment and seizure. In certain embodiments, a symptom or hallmark is one or more or all of dystonia (hypertonia and hypotonis), gross motor delay, developmental delay and poor or absent speech.

[0115] In alternative embodiments, “ameliorate” with reference to a treatment means improvement in at least one symptom or hallmark relative to the same symptom or hallmark in the absence of the treatment. In certain embodiments, amelioration is reduction in severity or frequency of a symptom or hallmark or delayed onset or slowing of progression in severity or frequency of a symptom or hallmark. Progression or severity of a symptom or hallmark can be determined by known subjective or objective measures.

[0116] In alternative embodiments, “terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide. PATENT

[0117] 7328.158159PCT / NLM-1002-PC

[0118] In alternative embodiments, ’‘target nucleic acid,” which includes “target RNA,” means a nucleic acid that an antisense compound is designed to affect. Target RNA means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified. “Target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize. A target region can be or can include a genetic variation site or portion thereof, and a genetic variation site can be a differentiating genetic variation site that is different between two alleles. A target region can be on a target allele and a target allele can be an allelic variant. A mutant allele and / or a wild-type allele can include a target region.

[0119] In alternative embodiments, “targeted to” means an oligomeric compound designed to hybridize to a target region of a MAPK8IP3 / JIP3 nucleic acid. A modified oligonucleotide of a oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid can be at least 80% complementary to. or at least 85% complementary' to, or at least 90% complementary to, or at least 95% complementary to, or 100% complementary to, an equal length target region portion of a MAPK8IP3 / JIP3 nucleic acid. An “equal length portion” and “equal length target region portion” can be a portion of contiguous nucleobases within a MAPK8IP3 / JIP3 nucleic acid nucleobase sequence, for example within SEQ ID NO: 1 or SEQ ID NO:2 or SEQ ID NO:38. In certain embodiments, an oligomeric compound oligonucleotide is 100% complementary to an equal length target region portion of a MAPK8IP3 / JIP3 nucleic acid. In certain embodiments, an oligomeric compound oligonucleotide is 100% complementary' to an equal length target region portion of a MAPK8IP3 / JIP3 nucleic acid except for a one- n ud eobase mismatch.

[0120] In certain embodiments, “allele” refers to one member of a pair of genes or one member of a series of different forms of a nucleic acid sequence that can exist at a single locus or marker on a specific chromosome. For a diploid organism or cell or for autosomal chromosomes, each allelic pair normally occupies corresponding positions (loci) on a pair of homologous chromosomes, one inherited from the mother and one inherited from the father. If these alleles are identical, the organism or cell is “homozygous” for that allele. If the alleles differ, the organism or cell is “heterozy gous” for that allele. The term “allele” can refer to genomic nucleic acid, expressed RNA (for example, transcribed and / or processed RNA (pre-RNA or mRNA PATENT

[0121] 7328.158159PCT / NLM-1002-PC for example)) and / or expressed protein. A “MAPK8IP3 / JIP3” allele refers to one member of a pair of MAPK8IP3 / JIP3 genes on a specific chromosome for example.

[0122] In certain embodiments, '‘allelic variant” refers to one of the pair of genes or nucleic acid sequence existing at a single locus. In certain embodiments, “allelic variant nucleic acid” refers to a chromosome nucleic acid or transcription product nucleic acid such as a pre-mRNA or mRNA corresponding to a particular MAPK81P3 / J1P3 allele, for example. Allelic variants can include one or multiple genetic variation sites. Allelic variants typically include a first allele (or first allelic variant) containing a first genotype at a genetic variation site and a second allele (or second allelic variant) containing a second genotype at the genetic variation site. At each particular genetic variation site the allelic variants can have the same genotype (homozygous at the particular genetic variation site) or different genotype (heterozy gous at the particular genetic variation site). In instances where a first genotype of a first allelic variant is different than a second genotype of a second allelic variant at a genetic variation site, the genetic variation site can be a differentiating genetic variation site. A differentiating genetic variation site can be a pathogenic genetic variation site, a first allelic variant can be a mutant allele containing a pathogenic genetic variant at the pathogenic genetic variation site, and a second allelic variant can be a wild-ty pe allele not containing the pathogenic genetic variant present on the mutant allele at the pathogenic genetic variation site. A differentiating genetic variation site can be anon- pathogenic genetic variation site, a first allelic variant can include a first genetic variant at the non-pathogenic genetic variation site, and a second allelic variant can include a second genetic variant different than the first genetic variant at the non- pathogenic genetic variation site. An allelic variant can be referred to as a major allele or a minor allele, as defined herein.

[0123] In certain embodiments, '‘genetic variation” means a variation of one or more nucleobases between allelic variants of an individual and / or between genomes of individuals of the same species at a particular polymorphic position. A genetic variation generally occurs at a “genetic variation position” or at “genetic variation positions” within a “genetic variation site.” “Genetic variation position(s)” refers to the nucleobase position(s) of the polymorphic genetic variation on a reference nucleobase sequence within a genetic variation site. “Genetic variation site” refers to the genetic variation position(s) and linked nucleobases on one or both sides (5’ side PATENT

[0124] 7328.158159PCT / NLM-1002-PC and / or 3’ side) of the genetic variation position(s), which can be contained in a target region to which an oligomeric compound is targeted. In certain embodiments, a genetic variation position is flanked by conserved nucleobase sequences within a genetic variation site. A genetic variation can be a substitution of one nucleobase with another nucleobase, referred to as a single nucleobase variation (SNV); a substitution of a portion of linked nucleobases with a portion containing an equal number of linked nucleobases containing at least two different nucleobases; a substitution of one nucleobase with two or more nucleobases (an insertion); and / or a substitution of multiple linked nucleobases with a single nucleobase (a deletion). Different genetic variation sites can be in linkage disequilibrium (defined herein). A genetic variation can be a single nucleotide variation (SNV) or a single nucleotide polymorphism (SNP). A genetic variation position can be a SNV position or SNP position and a genetic variation site can be a SNV site that includes the SNV position or a SNP site that includes the SNP position. A genetic variation site can be a pathogenic genetic variation site, a non-pathogenic genetic variation site and / or a differentiating genetic variation site, each of which are defined herein.

[0125] In certain embodiments, "single nucleotide variation" or "SNV" is a particular type of genetic variation for which there is a single nucleotide variant at a particular polymorphic genetic variation position within a genetic variation site. A SNV typically is a single nucleotide substitution, and in some cases can be a single nucleotide deletion or insertion at a particular position within a site. A SNV can be a single nucleotide polymorphism (SNP) that occurs relatively frequently in genomes and contributes to genetic diversity. A SNV can be a variation that occurs less frequently than a SNP in certain instances. A SNV can be a '‘synonymous SNV,” also referred to as a “silent SNV,” that does not result in an amino acid substitution in a translated expression product. A SNV can be a “non-synonymous SNV,” also referred to as a “coding SNV.” that results in an amino acid substitution in a translated expression product relative to a reference nucleobase sequence. A mutant allele can include a pathogenic single nucleotide variant, and the pathogenic single nucleotide variant can be a non-synonymous SNV. A non-pathogenic single nucleotide variant on a mutant allele or wild-type allele can be (i) a synonymous SNV, (ii) a non- synonymous SNV. (iii) a major allele SNV, (iv) a minor allele SNV, (v) contain the same SNV position nucleotide in a MAPK8IP3 / JIP3 reference nucleobase sequence, PATENT

[0126] 7328.158159PCT / NLM-1002-PC or (vi) contain a different SNV position nucleotide of a MAPK8IP3 / JIP3 reference nucleobase sequence, or (vii) a combination of (i) and (iii); (i) and (iv); (ii) and (iii);

[0127] (ii) and (iv); (i), (iii) and (v); (i), (iii) and (vi); (i), (iv) and (v); (i). (iv) and (vi); (ii),

[0128] (iii) and (v); (ii), (iii) and (vi); (ii). (iv) and (v); or (ii). (iv) and (vi). An oligomeric compound oligonucleotide can be targeted to a SNV site. In certain embodiments, a nucleobase of the oligonucleotide that anneals to and aligns with the SNV position in the target region can occur at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of the oligonucleotide, counted from the 5' end of the oligonucleotide. The remainder of the oligonucleotide bases can have sufficient complementarity to the SNV site to facilitate hybridization.

[0129] In alternative embodiments, ’‘pathogenic genetic variation site” means a genetic variation site comprising a pathogenic genetic variant present in a mutant allele nucleic acid or a non-pathogenic genetic variant present in a wild-type allele. A pathogenic genetic variant typically is associated with a medical condition and can cause the medical condition. A genetic variant at a pathogenic genetic variation site associated with a medical condition is referred to as a “pathogenic genetic variant.” A pathogenic variation site can be a differentiating genetic variation site targeted by an oligomeric compound. A pathogenic allelic variant is heterozygous in certain embodiments, and is present on a mutant allele and not on a wild-type allele in certain embodiments. Presence of pathogenic genetic variant on an allele can result in a wildtype protein loss of function (LOF). A pathogenic genetic variant on an allele may not result in a LOF and is referred to as a “non-LOF genetic variant.” A non-LOF genetic variant can be a dominant-negative (DN) genetic variant, which typically results in expression of a mutant protein that interferes with wild-type protein activity. A non- LOF genetic variant can be a gain-of-function (GOF) genetic variant, which typically results in a mutant protein activity not observed for wild-type protein. A GOF genetic variant phenotype can occur through various mechanisms, such as different substrate activity, different binding target specificity; constitutive activation, or protein aggregation of a mutant protein, for example, and can be a toxic GOF (TGOF) genetic variant in certain instances. A pathogenic genetic variation site can be a differentiating genetic variation site targeted by an oligomeric compound. In certain embodiments, a target region of a mutant allele targeted by an oligomeric compound oligonucleotide can be within a pathogenic genetic variation site or can include a pathogenic genetic PATENT

[0130] 7328.158159PCT / NLM-1002-PC variation site, typically contain the pathogenic genetic variation position(s) and ty pically includes the pathogenic genetic variant at the pathogenic genetic variation position(s). A pathogenic allelic variant can be heterozygous, present on a mutant allele and not on a wild-type allele, in certain embodiments.

[0131] In certain embodiments, “non-pathogenic genetic variation site” means a genetic variation site that does not include a pathogenic genetic variation position. A mutant allele and a wild-ty pe allele can contain one or more non-pathogenic genetic variation sites. A genetic variant of a non-pathogenic genetic variation site sometimes is present in a reference sequence and sometimes is not present in a reference sequence (for example, a reference genomic sequence of SEQ ID NO: 1 or a reference cDNA sequence of SEQ ID NO:2 or a reference CDS of SEQ ID NO:38). A non-pathogenic genetic variation site can be a differentiating genetic variation site targeted by an oligomeric compound. In certain embodiments, a mutant allele contains a first genetic variant at a polymorphic position at a non-pathogenic genetic variation site and a wild-type allele contains a second genetic variant at the polymorphic position or the non-pathogenic genetic variation site different than the first genetic variant. In certain embodiments, a target region of an allele targeted by an oligomeric compound oligonucleotide (a mutant allele for example) can be within a non-pathogenic genetic variation site or can include a non-pathogenic genetic variation site, typically contains a non-pathogenic genetic variation position and optionally contains the first genetic variant at the non-pathogenic genetic variation position in a mutant allele.

[0132] In certain embodiments, '‘differentiating variation” and “differentiating genetic variation'’ mean a genetic variation permitting differentiation between different alleles and selective targeting of an allelic variant. A differentiating genetic variant typically occurs at a polymorphic differentiating genetic variation position within a differentiating genetic variation site for a particular allele. Each allelic variant can include a different genetic variant at a differentiating genetic variation site. A differentiating genetic variation can be a heterozygous genetic variation for an individual or individuals in a population. A differentiating variation site can be a pathogenic genetic variation site. A differentiating variation site can be a non- pathogenic genetic variation site. In certain embodiments, a particular genetic variant at a differentiating genetic variation site is selectively targeted by an oligomeric PATENT

[0133] 7328.158159PCT / NLM-1002-PC compound, and such an oligomeric compound can be used to selectively target an allele containing the genetic variant targeted.

[0134] In certain embodiments, '‘mutant allele” refers to an allele (allelic variant) that ty pically includes a pathogenic genetic variant, thereby having a genoty pe associated with a medical condition associated with the pathogenic genetic variant. A mutant allele can be referred to as a "pathogenic allele.” For example, a “mutant MAPK8IP3 / JIP3 allele” refers to a MAPK8IP3 / JIP3 allele containing a pathogenic genetic variant, thereby having a genoty pe associated with a medical condition, and can be referred to as a “pathogenic MAPK8IP3 / JIP3 allele.” A mutant allele can be referred to as a “mutant allelic variant” or “pathogenic allelic variant.” In addition to including a pathogenic genetic variant associated with a medical condition, a mutant allele can include a non-pathogenic genetic variation site and a particular genotype at the non-pathogenic genetic variation site. For example, a mutant allele can include multiple non-pathogenic genetic variation sites and a particular genotype at each of the non-pathogenic genetic variation sites.

[0135] In certain embodiments, “wild-type allele” refers to an allele (allelic variant) that typically does not include the pathogenic genetic variant included on a mutant allele at a pathogenic genetic variation site, and does not have a genotype associated with the medical condition associated with the pathogenic genetic variant. A wild-type allele can be referred to as a “non-pathogenic allele.” For example, a “wild-type MAPK8IP3 / JIP3 allele” refers to a MAPK8IP3 / JIP3 allele not containing a pathogenic genetic variant included on a mutant MAPK8IP3 / JIP3 allele, thereby not having a genoty pe associated with the medical condition associated with the pathogenic genetic variant, and can be referred to as a “non-pathogenic MAPK8IP3 / JIP3 allele.” As for a mutant allele, a wild-type allele can include a particular genotype at the non-pathogenic genetic variation site. For example, a wildtype allele can include a particular genotype at each of multiple non-pathogenic genetic variation sites. At each particular non-pathogenic genetic variation site, the genotype for the wild-type allele may be the same as the genotype for the mutant allele (homozygous at the particular non-pathogenic genetic variation site and the non-pathogenic genetic variation site is not a differentiating genetic variation site) or the genoty pe for the wild ty pe allele may be different than the genotype for the mutant PATENT

[0136] 7328.158159PCT / NLM-1002-PC allele (heterozygous at the particular non-pathogenic genetic variation site and the non-pathogenic genetic variation site is a differentiating genetic variation site).

[0137] In certain embodiments, '‘linkage disequilibrium” is non-random association of different loci (including genetic variation sites for example) in a given population. Loci are in linkage disequilibrium when the frequency of association of their different alleles is higher or lower than expected if the loci were independent and associated randomly. ‘'Haplotype” means a set of alleles of closely linked loci on a chromosome that generally are in are in linkage equilibrium and generally are inherited together. A haplotype may include two, three, four, or more loci or alleles. The set of alleles in a haplotype along a given segment of a chromosome generally are transmitted to progeny together unless there has been a recombination event.

[0138] In certain embodiments, "major allele” refers to an allele containing a particular genetic variant at a polymorphic site (a SNV nucleotide at a SNV position for example) present in a statistically significant proportion of individuals in a human population. In certain embodiments, a “minor allele” refers to an allele containing a different genetic variant at a polymorphic site (a different SNV nucleotide at the SNV position for example) present in a relatively smaller proportion of individuals in the population than the major allele.

[0139] In certain embodiments, '‘selectively targeted to” means an oligomeric compound designed to hybridize to a target region of one MAPK8IP3 / JIP3 nucleic acid species preferentially over hybridizing to another target region of another MAPK8IP3 / JIP3 nucleic acid species. In certain embodiments, an oligomeric compound is targeted to a genetic variation site of a MAPK8IP3 / JIP3 nucleic acid species and is selectively targeted to a genetic variant at the site present on one MAPK8IP3 / JIP3 nucleic acid species and not present on another MAPK8IP3 / JIP3 nucleic acid species. In certain embodiments, an oligomeric compound is targeted to a genetic variation site of a MAPK8IP3 / JIP3 nucleic acid and is selectively targeted to a genetic variant at the site present on one MAPK8IP3 / JIP3 allelic variant and not present on another MAPK8IP3 / JIP3 allelic variant. In certain embodiments, an oligomeric compound is targeted to a genetic variation site of a MAPK8IP3 / JIP3 nucleic acid and is selectively targeted to a genetic variant at the site present on a mutant MAPK8IP3 / JIP3 allelic variant (pathogenic allelic variant) and not present on a wild-type MAPK8IP3 / JIP3 PATENT

[0140] 7328.158159PCT / NLM-1002-PC allelic variant. In certain embodiments, a modified oligonucleotide of a selectively targeted oligomeric compound is X% complementary to an equal length portion of a first allele nucleic acid (mutant allele or pathogenic allele for example) and Y% complementary to an equal length portion of a second allele nucleic acid (wild type allele, for example), where (i) X% and Y% each is nucleobase complementarity, (ii) X% and Y% are not equal, and (iii) X% is greater than Y%. In certain embodiments, a subtraction product of X% minus Y% is 1% to 10% or optionally 4% to 6% (for example, 2%, 3%, 4%, 5%, 6%, 7%. 8% or 9%, or fractional percentages between 1% to 10%) and sometimes is about 5%. In certain embodiments, a first MAPK8IP3 / J1P3 allele nucleic acid contains a nucleobase variant at a genetic variation position that is different from a corresponding nucleobase variant at the genetic variation position in a second MAPK8IP3 / JIP3 allele. In certain embodiments, the nucleobase sequence of the modified oligonucleotide contains a nucleobase (i) complementary to the nucleobase variant at the genetic variation position of the first MAPK8IP3 / JIP3 allele nucleic acid, and (ii) not complementary to the nucleobase variant at the genetic variation position of the second MAPK8IP3 / JIP3 allele nucleic acid. In certain embodiments, the corresponding equal length portion of the second MAPK8IP3 / JIP3 allele nucleic acid is identical to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one-nucleobase mismatch or two-nucleobase mismatch. In certain embodiments, a nucleobase sequence of a modified oligonucleotide of an oligomeric compound is 100% identical to an equal length portion of a first MAPK8IP3 / JIP3 allele nucleic acid and not 100% identical to a corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid. In certain embodiments, the corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid is fully complementary to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one-nucleobase mismatch or two-nucleobase mismatch. In certain embodiments, at least one nucleobase mismatch is at a genetic variation position in the second MAPK8IP3 / JIP3 allele nucleic acid. In certain embodiments X% is 100% nucleobase complementarity to the equal length portion of the first allele nucleic acid and Y% is a precent corresponding to full nucleobase complementarity to the equal length portion of the second allele nucleic acid except for a one-nucleobase mismatch or except for a two- nucleobase mismatch. PATENT

[0141] 7328.158159PCT / NLM-1002-PC

[0142] In certain embodiments, '‘target allele” means a MAPK8IP3 / JIP3 allele containing a target region to which an oligomeric compound is targeted. In certain embodiments, a target region includes a differentiating genetic variation site, which in certain instances is a heterozygous differentiating site. A MAPK8IP3 / JIP3 allele containing a particular allelic variant at the differentiating genetic variation site can be targeted selectively by an oligomeric compound. In certain embodiments, a target region does not include a genetic variation site or does not include a differentiating genetic variation site (allelic variants at a genetic variation site can be homozygous for example), and MAPK8IP3 / JIP3 alleles can be targeted without allele-selectivity.

[0143] In alternative embodiments, “genotype” means an identification of one or more nucleobases in genomic nucleic acid at a particular genetic location. The particular location or site can include or be a genetic variation position or a genetic variation position site. A genotype can be identified in nucleic acid from an individual or group of individuals. A genotype can be a nucleobase, nucleobase sequence or symbol representative of the nucleobase or nucleobases. A genotype can be determined in situ or for sample nucleic acid.

[0144] In alternative embodiments, '‘sample nucleic acid” means nucleic acid from a cell, tissue or subject, and can be nucleic acid isolated from cell, tissue or subject. A sample from a subject can be a fluid or solid sample in certain instances.

[0145] Exemplary7embodiments

[0146] Non-limiting embodiments of the technology are described hereafter in a numbered format starting with embodiment Al (“Al” is “embodiment Al” and “B2” is “embodiment B2” for example).

[0147] Al. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary7to an equal length portion of a MAPK8IP3 / JIP3 nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

[0148] A2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and comprising or consisting of a PATENT

[0149] 7328.158159PCT / NLM-1002-PC nucleobase sequence containing at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of:

[0150] SEQ ID NO:3 to SEQ ID NO:37; or

[0151] SEQ ID NO:4, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:25, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:35, SEQ ID NO:36 or SEQ ID NO:37; or

[0152] SEQ TD NO:3, SEQ ID NO:5. SEQ ID NO: 1 1 , SEQ ID NO: 16, SEQ ID NO:22. SEQ ID NO:27. SEQ ID NO:32 or SEQ ID NO’34; or

[0153] SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

[0154] A3. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and comprising or consisting of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18. at least 19, or 20 contiguous nucleobases complementary to: an equal length portion of nucleobases 493-18391 of SEQ ID NO: 1 ; or an equal length portion of nucleobases 3722-13231 of SEQ ID NO: 1; or an equal length portion of nucleobases 23414-37166 of SEQ ID NO: 1; or an equal length portion of nucleobases 23736-31642 of SEQ ID NO: 1; or an equal length portion of nucleobases 10080-10099, 9427-9446, 3836-3855.

[0155] 4535-4554, 8704-8723, 13212-13231 , 11562-11581 , 10079-10098, 4534-4553, 13211-13230, 3722-3741, 13197-13216, 9226-9245, 4994-5013 or 3892-3911 of SEQ ID NO:1; or an equal length portion of nucleobases 23736-23755, 31623-31642. 24132- 24151, 24130-24149, 24131-24150, 24128-24147, 25456-25475 or 25173-25192 of SEQ ID NO: l; or an equal length portion of nucleobases 23736-23755 of SEQ ID NO: 1 ; or an equal length portion of nucleobases 10079-10099, 10079-10098 or 10080- 10099 of SEQ ID NO: l; or an equal length portion of nucleobases 31623-31642 of SEQ ID NO: 1; or PATENT

[0156] 7328.158159PCT / NLM-1002-PC an equal length portion of nucleobases 20194-20213; 40101 -40120; 47601 - 47620; 43114-43133; 48907-48926; 42896-42915; 48108-48127; 43831-43850; 49113-49132; 48906-48925; 43007-43026 or 43830-43849of SEQ ID NO: 1; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

[0157] A4. The oligomeric compound of any of embodiments Al -A3, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence that is at least 85%, at least 90%, at least 95%, or 100% complementary to an equal length portion of a MAPK81P3 / J1P3 nucleic acid, wherein the MAPK81P3 / JIP3 nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO:2 or SEQ ID NO:38.

[0158] A5. The oligomeric compound of any of embodiments A1-A4, wherein the modified oligonucleotide consists of 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30. 14 to 50. 15 to 20. 15 to 25,

[0159] 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25,

[0160] 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30,

[0161] 19 to 50, 20 to 25, 20 to 30, or 20 to 50 linked nucleosides.

[0162] A6. The oligomeric compound of any one of embodiments A1-A5, wherein the MAPK8IP3 / JIP3 nucleic acid is a human MAPK8IP3 / JIP3 nucleic acid.

[0163] A7. The oligomeric compound of any one of embodiments A1-A7, wherein the MAPK8IP3 / JIP3 nucleic acid is a mutant MAPK8IP3 / JIP3 nucleic acid.

[0164] A8. The oligomeric compound of embodiment A7, wherein the mutant MAPK8IP3 / JIP3 nucleic acid comprises a pathogenic genetic variant.

[0165] A9. The oligomeric compound of embodiments A8, wherein the pathogenic genetic variant is associated with one or more phenotypes chosen from: increased cell degeneration; reduced cell proliferation; activation of the JNK signaling pathway; enhanced pro-apoptotic signaling via JNK; modification of MAPK8IP3 / JIP3 binding partner interactions; increased MAPK8IP3 / JIP3 expression; reduced JIP4 expression; altered MAPK8IP3 / JIP3 subcellular localization; reduced MAPK8IP3 / JIP3 binding affinity to JIP4; reduced MAPK8IP3 / JIP3 / JIP4 heterodimer formation; increased MAPK8IP3 / JIP3 binding affinity to KJF5b; decreased axon trafficking; decreased endosome mobility along microtubules in axons; decreased late endosome mobility’ along microtubules in axons; and decreased dopamine receptor 1 (DI) signaling; PATENT

[0166] 7328.158159PCT / NLM-1002-PC optionally wherein each phenotype is for cells relative to cells not containing a mutant MAPK8IP3 / JIP3.

[0167] A10. The oligomeric compound of any one of embodiments A1-A9, which is capable of one or more of: reducing cell toxicity; increasing cell proliferation; increasing axon trafficking; increasing endosome mobility along microtubules in axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling.

[0168] Al l. The oligomeric compound of embodiment A9 or A 10, wherein the cell toxicity is neuronal or fibroblast cell toxicity and the cell proliferation is neuronal cell proliferation or fibroblast cell proliferation.

[0169] Al 2. The oligomeric compound of any one of embodiments A8-A11, wherein: the mutant MAPK8IP3 / JIP3 nucleic acid comprises a pathogenic genetic variant selected from: C.1735OT. C.1732OT, c.281A>G, c.1714 OT, c.ClllG, c57C>G, c.65delG, C.C3436T, C.C1732T, C.CT1331C, c,1544G>A, c.2447OA and c,1364A>G, and / or results in a MAPK8IP3 / JIP3 protein comprising a variant selected from p.(Arg579Cys), p.(Glu455Gly) and p.(Tyr94Cys); or the pathogenic variant:

[0170] (i) is at a rsl567203083, rs770703007, rsl567128142, rsl567214097 or rs 1567198751 pathogenic genetic variation site; or

[0171] (ii) is at a rsl567203083 pathogenic genetic variation site; or

[0172] (iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argl l47Cys, p.Argll46Cys. p.Argll40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His. p.Arg521His, p.Arg515His, p.Ala816Glu. р.Ala815Glu, p.Ala809Glu, p.Glu455Gly, p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or

[0173] (iv) encodes a p.Arg579Cys, p.Arg578Cys or p.Arg572Cys amino acid substitution; or

[0174] (v) encodes a p.Arg579Cys amino acid substitution; or

[0175] (vi) encodes or is C.1735OT, C.1732OT, C.1714OT, c.281A>G, c.lllOG, c.65del, C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c,1331T>C, c,1313T>C, с, 1565G>A, c. 1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c. 1364A>G, c, 1361A>G or c, 1343A>G: or

[0176] (vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or

[0177] (viii) encodes or is C.1735OT. PATENT

[0178] 7328.158159PCT / NLM-1002-PC

[0179] A 13. The oligomeric compound of embodiment A 12, wherein the MAPK8IP3 / JIP3 nucleic acid comprises a C.1735OT pathogenic genetic variant, and / or a pathogenic genetic variation resulting in a p.Arg579Cys variation in a MAPK8IP3 / JIP3 protein.

[0180] A14. The oligomeric compound of any one of embodiments A8-A13, wherein the pathogenic genetic variant is in a MAPK8IP3 / JIP3 nucleic acid exon.

[0181] Al 5. The oligomeric compound of any one of embodiments A8-A14, wherein the oligomeric compound oligonucleotide is 100% complementary to a portion of a MAPK81P3 / J1P3 nucleic acid containing the pathogenic genetic variant.

[0182] Al 6. The oligomeric compound of any one of embodiments A8-A15, wherein the oligomeric compound oligonucleotide is 100% complementary to a portion of a MAPK8IP3 / JIP3 nucleic acid containing a c. 1735OT genetic variation in SEQ ID NO:38.

[0183] A 17. The oligomeric compound of any one of embodiments A8-A14, wherein the oligomeric compound oligonucleotide is complementary to a portion of a MAPK8IP3 / JIP3 nucleic acid not containing the pathogenic genetic variation position and / or pathogenic genetic variation site.

[0184] Al 8. The oligomeric compound of any one of embodiments Al -Al 7, which is not selective for a MAPK8IP3 / JIP3 allele and is not allele selective.

[0185] Al 9. The oligomeric compound of embodiment Al 8, which is capable of reducing expression of a first MAPK8IP3 / JIP3 allele relative to expression of a second MAPK8IP3 / JIP3 allele by less than 2-fold, optionally at the ICso concentration of the oligomeric compound for the first MAPK8IP3 / JIP3 allele or the second MAPK8IP3 / JIP3 allele.

[0186] A20. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides, wherein: the modified oligonucleotide comprises or consists of a nucleobase sequence that is at least 80% complementary' to an equal length portion of a genetic variation site of a MAPK8IP3 / JIP3 nucleic acid; the equal length portion of the genetic variation site contains a dilferentiating genetic variation; and PATENT 7328.158159PCT / NLM-1002-PC the modified oligonucleotide comprises a modified nucleoside, or a modified intemucleoside linkage, or a modified nucleoside and a modified intemucleoside linkage.

[0187] A21. The oligomeric compound of embodiment A20, which is capable of selectively reducing expression of a MAPK8IP3 / JIP3 allelic variant.

[0188] A22. The oligomeric compound of embodiment A20 or A21, wherein: the genetic variation site comprises a substitution, deletion and / or insertion, or optionally the genetic variation site is a single nucleotide variation site, or optionally wherein the single nucleotide variation site comprises a synonymous single nucleotide variation.

[0189] A23. The oligomeric compound of embodiment A22, wherein: the genetic variation site comprises a genetic variation position and the modified oligonucleotide comprises at least one nucleoside aligned with the genetic variation position; or optionally the single nucleotide variation site comprises a single nucleotide variation position and the modified oligonucleotide comprises a nucleoside aligned with the single nucleotide variation position.

[0190] A24. The oligomeric compound of embodiment A23, wherein: the modified oligonucleotide comprises a nucleoside aligned with and complementary to a nucleoside at the genetic variation position; or optionally the modified oligonucleotide comprises a nucleoside aligned with and complementary to a nucleoside at the single nucleotide variation position.

[0191] A25. The oligomeric compound of embodiment A24, wherein: the modified oligonucleotide comprises at least one nucleoside aligned with and complementary to a first nucleoside at the genetic variation position of a first MAPK8IP3 / JIP3 allelic variant and not complementary to a second nucleoside at the genetic variation position of a second MAPK8IP3 / JIP3 allelic variant; or optionally the modified oligonucleotide comprises a nucleoside aligned with and complementary to a first nucleoside at the single nucleotide variation position of a first MAPK8IP3 / JIP3 allelic variant and not complementary to a second nucleoside at the single nucleotide variation position of a second MAPK8IP3 / JIP3 allelic variant.

[0192] A26. The oligomeric compound of embodiment A25, wherein the modified oligonucleotide is capable of selectively reducing expression of the first PATENT 7328.158159PCT / NLM-1002-PC

[0193] MAPK8IP3 / JIP3 allelic variant to a greater extent than expression of the second MAPK8IP3 / JIP3 allelic variant.

[0194] A27. The oligomeric compound of embodiment A26, wherein: the modified oligonucleotide is capable of selectively reducing expression of the first MAPK8IP3 / JIP3 allelic variant by at least 2-fold compared to expression of the second MAPK81P3 / JIP3 allelic variant; or optionally the oligomeric compound selectively reduces expression of the first MAPK8IP3 / JIP3 allelic variant according to a selectivity ratio of at least 2 or greater than 2; or optionally the selectivity ratio is (i) inhibition of expression of the second MAPK8IP3 / JIP3 allelic variant to (ii) inhibition of expression of the first MAPK8IP3 / JIP3 allelic variant; or optionally the inhibition of expression of the second SCN2A allelic variant is an IC50 value and the inhibition of expression of the first SCN2A allelic variant is an IC50 value.

[0195] A28. The oligomeric compound of any one of embodiments A23-A27, wherein: the modified oligonucleotide consists of 10-30 linked nucleosides and the nucleoside at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with a nucleoside in the genetic variation position, or optionally aligns with the single nucleotide variation position; or the modified oligonucleotide consists of 18-22 linked nucleosides, or optionally 20 linked nucleosides, and the nucleoside at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with a nucleoside in the genetic variation position, or optionally aligns with the single nucleotide variation position.

[0196] A29. The oligomeric compound of any one of embodiments A23-A28, w erein the modified oligonucleotide consists of 18-22 linked nucleosides, or optionally 20 linked nucleosides, and comprises: a 5’-region consisting of linked 5’-region nucleosides; a central region consisting of linked central region nucleosides; PATENT 7328.158159PCT / NLM-1002-PC a 3’-region consisting of linked 3’-region nucleosides; the central region comprises a 5’ terminus; and the nucleoside at position 1, 2, 3. 4, 5, 6, 7, 8, 9 or 10 of the central region, as counted from the 5' terminus of the central region, aligns with a nucleoside in the genetic variation position, or optionally aligns with the single nucleotide variation position.

[0197] A30. The oligomeric compound of any one of embodiments A20-A29, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site in: (i) a MAPK8IP3 / JIP3 intron, optionally wherein the intron is chosen from intron 1 or intron 8, or optionally wherein the intron is intron 1; or (ii) a MAPK8IP3 / JIP3 exon, optionally wherein the exon is exon 31 or exon 32.

[0198] A31. The oligomeric compound of any one of embodiments A1-A12. wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic vanation site within or comprising:

[0199] (i) a chromosome 16 portion chosen from: positions 1706658-1724556, 1748721- 1758147, 1768477-1768626 or 1768703-1770351; or

[0200] (ii) a portion of SEQ ID NO: 1 chosen from: positions 493-18391. 42556-51982, 62312-62461 or 62538-64186; or

[0201] (iii) a chromosome 16 portion between positions 1706658-1724556; or

[0202] (iv) a portion of SEQ ID NO: 1 between positions 493-18391.

[0203] A32. The oligomeric compound of any one of embodiments A20-A31, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases PATENT

[0204] 7328.158159PCT / NLM-1002-PC complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site chosen from:

[0205] (i) rsl7135499. rsl7135500, rsl2922553, rsl 1860323, rsl 1865685. rs35988159, rs34950492, rsl2930313, rsl2925525. rs8063431, rs9788926, rs2076431 or rs2575329; or

[0206] (ii) rsl7135499, rsl7135500, rs34950492, rs35988159, rs9788926, rs2076431 or rs2575329; or

[0207] (hi) rs34950492 and rs35988159; or

[0208] (iv) rsl7135500.

[0209] A33. The oligomeric compound of any one of embodiments A20-A32, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site comprising:

[0210] (i) a chromosome 16 position chosen from: chrl6:1709793, chrl6: 1709852, chrl6: 1710090, chrl6:1714342, chrl6: 1714343, chrl 6: 1714886, chrl6: 1714898, chrl6: 1715231, chrl6: 1723913, chrl6: 1754356, chrl 6: 1757779, chrl6: 1768502 or chrl 6: 1769432; or

[0211] (ii) a position in SEQ ID NO: 1 chosen from position: 3628, 3687, 3925, 8177, 8178, 8721, 8733, 9066, 17748, 48191, 51614, 62337 or 63267; or

[0212] (iii) chromosome 16 position chrl 6: 1709852; or

[0213] (iv) SEQ ID NO: 1 position 3687.

[0214] A34. The oligomeric compound of any one of embodiments A20-A33, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site comprising or wi thin:

[0215] (i) a chromosome 16 portion chosen from: chrl6: 1709763-1709823, chrl 6: 1709822- 1709882, chrl6: 1710060-1710120, chrl6:1714312-1714372, chrl6: 1714313- 1714373, chrl6: 1714856-1714916, chrl6:1714868-1714928, chrl6: 1715201- PATENT

[0216] 7328.158159PCT / NLM-1002-PC

[0217] 1715261, chrl6: 1723883-1723943, chrl6:1754326-1754386, chrl6: 1757749- 1757809, chrl6: 1768472-1768532 or chrl 6: 1769402- 1769462; or

[0218] (ii) a portion of SEQ ID NO:1 chosen from: 3598-3658, 3657-3717, 3895-3955, 8147-8207. 8148-8208, 8691-8751, 8703-8763, 9036-9096. 17718-17778, 48161- 48221, 51584-51644, 62307-62367 or 63237-63297; or

[0219] (iii) a nucleobase sequence of one of SEQ ID NO:90 to SEQ ID NO: 102; or

[0220] (iv) a chromosome 16 portion between positions 1709822-1709882; or

[0221] (v) a portion of SEQ ID NO: 1 between positions 3657-3717; or

[0222] (vii) a nucleobase sequence of SEQ ID NO:91.

[0223] A35. The oligomeric compound of any one of embodiments A20-A34, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic vanation site comprising or within:

[0224] (i) a chromosome 16 portion chosen from: chrl6: 1709785-1709810, chrl 6: 1709840- 1709865, chrl6: 1714873-1714916, chrl6:1757763-1757790, chrl6: 1768489- 1768509 or chrl6: 1769422-1769447; or

[0225] (ii) a portion of SEQ ID NO: 1 chosen from positions: 3620-3645. 3675-3700, 8708- 8751 , 51598-51625, 62324-62344 or 63257-63282; or

[0226] (iii) a nucleobase sequence of one of SEQ ID NO: 103 to SEQ ID NO: 108; or

[0227] (iv) a chromosome 16 portion between positions 1709840-1709865; or

[0228] (v) a portion of SEQ ID NO: 1 between positions 3675-3700; or

[0229] (vi) a nucleobase sequence of SEQ ID NO: 104.

[0230] A36. The oligomeric compound of any one of embodiments Al -Al 2. wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site comprising or within:

[0231] (i) a chromosome 16 portion chosen from: chrl6: 1709844-1709863, chrl6:1714336- 1714355, chrl6: 1754340-1754359, chrl6:1714892-1714911, chrl6: 1714879- 1714898. chrl6: 1757771-1757790, chrl6: 1768490-1768509, chrl6: 1714888- PATENT

[0232] 7328.158159PCT / NLM-1002-PC

[0233] 1714907, chrl6: 1710085-1710104, chrl 6: 1709791 -1709810, chrl6: 1768489- 1768508, chrl6: 1709841-1709860, chrl 6: 1709840-1709859, chrl6: 1709785- 1709804, chrl6: 1709846-1709865, chrl6:1714873-1714892, chrl6: 1714884- 1714903. chrl6: 1714891-1714910, chrl6: 1714897-1714916, chrl6: 1715217- 1715236, chrl6: 1723903-1723922, chrl6: 1757763-1757782, chrl6: 1769422- 1769441, chrl6: 1714882-1714901 or chrl 6: 1769428- 1769447; or

[0234] (ii) a portion of SEQ ID NO:1 chosen from: 3679-3698, 8171-8190, 48175-48194, 8727-8746. 8714-8733, 51606-51625, 62325-62344, 8723-8742, 3920-3939, 3626- 3645, 62324-62343, 3676-3695, 3675-3694, 3620-3639, 3681-3700, 8708-8727, 8719-8738, 8726-8745, 8732-8751, 9052-9071, 17738-17757, 51598-51617, 63257- 63276, 8717-8736 or 63263-63282; or

[0235] (iii) a nucleobase sequence of one of SEQ ID NO:65 to SEQ ID NO: 89; or

[0236] (iv) a chromosome 16 portion between positions 1709844-1709863; or

[0237] (v) a portion of SEQ ID NO: 1 between positions 3679-3698; or

[0238] (vi) a nucleobase sequence of SEQ ID NO:65.

[0239] A37. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within: intron 1 ; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO: 1; rsl 7135499 genetic variation site; chromosome 16 positions 1709763-1709823; positions 3598-3658 of SEQ ID NO: 1; the nucleobase sequence of SEQ ID NO:90; chromosome 16 positions 1709785-1709810; positions 3620-3645 of SEQ ID NO: 1; a nucleobase sequence of SEQ ID NO: 103; or a nucleobase sequence of SEQ ID NO:78 or SEQ ID NO:74.

[0240] A38. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12. at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary’ to an equal length portion of contiguous nucleobases within: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO: 1; rsl7135500 genetic variation site; chromosome 16 positions 1709822-1709882; PATENT

[0241] 7328.158159PCT / NLM-1002-PC positions 3657-3717 of SEQ ID NO:1 ; nucleobase sequence of SEQ ID NO:91 ; chromosome 16 positions 1709840-1709865; positions 3675-3700 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 104; nucleobase sequence of SEQ ID NO:77, SEQ ID NO:76, SEQ ID NO:65 or SEQ ID NO:79; or nucleobase sequence of SEQ ID NO:65.

[0242] A39. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO: 1; rs35988159 genetic variation site; chromosome 16 positions 1714856-1714916; positions 8691-8751 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:95; rs34950492 genetic variation site; chromosome 16 positions 1714868-1714928; positions 8703-8763 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:96; rs34950492 and rs35988159 genetic variation sites; chromosome 16 positions 1714873-1714916; positions 8708-8751 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 105; or nucleobase sequence of SEQ ID NO:69, SEQ ID NO:88, SEQ ID NO:81. SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:68, SEQ ID NO:83 or SEQ ID NO: 80.

[0243] A40. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within: intron 8; chromosome 16 positions 1748721-1758147; positions 42556-51982 of SEQ ID NO: 1; rs9788926 genetic variation site; chromosome 16 positions 1757749-1757809; positions 51584-51644 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 100; chromosome 16 positions 1757763-1757790; positions 51598-51625 of SEQ ID NO: 1 ; nucleobase sequence of SEQ ID NO: 106; or nucleobase sequence of SEQ ID NO: 86 or SEQ ID NO:70. PATENT

[0244] 7328.158159PCT / NLM-1002-PC

[0245] A41. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within: exon 31; chromosome 16 positions 1768477-1768626; positions 62312-62461 of SEQ ID NO: 1; rs8063431 genetic variation site; chromosome 16 positions 1754326-1754386; positions 48161-48221 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:99; chromosome 16 positions 1768489-1768509; positions 62324-62344 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 107; or nucleobase sequence of SEQ ID NO:75 or SEQ ID NO:71.

[0246] A42. The oligomeric compound of any one of embodiments A20-A36, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8. at least 9, at least 10, at least 11. at least 12. at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary’ to an equal length portion of contiguous nucleobases within: exon 32; chromosome 16 positions 1768703-1770351; positions 62538-64186 of SEQ ID NO: 1; rs2575329 genetic variation site; chromosome 16 positions 1769402-1769462; positions 63237-63297 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 102; chromosome 16 positions 1769422-1769447; positions 63257-63282 of SEQ ID NO: 1 ; nucleobase sequence of SEQ ID NO: 108; or nucleobase sequence of SEQ ID NO:87 or SEQ ID NO:89.

[0247] A43. The oligomeric compound of any one of embodiments A20-A42, wherein the genetic variation site, or optionally the single nucleotide variation site, comprises: (i) a nucleotide variant at the genetic variation position described in Table D; or (ii) the “vl ” variant at the genetic variation position described in Table D; or (iii) the “v2” variant at the genetic variation position described in Table D.

[0248] A44. The oligomeric compound of any one of embodiments A20-A43, wherein the modified oligonucleotide comprises or consists of 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleobases of:

[0249] (i) SEQ ID NO:40 to SEQ ID NO:64; or

[0250] (ii) SEQ ID NO:40; or PATENT 7328.158159PCT / NLM-1002-PC

[0251] (lii) SEQ ID NO:53 or SEQ ID NO:49; or

[0252] (iv) SEQ ID NO:52, SEQ ID NO:51, SEQ ID NO:40 or SEQ ID NO:54; or

[0253] (v) SEQ ID NO:44, SEQ ID NO 53, SEQ ID NO:56, SEQ ID NO:47. SEQ ID NO:57, SEQ ID NO:43, SEQ ID NO:58 or SEQ ID NO:55; or

[0254] (vi) SEQ ID NO:61 or SEQ ID NO:45; or

[0255] (vii) SEQ ID NO:50 or SEQ ID NO:46; or

[0256] (viii) SEQ ID NO:62 or SEQ ID NO:64.

[0257] A45. The oligomeric compound of any one of embodiments A20-A44, the modified oligonucleotide comprises or consists of anucleobase sequence that is at least 85% complementary to, or at least 90% complementary’ to. or at least 95% complementary; or is 100% complementary' to, an equal length portion of the genetic variation site.

[0258] A46. The oligomeric compound of any of embodiments A20-A45, wherein the modified oligonucleotide consists of 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25,

[0259] 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30. 16 to 50, 17 to 20, 17 to 25,

[0260] 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50. 19 to 20. 19 to 25, 19 to 30,

[0261] 19 to 50, 20 to 25, 20 to 30, or 20 to 50 linked nucleosides.

[0262] A47. The oligomeric compound of any one of embodiments A20-A46, wherein the modified oligonucleotide consists of 18-22 linked nucleosides, 19-21 linked nucleosides or 20 linked nucleosides.

[0263] A48. The oligomeric compound of any one of embodiments A20-A47, wherein the genetic variation site comprises a genetic variant present in at least 20% of a population.

[0264] A49. The oligomeric compound of embodiment A36, wherein the genetic variant is present in at least 25% of a population, or at least 30% of a population, or at least 35% of a population, or at least 40% of a population, or at least 45% of a population, or at least 50% of a population, or at least 55% of a population, or at least 60% of a population, or at least 65% of a population, or at least 70% of a population, or at least 75% of a population, or at least 80% of a population, or at least 85% of a population, or at least 90% of a population. PATENT

[0265] 7328.158159PCT / NLM-1002-PC

[0266] A50. The oligomeric compound of any one of embodiments A21 -A49, wherein the MAPK8IP3 / JIP3 allelic variant is a mutant MAPK8IP3 / JIP3 allelic variant associated with a medical condition.

[0267] A51. The oligomeric compound of embodiments A50, wherein the mutant MAPK8IP3 / JIP3 allelic variant comprises a pathogenic genetic variant associated with a medical condition.

[0268] A52. The oligomeric compound of embodiment A51 , wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, which optionally is a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’s-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0269] A53. The oligomeric compound of embodiment A51 or A52, wherein the pathogenic genetic variant is associated with a non-loss of function phenotype.

[0270] A54. The oligomeric compound of embodiment A53, wherein the non-loss of function phenotype is a dominant negative phenotype, a gain of function phenotype or toxic gain of function phenotype.

[0271] A55. The oligomeric compound of any one of embodiments A51-A54, wherein the pathogenic genetic variant:

[0272] (i) is in exon 16, is in a rs!567203083 polymorphic site, is at chromosome 16 position 1762843, is at position 56678 of SEQ ID NO: 1, is a C.1735OT pathogenic genetic variant, is a C.1732OT pathogenic genetic variant, is a C.1714OT pathogenic genetic variant, encodes a p. Arg579Cys substitution in a JIP3 protein, encodes a р.Arg578Cys substitution in a JIP3 protein, or encodes a p.Arg572Cys amino acid substitution in a JIP3 protein; or

[0273] (ii) is at chromosome 16 position 1706620, is at position 455 of SEQ ID NO:1, is a с.281A>G pathogenic genetic variant, or encodes a p.Tyr94Cys amino acid substitution in a JIP3 protein; or

[0274] (iii) is in a rs770703007 polymorphic site, is at chromosome 16 position 1706450, is at position 285 of SEQ ID NO: 1, is a c. lllOG pathogenic genetic variant, or encodes a p.Tyr37Ter modification of a JIP3 protein; or PATENT

[0275] 7328.I58I59PCT / NLM-I002-PC

[0276] (iv) is in a rsl 567128142 polymorphic site, is at chromosome 16 position 1706404, is at position 239 of SEQ ID NO: 1, is a c.65del pathogenic genetic variant, or encodes a р.Gly22AlafsTer3 modification of a JIP3 protein; or

[0277] (v) is in a rsl567214097 polymorphic site, is at chromosome 16 position 1767834, is at position 61669 of SEQ ID NO: 1, is a C.3439OT pathogenic genetic variant, is a C.3436OT pathogenic genetic variant, is a C.3418OT pathogenic genetic variant, encodes a p.Argl 147Cys substitution in a JIP3 protein, encodes a p.Argl 146Cys substitution in a JIP3 protein, or encodes a p.Argl 140Cys amino acid substitution in a J1P3 protein; or

[0278] (vi) is in a rsl567198751 polymorphic site, is at chromosome 16 position 1760409, is at position 54244 of SEQ ID NO: 1, is a c. 1334T>C pathogenic genetic variant, is a с.!331T>C pathogenic genetic variant, is a C.1313T>C pathogenic genetic variant, encodes a p.Leu445Pro substitution in a JIP3 protein, encodes a p.Leu444Pro substitution in a JIP3 protein, or encodes a p.Leu438Pro amino acid substitution in a JIP3 protein; or

[0279] (vii) is at chromosome 16 position 1762376, is at position 56211 of SEQ ID NO: 1, is a c,1565G>A pathogenic genetic variant, is a c, 1562G>A pathogenic genetic variant, is a c. 1544G>A pathogenic genetic variant, encodes a p. Arg522His substitution in a JIP3 protein, encodes a p.Arg521His substitution in a JIP3 protein, or encodes a p.Arg515His amino acid substitution in a JIP3 protein; or

[0280] (viii) is at chromosome 16 position 1765960, is at position 59795 of SEQ ID NO: 1, is a C.2447OA pathogenic genetic variant, is a C.2444OA pathogenic genetic variant, is a C.2426OA pathogenic genetic variant, encodes a p. Ala816Glu substitution in a JIP3 protein, encodes a p.Ala815Glu substitution in a JIP3 protein, or encodes a р.Ala809Glu amino acid substitution in a JIP3 protein; or

[0281] (ix) is at chromosome 16 position 1760439, is at position 54274 of SEQ ID NO: 1, is a с. 1364A>G pathogenic genetic variant, is a c. 1361 A>G pathogenic genetic variant, is a c,1343A>G pathogenic genetic variant, encodes a p.Glu455Gly substitution in a JIP3 protein, encodes a p.Glu454Gly substitution in a JIP3 protein, or encodes a p.Glu448Gly amino acid substitution in a JIP3 protein.

[0282] A55. 1. The oligomeric compound of any one of embodiments A51-A55, wherein the pathogenic genetic variant: PATENT

[0283] 7328.158159PCT / NLM-1002-PC

[0284] (i) is at a rs 1567203083, rs770703007, rsl 567128142, rsl 567214097 or rsl567198751 pathogenic genetic variation site; or

[0285] (ii) is at a rsl567203083 pathogenic genetic variation site; or

[0286] (iii) encodes a p.Arg579Cys. p.Arg578Cys, p.Arg572Cys. p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argll47Cys, p.Argl l46Cys, p.Argl l40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515His, p.Ala816Glu, р.Ala815Glu, p.Ala809Glu, p.Glu455Gly, p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or

[0287] (iv) encodes a p.Arg579Cys. p. Arg578Cys or p.Arg572Cys amino acid substitution; or

[0288] (v) encodes a p.Arg579Cys amino acid substitution; or

[0289] (vi) encodes or is C.1735OT, C.1732OT, C.1714OT, c.281A>G, c.lllOG, c.65del, C.3439OT, C.3436OT, C.3418OT. c, 1334T>C, c, 1331T>C. c, 1313T>C,

[0290] С.1565G>A, C.1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c,1364A>G, C.1361A>G or c, 1343A>G; or

[0291] (vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or

[0292] (viii) encodes or is C.1735OT.

[0293] A56. The oligomeric compound of any one of embodiments A51 -A55. 1 , wherein the equal length portion of the genetic variation site contains the pathogenic genetic variation position, or contains the pathogenic genetic variation site or portion thereof.

[0294] A57. The oligomeric compound of any one of embodiments A51-A55. 1, wherein the equal length portion of the genetic variation site does not contain the pathogenic genetic variation position, or does not contain the pathogenic genetic variation site or portion thereof.

[0295] A58. The oligomeric compound of any one of embodiments A20-A57, which is single-stranded.

[0296] A59. The oligomeric compound of any one of embodiments A20-A58, wherein the modified oligonucleotide is 85% or more complementary to, or optionally 90% or more complementary to, or optionally 95% or more complementary to, or optionally 100% complementary to, an equal length portion of a first MAPK8IP3 / JIP3 allele nucleic acid. PATENT

[0297] 7328.158159PCT / NLM-1002-PC

[0298] A60. The oligomeric compound of embodiment A59, wherein the first

[0299] MAPK8IP3 / JIP3 allele nucleic acid is a mutant MAPK8IP3 / JIP3 allele nucleic acid.

[0300] A61. The oligomeric compound of embodiment A59 or A60, wherein the first MAPK8IP3 / JIP3 allele nucleic acid is a mutant MAPK8IP3 / JIP3 allele nucleic acid containing a pathogenic genetic variant.

[0301] A62. The oligomeric compound of any one of embodiments A59-A61, wherein the pathogenic genetic variant is not within the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid.

[0302] A63. The oligomeric compound of any one of embodiments A59-A62, wherein the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid contains a genetic variation site, which optionally is a differentiating genetic variation site, and does not contain a pathogenic genetic variation site.

[0303] A64. The oligomeric compound of any one of embodiments A59-A63, wherein a second MAPK8IP3 / JIP3 allele nucleic acid is a wild type MAPK8IP3 / JIP3 allele nucleic acid.

[0304] A65. The oligomeric compound of embodiment A64, wherein the first MAPK8IP3 / JIP3 allele nucleic acid is a mutant MAPK8IP3 / JIP3 allele nucleic acid containing a pathogenic genetic variant and the second MAPK8IP3 / JIP3 allele nucleic does not contain the pathogenic genetic variant present in the first MAPK8IP3 / JIP3 allele nucleic acid.

[0305] A66. The oligomeric compound of any one of embodiments A59-A65, wherein the modified oligonucleotide is X% complementary to an equal length portion of a first MAPK8IP3 / JIP3 allele nucleic acid and Y% complementary to an equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid, and (i) X% and Y% each is nucleobase complementarity, (ii) X% and Y% are not equal, and (iii) X% is greater than Y%.

[0306] A67. The oligomeric compound of embodiment A66, wherein a subtraction product of X% minus Y% is 1% to 10%, optionally 4% to 6% and optionally about 5%.

[0307] A68. The oligomeric compound of embodiment A66 or A67, wherein X% is 100% nucleobase complementarity to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid and Y% is a precent equal to full nucleobase complementarity to PATENT

[0308] 7328.158159PCT / NLM-1002-PC the equal length portion of the second MAPK81P3 / JIP3 allele nucleic acid except for a one-nucleobase mismatch or except for a two-nucleobase mismatch, or except for an insertion or deletion of 1-8 nucleosides or 1-3 nucleosides.

[0309] A69. The oligomeric compound of embodiment A68, wherein at least one nucleobase mismatch is at a genetic variation position in the second MAPK8IP3 / JIP3 allele nucleic acid.

[0310] A70. The oligomeric compound of any one of embodiments A20-A66, wherein a first MAPK8IP3 / JIP3 allele nucleic acid contains a nucleobase variant at a genetic variation position that is different from a corresponding nucleobase variant at the genetic variation position in a second MAPK8IP3 / JIP3 allele.

[0311] A71. The oligomeric compound of embodiment A70, wherein the nucleobase sequence of the modified oligonucleotide contains a nucleobase (i) complementary to the nucleobase variant at the genetic variation position of the first MAPK8IP3 / JIP3 allele nucleic acid, and (ii) not complementary to the nucleobase variant at the genetic variation position of the second MAPK8IP3 / JIP3 allele nucleic acid.

[0312] A72. The oligomeric compound of embodiment A70 or A71, wherein the corresponding equal length portion of the second MAPK8IP3 / JIP3 allele nucleic acid is identical to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one-nucleobase mismatch or two-nucleobase mismatch.

[0313] A73. The oligomeric compound of embodiment A72, wherein the corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid is identical to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one- nucleobase mismatch.

[0314] A74. The oligomeric compound of any one of embodiments A20-A73, wherein: the nucleobase sequence of the modified oligonucleotide is 100% complementary to an equal length portion of a first MAPK8IP3 / JIP3 allele nucleic acid and not 100% complementary to a corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid; or optionally the first MAPK8IP3 / JIP3 allele nucleic acid is a mutant MAPK8IP3 / JIP3 allele nucleic acid containing a pathogenic genetic variant not present in the second MAPK8IP3 / JIP3 allele nucleic acid. PATENT

[0315] 7328.158159PCT / NLM-1002-PC

[0316] A75. The oligomeric compound of embodiment A74, wherein the corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid is identical to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one- nucleobase mismatch or two-nucleobase mismatch, or except for an insertion or deletion of 1-8 nucleosides or 1-3 nucleosides.

[0317] A76. The oligomeric compound of embodiment A75, wherein the corresponding equal length portion of a second MAPK8IP3 / JIP3 allele nucleic acid is identical to the equal length portion of the first MAPK8IP3 / JIP3 allele nucleic acid except for a one- nucleobase mismatch.

[0318] A77. The oligomeric compound of embodiment A75 or A76, wherein at least one nucleobase mismatch is at a genetic variation position in the second MAPK8IP3 / JIP3 allele nucleic acid.

[0319] Bl. The oligomeric compound of any one of embodiments A1-A77, wherein the modified oligonucleotide comprises at least one modified nucleoside.

[0320] B2. The oligomeric compound of embodiment Bl, wherein the at least one modified nucleoside comprises a modified sugar.

[0321] B3. The oligomeric compound of embodiment B2, wherein the modified sugar comprises a bicyclic sugar.

[0322] B4. The oligomeric compound of embodiment B3, wherein the bicyclic sugar comprises a 2’-4’ bridge selected from -O-CH2- and -O-CH(CH3)-.

[0323] B5. The oligomeric compound of embodiment Bl, wherein the at least one modified nucleoside comprises a non-bicyclic modified sugar.

[0324] B6. The oligomeric compound of embodiment B5, wherein the non-bicyclic modified sugar moiety is a 2’ -substituted sugar moiety or a 5 ’-substituted sugar moiety.

[0325] B7. The oligomeric compound of embodiment B6, wherein the 2’-substitued sugar moiety is a 2 -MOE sugar moiety, a 2’-0Me sugar moiety or a 2’-F sugar moiety; or the 5 ’-substituted sugar moiety is a 5’-methyl modified sugar moiety or 5’- ethyl modified sugar moiety7.

[0326] B8. The oligomeric compound of embodiment Bl, wherein the at least one modified nucleoside comprises a sugar surrogate. PATENT

[0327] 7328.158159PCT / NLM-1002-PC

[0328] B9. The oligomeric compound of embodiment B8, wherein the sugar surrogate is selected from morpholino, modified morpholino, glycol nucleic acid (GNA), sixmembered tetrahydropyran (THP), and F-hexitol nucleic acid (F-HNA).

[0329] BIO. The oligomeric compound of any one of embodiments A1-B9. wherein the modified oligonucleotide is a gapmer.

[0330] Bit. The oligomeric compound of any one of embodiments Al -BIO, wherein the modified oligonucleotide comprises at least one modified intemucleoside linkage.

[0331] B12. The oligomeric compound of embodiment Bll, wherein the at least one modified intemucleoside linkage is a phosphorothioate intemucleoside linkage.

[0332] B13. The oligomeric compound of any one of embodiments A1-B12, wherein the modified oligonucleotide comprises at least one phosphodiester intemucleoside linkage.

[0333] B14. The oligomeric compound of any one of embodiments Bl 3, wherein the modified oligonucleotide comprises phosphodi ester intemucleoside linkages and a phosphorothioate intemucleoside linkages.

[0334] B15. The oligomeric compound of any one of embodiments B11-B14, wherein the modified oligonucleotide comprises at least one mesyl phosphoramidate linkage.

[0335] B16. The oligomeric compound of any one of embodiments B 11-B15, wherein the modified oligonucleotide comprises at least one busyl phosphoramidate linkage.

[0336] Bl 7. The oligomeric compound of any one of embodiments B11-B16, wherein at least 4. at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15. at least 16. at least 17. at least 18, or 19 intemucleoside linkages of the modified oligonucleotide are phosphorothioate intemucleoside linkages.

[0337] Bl 8. The oligomeric compound of any one of embodiments B11-B17, wherein the modified oligonucleotide comprises an intemucleoside linkage motif (from 5' to 3’) selected from soooossssssssssooss, sososssssssssssooss and sooosssssssssssooss, wherein each “s” represents a phosphorothioate intemucleoside linkage and each “o” represents a phosphodiester intemucleoside linkage.

[0338] Bl 9. The oligomeric compound of any one of embodiments Al -Bl 8, wherein the modified oligonucleotide comprises at least one modified nucleobase.

[0339] B20. The oligomeric compound of embodiment Bl 9, wherein the modified nucleobase is a 5-methylcytosine. PATENT

[0340] 7328.158159PCT / NLM-1002-PC

[0341] B21 . The oligomeric compound of embodiment B20, wherein each cytosine is a 5-methylcytosine.

[0342] B22. The oligomeric compound of any one of embodiments A1-B21, comprising a deoxy region consisting of two or more contiguous nucleosides each comprising a 2'-beta-deoxyribosyl sugar moiety.

[0343] B23. The oligomeric compound of embodiment B22, wherein the deoxy region consists of 3, 4, 5. 6, 7, 8, 9, 10, or 3-10, contiguous nucleosides, each comprising a 2'-beta-deoxyribosyl sugar moiety.

[0344] B24. The oligomeric compound of embodiment B22 or B23, wherein each nucleoside immediately adjacent to the deoxy region comprises a modified sugar.

[0345] B25. The oligomeric compound of any one of embodiments A1-B25, wherein the modified oligonucleotide comprises: a 5 ’-region consisting of 1-6 linked 5 ’-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3’-region consisting of 1-6 linked 3’-region nucleosides; wherein: each of the 5 ’-region nucleosides and each of the 3 ’-region nucleosides comprises a modified sugar moiety, and three or more of the central region nucleosides comprise a 2’-beta-D-deoxyribosyl sugar moiety.

[0346] B26. The oligomeric compound of any one of embodiments A1-B25, wherein the modified oligonucleotide comprises: a 5’-region consisting of 5 linked 5’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3’-region consisting of 5 linked 3’-region nucleosides; wherein: each of the 5 ’-region nucleosides and each of the 3 ’-region nucleosides comprises a modified sugar moiety, and three or more of the central region nucleosides comprise a 2’-beta-deoxyribosyl sugar moiety.

[0347] B27. The oligomeric compound of embodiment B25 or B26, wherein each of the 5'-region nucleosides and each of the 3’-region nucleosides comprises a 2’- substituted sugar moiety.

[0348] B28. The oligomeric compound of embodiment B27, wherein each of the 5’- region nucleosides and each of the 3’-region nucleosides comprises a 2’-MOE sugar moiety. PATENT

[0349] 7328.158159PCT / NLM-1002-PC

[0350] B29. The oligomeric compound of any one of embodiments B25-B28, wherein the central region comprises four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten central region nucleosides comprising a 2'-beta- deoxyribosyl sugar moiety.

[0351] B30. The oligomeric compound of any one of embodiments B25-B29, wherein the central region comprises 1, 2, 3, 4 or 5, or 1 to 5, modified sugar moieties.

[0352] B31. The oligomeric compound of embodiment B30, wherein one or more of the modified sugar moieties is a non-bicyclic modified sugar moiety.

[0353] B32. The oligomeric compound of embodiment B30 or B31, wherein one or more of the modified sugar moieties is a bicyclic modified sugar moiety.

[0354] B33. The oligomeric compound of any one of embodiments B30-B32, wherein one or more of the modified sugar moieties comprises a 2’ substituent.

[0355] B34. The oligomeric compound of embodiment B33, wherein one or more of the modified sugar moieties is a 2’-0Me modified sugar moiety.

[0356] B35. The oligomeric compound of any one of embodiments B30-B34, wherein one or more of the modified sugar moieties comprises a 5’ substituent.

[0357] B36. The oligomeric compound of embodiment B35, wherein one or more of the modified sugar moieties is a 5 ’-methyl modified sugar moiety or 5 ’-ethyl modified sugar moiety.

[0358] B37. The oligomeric compound of any one of embodiments B25-B36, wherein: the central region comprises a 5’ terminus; and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety.

[0359] B38. The oligomeric compound of embodiment B37, wherein position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety comprising a 2’ substituent.

[0360] B39. The oligomeric compound of embodiment B38, wherein the modified sugar moiety independently is a 2’-0Me modified sugar moiety.

[0361] B40. The oligomeric compound of any one of embodiments B25-B39, wherein: PATENT

[0362] 7328.158159PCT / NLM-1002-PC the central region comprises a 5’ terminus; and position 3, or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety.

[0363] B41. The oligomeric compound of embodiment B40, wherein position 3, or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central region, each independently comprises modified sugar moiety comprising a 5’ substituent.

[0364] B42. The oligomeric compound of embodiment B41, wherein position 3, or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central region, each independently comprises a 5 ’-methyl modified sugar moiety.

[0365] B43. The oligomeric compound of embodiment B42, wherein the 5 ’-methyl modified sugar moiety independently is a R-5’ -methyl modified sugar moiety or a S- 5 ’-methyl modified sugar moiety.

[0366] B44. The oligomeric compound of any one of embodiments B25-B43, wherein the central region comprises 1. 2, 3, 4 or 5, or 1 to 5, mesyl phosphorami dite and / or busyl phosphoramidite intemucleoside linkages.

[0367] B45. The oligomeric compound of embodiment B44, wherein: the central region comprises a 5’ terminus; and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a mesyl phosphoramidite and / or a busyl phosphoramidite intemucleoside linkage.

[0368] B46. The oligomeric compound of any one of embodiments B25-B45, wherein the central region comprises 1. 2, 3, 4 or 5, 1 to 5, alkylphosphonate intemucleoside linkages.

[0369] B47. The oligomeric compound of embodiment B46, wherein: the central region comprises a 5’ terminus; and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises an alkylphosphonate intemucleoside linkage. PATENT

[0370] 7328.158159PCT / NLM-1002-PC

[0371] B48. The oligomeric compound of embodiment B46 or B47, wherein the alkylphosphonate intemucleoside linkage comprises methoxypropyl (MOP).

[0372] B49. The oligomeric compound of any one of embodiments B25-B48, wherein the central region comprises the deoxy region of any one of embodiments B22-B24.

[0373] B50. The oligomeric compound of embodiment B49. wherein the modi fi ed oligonucleotide comprises a sugar motif of 5’-eeeeeddddddddddeeeee~3’. wherein each "d " represents a 2’-beta-D-deoxyribosyl sugar moiety, each “e” represents a 2’- MOE sugar moiety.

[0374] B51. The oligomeric compound of any one of embodiments A1-B50, wherein the modified oligonucleotide consists of 12-30, 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 18-22, or 18-20 linked nucleosides, or a pharmaceutically acceptable salt thereof.

[0375] B52. The oligomeric compound of any one of embodiments Al -B51, wherein the modified oligonucleotide consists of 20 linked nucleosides, or a pharmaceutically acceptable salt thereof.

[0376] B53. The oligomeric compound of embodiment B51 or B52, which is a pharmaceutically acceptable salt comprising one or more cations selected from sodium, potassium, calcium and magnesium.

[0377] B54. The oligomeric compound of any one of embodiments A1-B53, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[0378] B55. The oligomeric compound of any one of embodiments A1-B54, wherein the oligomeric compound consists of the modified oligonucleotide.

[0379] B56. The oligomeric compound of any one of embodiments A1 -B54, wherein the oligomeric compound comprises a conjugate group.

[0380] B57. The oligomeric compound of embodiment B56, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

[0381] B58. The oligomeric compound of embodiment B57, wherein the conjugate linker is a phosphodiester linker.

[0382] B59. The oligomeric compound of embodiment B57, wherein the conjugate linker consists of a single bond.

[0383] B60. The oligomeric compound of any one of embodiments B57-B59, wherein the conjugate linker is cleavable. PATENT

[0384] 7328.158159PCT / NLM-1002-PC

[0385] B61. The oligomeric compound of any one of embodiments B57-B60, wherein the conjugate linker comprises 1-3 linker-nucleosides.

[0386] B62. The oligomeric compound of any one of embodiments B56-B61, wherein the conjugate group is attached to the modified oligonucleotide at the 5 ’-end of the modified oligonucleotide.

[0387] B63. The oligomeric compound of any one of embodiments B56-B62, wherein the conjugate group is attached to the modified oligonucleotide at the 3 ’-end of the modified oligonucleotide.

[0388] B64. The oligomeric compound of any one of embodiments A1-B63, wherein the oligomeric compound comprises a terminal group.

[0389] B65. The oligomeric compound of any one of embodiments A1-B64, wherein the oligomeric compound does not comprise linker-nucleosides.

[0390] B66. The oligomeric compound of any one of embodiments A20-B65, comprising or consisting of:

[0391] 5'-A-mC-mU-A-A-T-A-T-T-mC-A-mC-A-T-G-mU-mC-A-mU-mC-3' (SEO

[0392] ID NO : 116), wherein:

[0393] “m” is methyl; each of the underlined nucleosides is a modified nucleoside comprising a 2’ -MOE sugar moiety; optionally each of the nucleosides not underlined comprises a 2’-beta- deoxyribosyl sugar moiety; optionally each mU is a 5-methyluridine; or optionally each mC is a 5 -methylcytidine.

[0394] B67. The oligomeric compound of any one of embodiments A20-B66, comprising or consisting of (SEQ ID NO: 117): 2'-0-(2-methoxyethyl)-adenosine-(3'-0->5'-0)- 2'-0-(2-methoxyethyl)-5-methylcytidine-(3'-0->5'-0)- 2'-0-(2-methoxyethyl)-5-methyluridine-(3'-0^>5'-0)- 2 -0-(2-methoxyethyl)-adenosine-(3'-0^5'-0)- 2'-0-(2-methoxyethyl)-adenosine-(3'-0->5'-0)- 2'-0-(2-deoxy)-thymidine-(3'-0— >5'-O)- 2'-0-(2-deoxy)-adenosine-(3'-0->5'-0)- 2 -0-(2-deoxy)-thymidine-(3'-0^5'-0)- 2'-0-(2-deoxy)-thymidine-(3'-0->5'-0)-

[0395] 2 -0-(2-deoxy)-5-methylcytidine -(3'-O-»5'-O)-

[0396] 2 -0-(2-deoxy)-adenosine-(3'-0->5'-0)-

[0397] 2'-0-(2-deoxy)-5-methylcytidine -(3'-0->5'-0)-

[0398] 2 -0-(2-deoxy)-adenosine-(3'-0^5'-0)- PATENT

[0399] 7328.158159PCT / NLM- 1002-PC

[0400] 2'-0-(2-deoxy)-thymidine-(3'-0^5'-0)-

[0401] 2 -0-(2-deoxy)-guanosine-(3'-0->5'-0)-

[0402] 2 -0-(2-methoxyethyl)-5-methyluridine-(

[0403] 2'-0-(2-methoxyethyl)-5-methylcytidine -

[0404] 2 -0-(2-methoxyethyl)-adenosine-(3'-0

[0405] 2 -0-(2-methoxyethyl)-5-methyluridine-(

[0406] 2'-0-(2-methoxyethyl)-5-methylcytidine -nonadecasodium salt.

[0407] B68. The oligomeric compound of any one of embodiments A20-B67, comprising or consisting of:

[0408] Cl. A composition, comprising an oligomeric compound of any one of embodiments A1-B68.

[0409] C2. The composition of embodiment C l, wherein the oligomeric compound comprises at least one phosphorothioate intemucleoside linkage, and the composition comprises a plurality7of the oligomeric compound in a population of oligomeric compounds.

[0410] C3. The composition of embodiment C2, wherein the population is a chirally enriched population, wherein the population is enriched for modified oligonucleotides PATENT

[0411] 7328.158159PCT / NLM-1002-PC comprising at least one particular phosphorothioate intemucleoside linkage having a particular stereochemical configuration.

[0412] C4. The composition of embodiment C3, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate intemucleoside linkage having a (Sp) configuration.

[0413] C5. The composition of embodiment C3, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate intemucleoside linkage having a (Rp) configuration.

[0414] C6. The composition of embodiment C3. wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate intemucleoside linkage.

[0415] C7. The composition of embodiment C6, wherein the population is enriched for modified oligonucleotides having a (Sp) configuration at each phosphorothioate intemucleoside linkage or for modified oligonucleotides having a (Rp) configuration at each phosphorothioate intemucleoside linkage.

[0416] C8. The composition of embodiment C3, wherein the population is enriched for modified oligonucleotides having a (Rp) configuration at one particular phosphorothioate intemucleoside linkage and a (Sp) configuration at each of the remaining phosphorothioate intemucleoside linkages.

[0417] C9. The composition of embodiment C3, wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate intemucleoside linkages in (Sp). (Sp) and (Rp) configurations, in the 5’ to 3’ direction.

[0418] CIO. The composition of embodiment C2, wherein the phosphorothioate intemucleoside linkages of the modified oligonucleotides in the population are stereorandom.

[0419] Cl l. The composition of any one of embodiments Cl -CIO, wherein the modified oligonucleotides in the population is single stranded.

[0420] C12. A composition of any one of embodiments Cl-Cll, comprising an oligomeric duplex, wherein: the oligomeric compound of any one of embodiments A1-B68 is a first oligomeric compound; the oligomeric duplex comprises the first oligomeric compound and a second oligomeric compound; and PATENT

[0421] 7328.158159PCT / NLM-1002-PC the second oligomeric compound comprises a second modified oligonucleotide.

[0422] C13. The composition of embodiment Cl 2, wherein: the second modified oligonucleotide consists of 12 to 50 linked nucleosides; and the nucleobase sequence of the second modified oligonucleotide comprises a complementary’ region of at least 12 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide.

[0423] C14. The composition of embodiment Cll or C12, wherein the modified oligonucleotide of the first oligomeric compound and / or the second oligomeric compound comprises a 5’-stabilized phosphate group.

[0424] C15. The composition of embodiment Cl 4, wherein the stabilized phosphate group comprises a cyclopropyl phosphonate or a vinyl phosphonate.

[0425] Cl 6. The composition of any one of embodiments C12-C15. wherein at least one nucleoside of the second modified oligonucleotide comprises a modified sugar moiety.

[0426] C17. The composition of embodiment Cl 6, wherein the modified sugar moiety of the second modified oligonucleotide comprises a bicyclic sugar moiety.

[0427] C18. The composition of embodiment C17, wherein the bicyclic sugar moiety comprises a 2’-4’ bridge selected from -O-CH2- and -O-CH(CH3)-.

[0428] C19. The composition of embodiment C18, wherein the modified sugar moiety’ of the second modified oligonucleotide comprises a non-bicyclic modified sugar moiety.

[0429] C20. The composition of embodiment Cl 9, wherein the non-bicyclic modified sugar moiety7of the second modified oligonucleotide is a 2’-OMe sugar moiety’ or a 2’-F sugar moiety'.

[0430] C21. The composition of any one of embodiments C12-C120, wherein at least one nucleoside of the second modified oligonucleotide comprises a sugar surrogate.

[0431] C22. The composition of any one of embodiments C12-C21, wherein the second modified oligonucleotide comprises at least one modified intemucleoside linkage.

[0432] C23. The composition of embodiment C22. wherein the at least one modified intemucleoside linkage of the second modified oligonucleotide is a phosphorothioate intemucleoside linkage. PATENT

[0433] 7328.158159PCT / NLM-1002-PC

[0434] C24. The composition of any one of embodiments C12-C23, wherein the second modified oligonucleotide comprises at least one mesyl phosphoramidate (MsPA) linkage.

[0435] C25. The composition of embodiment C23. wherein each intemucleoside linkage of the second modified oligonucleotide is independently selected from a phosphodiester intemucleoside linkage and a phosphorothioate intemucleoside linkage.

[0436] C26. The composition of any one of embodiments C12-C25, wherein the second modified oligonucleotide comprises at least one modified nucleobase.

[0437] C27. The composition of embodiment C26, wherein the at least one modified nucleobase is 5-methylcytosine.

[0438] C28. The composition of any one of embodiments C12-C27, wherein the second oligomeric compound comprises a conjugate group.

[0439] C29. The composition of embodiment C28, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

[0440] C30. The composition of embodiment C29, wherein the conjugate linker consists of a single bond.

[0441] C31. The composition of embodiment C29 or C30, wherein the conjugate linker is cleavable.

[0442] C32. The composition of any one of embodiments C29-C31, wherein the conjugate linker comprises 1-3 linker-nucleosides.

[0443] C33. The composition of any one of embodiments C29-C32. wherein the conjugate linker is a phosphodiester linker.

[0444] C34. The composition of any one of embodiments C28-C33, wherein the conjugate group is attached to the 5'-end of the second modified oligonucleotide.

[0445] C35. The composition of any one of embodiments C28-C33, wherein the conjugate group is attached to the 3 ’-end of the second modified oligonucleotide.

[0446] C36. The composition of any one of embodiments C28-C33, wherein the conjugate group is attached via the 2’ position of a ribosyl sugar moiety at an internal position of the second modified oligonucleotide.

[0447] C37. The composition of any one of embodiments C28-C36. wherein the conjugate group comprises a C22 alkyl, C20 alkyl, C16 alkyl, CIO alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C17 alkyl, C15 alky 1, C14 alkyl, C13 alkyl, C12 alkyl, Cll PATENT

[0448] 7328.158159PCT / NLM-1002-PC alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, CIO alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C17 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, Cl 1 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

[0449] C38. The composition of any one of embodiments C28-C37, wherein the conjugate group comprises a cell-targeting moiety.

[0450] C39. The composition of any one of embodiments C12-C38, wherein the second modified oligonucleotide comprises a terminal group.

[0451] C40. The composition of embodiment C39. wherein the terminal group is an abasic sugar moiety.

[0452] C41. A composition, comprising an antisense agent, the antisense agent comprising or consisting of an antisense compound, wherein the antisense compound is the oligomeric compound of any one of embodiments A1-B68 or is in a composition of any one of embodiments Cl-Cll.

[0453] C42. A composition, comprising an antisense agent, wherein the antisense agent is the oligomeric duplex of any one of embodiments C12-C40.

[0454] C43. The composition of embodiment C41 or C42, wherein the antisense agent is:

[0455] (i) an RNase H agent capable of reducing the amount of MAPK8IP3 / JIP3 nucleic acid through the activation of RNase H; or

[0456] (ii) an RNAi agent capable of reducing the amount of MAPK8IP3 / JIP3 nucleic acid through the activation of RISC / Ago2.

[0457] C44. The composition of any one of embodiments C41-C43, wherein the antisense agent comprises a conjugate group, and wherein the conjugate group comprises a cell -targeting moiety.

[0458] DI. A pharmaceutical composition comprising an oligomeric compound of any one of embodiments A1-B68 or a composition of any one of embodiments C1-C44, and a pharmaceutically acceptable diluent.

[0459] D2. The pharmaceutical composition of embodiment DI, wherein the pharmaceutically acceptable diluent is phosphate buffered saline (PBS) or artificial CSF (aCSF). PATENT

[0460] 7328.158159PCT / NLM-1002-PC

[0461] D3. The pharmaceutical composition of embodiment DI or D2, consisting essentially of the oligomeric compound of any one of embodiments A1-B68 or a composition of any one of embodiments C1-C44, and aCSF.

[0462] D4. The pharmaceutical composition of embodiment DI or D2, consisting essentially of the oligomeric compound of any one of embodiments A1-B68 or a composition of any one of embodiments C1-C44, and PBS.

[0463] El. A method for administering an oligomeric compound of any one of embodiments A1-B68, or a composition of any one of embodiments C1-C44. or pharmaceutical composition of any one of embodiments D1-D4, to a cell or tissue.

[0464] E2. A method for administering an oligomeric compound of any one of embodiments A1-B68, or a composition of any one of embodiments C1-C44, or pharmaceutical composition of any one of embodiments D1-D4, to a cell or tissue of a subject.

[0465] E3. The method of embodiment El or E2, wherein the oligomeric compound, composition or pharmaceutical composition is administered in vitro or ex vivo.

[0466] E4. The method of embodiment El or E2, wherein the oligomeric compound, composition or pharmaceutical composition is administered in vivo.

[0467] E5. The method of any one of embodiments E1-E4, wherein the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to reduce MAPK8IP3 / JIP3 expression, or optionally to selectively reduce expression of a MAPK8IP3 / JIP3 allelic variant, wherein MAPK8IP3 / JIP3 expression is a level of a MAPK8IP3 / JIP3 nucleic acid, or MAPK8IP3 / JIP3 protein or MAPK8IP3 / JIP3 nucleic acid and MAPK81P3 / JIP3 protein, and optionally wherein a level of a MAPK8IP3 / JIP3 nucleic acid is a level of a MAPK8IP3 / JIP3 pre-RNA and / or MAPK8IP3 / JIP3 mRNA.

[0468] E6. The method of embodiment E5. wherein the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to reduce MAPK8IP3 / JIP3 expression by 20% or more.

[0469] E7. A method for treating a medical condition, comprising administering an oligomeric compound of any one of embodiments A1-B68, or a composition of any one of embodiments C1-C44, or pharmaceutical composition of any one of embodiments D1-D4, to a cell or tissue of a subject in need thereof in an amount sufficient to treat the medical condition, wherein the medical condition optionally is a PATENT

[0470] 7328.158159PCT / NLM-1002-PC

[0471] MAPK8IP3 / JIP3-associated medical condition, a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson' s-like disease, Parkinson's disease, neurodevel opmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0472] E8. The method of embodiment E7, wherein the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to reduce MAPK8IP3 / JIP3 expression.

[0473] E9. The method of embodiment E8. wherein the oligomeric compound, composition pharmaceutical composition is administered in an amount sufficient to reduce MAPK8IP3 / JIP3 expression by 20% or more.

[0474] E10. The method of any one of embodiments E7-E9, wherein at least one symptom or hallmark of the medical condition is ameliorated.

[0475] El l. The method of embodiment E10, wherein the symptom or hallmark is one or more of: neurodevelopment impairment, intellectual disability, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality, physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity7, walking difficulties, visual impairment and seizure.

[0476] E12. The method of any one of embodiments E7-E11, wherein administering the oligomeric compound, composition or pharmaceutical composition reduces or delays onset or progression of one or more of one or more of: neurodevelopment impairment, intellectual disability7, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality, physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity7, walking difficulties, visual impairment and seizure.

[0477] E13. The method of any one of embodiments E1-E12, wherein the cell is or the tissue comprises a neuronal cell or fibroblast cell.

[0478] El 4. The method of any7one of embodiments El -El 3, wherein the cell is or the tissue comprises a human cell. PATENT

[0479] 7328.158159PCT / NLM-1002-PC

[0480] El 5. The method of any of one of embodiments E2-E14, wherein the oligomeric compound, the composition or the pharmaceutical composition is administered to the central nervous system or is administered systemically.

[0481] E16. The method of embodiment E15, wherein the oligomeric compound, the composition, or the pharmaceutical composition is administered intrathecally.

[0482] El 7. The method of any one of embodiments E2-E16, wherein the subject is human.

[0483] El 8. The method of any one of embodiments El -El 7, wherein the cell or tissue comprises a MAPK8IP3 / J1P3 nucleic acid comprising a pathogenic genetic variant associated with a medical condition.

[0484] E19. The method of embodiment El 8, wherein the pathogenic genetic variant is associated with a gain of function or toxic gain of function.

[0485] E20. The method of embodiment El 8 or El 9, wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease, neurodevel opmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0486] E21. The method of any one of embodiments E18-E20, wherein the pathogenic genetic variant is a pathogenic single nucleotide variation.

[0487] E22. The method of embodiment E21, wherein the pathogenic single nucleotide variant is a non-synonymous single nucleotide variant at a pathogenic genetic variation position and / or a pathogenic genetic variation site.

[0488] E23. The method of any one of embodiments E18-E24, wherein: the pathogenic genetic variant is selected from: C.1735OT, C.1732OT, c.281A>G, c.1714 OT, c.Cl llG, c57OG, c.65delG. C.C3436T, C.C1732T, C.CT1331C. c. 1544G>A, C.2447OA and c. 1364A>G, and / or results in a MAPK8IP3 / JIP3 protein containing a variant selected from p.(Arg579Cys), p.(Glu455Gly) and p.(Tyr94Cys); or the pathogenic genetic variant:

[0489] (i) is at a rsl567203083, rs770703007, rsl567128142, rsl567214097 or rs 1567198751 pathogenic genetic variation site; or

[0490] (ii) is at a rsl567203083 pathogenic genetic variation site; or PATENT

[0491] 7328.158159PCT / NLM-1002-PC

[0492] (iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr.37Ter. p.Gly22AlafsTer3, p.Argll47Cys, p.Argl l46Cys, p.Argll40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515His, p.Ala816Glu, р.Ala815Glu, p.Ala809Glu, p.Glu455Gly. p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or

[0493] (iv) encodes a p.Arg579Cys, p. Arg578Cys or p.Arg572Cys amino acid substitution; or

[0494] (v) encodes a p.Arg579Cys amino acid substitution; or

[0495] (vi) encodes or is C.1735OT, C.1732OT. C.1714OT, c.281A>G, c.lllOG, c.65del. C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c,1331T>C, c,1313T>C, с,1565G>A, c. !562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c.!364A>G, c. 1361A>G or c, 1343A>G; or

[0496] (vii) encodes or is c. 1735OT. C.1732OT or c. 1714OT; or

[0497] (viii) encodes or is c. 1735OT

[0498] E24. The method of embodiment E23, wherein the MAPK8IP3 / JIP3 nucleic acid comprises a C.1735OT pathogenic genetic variant and / or a genetic variation resulting in a p. Arg579Cys variation in a MAPK8IP3 / JIP3 protein.

[0499] E25. The method of any one of embodiments E18-E24, wherein the pathogenic genetic variant is associated with one or more phenotypes chosen from: increased cell degeneration; reduced cell proliferation; activation of the JNK signaling pathway; enhanced pro-apoptotic signaling via JNK; modification of MAPK8IP3 / JIP3 binding partner interactions; increased MAPK8IP3 / JIP3 expression; reduced JIP4 expression; altered MAPK8TP3 / JIP3 subcellular localization; reduced MAPK8IP3 / JTP3 binding affinity to JIP4; reduced MAPK8IP3 / JIP3 / JIP4 heterodimer formation; increased MAPK8IP3 / JIP3 binding affinity to KIF5b; decreased axon trafficking; decreased endosome mobility along microtubules in axons; decreased late endosome mobility along microtubules in axons; and decreased dopamine receptor 1 (DI) signaling; optionally wherein each phenotype is for cells relative to cells not containing a mutant MAPK8IP3 / JIP3.

[0500] E26. The method of any one of embodiments E1-E25, wherein administration is associated with one or more of: reducing cell toxicity; increasing cell proliferation; increasing axon trafficking; increasing endosome mobility along microtubules in PATENT

[0501] 7328.158159PCT / NLM-1002-PC axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling.

[0502] E27. The method of embodiment E25 or E26, wherein the cell toxicity is neuronal or fibroblast cell toxicity and the cell proliferation is neuronal cell proliferation or fibroblast cell proliferation.

[0503] E28. The method of any one of embodiments E1-E27, wherein administration reduces MAPK8IP3 / JIP3 expression, and: reduces JIP4 expression less than it reduces MAPK8IP3 / JIP3 expression or does not reduce JIP4 expression.

[0504] E29. The method of any one of embodiments E1-E28, wherein a cell, tissue or subject comprises a mutant MAPK8IP3 / JIP3 allele and the oligomeric compound administered is non-allele selective or is allele-selective.

[0505] E30. The method of embodiment E29, wherein: the mutant MAPK8IP3 / JIP3 expression and the wild-type MAPK8IP3 / JIP3 expression differ by less than 2-fold after administration, and optionally the mutant MAPK8IP3 / JIP3 expression and the wild-type MAPK8IP3 / JIP3 expression differ by less than 2-fold after administration at the IC50 concentration of the inhibitor for the wild-type protein; or the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to selectively reduce expression of the MAPK8IP3 / JIP3 allelic variant by at least 2-fold compared to expression of another MAPK8IP3 / JIP3 allelic variant; or optionally the oligomeric compound selectively reduces expression of a first MAPK8IP3 / JIP3 allelic variant according to a selectivity ratio of at least 2 or greater than 2; or optionally the selectivity ratio is (i) inhibition of expression of a second MAPK8IP3 / JIP3 allelic variant to (ii) inhibition of expression of the first MAPK8IP3 / JIP3 allelic variant; or optionally the inhibition of expression of the second SCN2A allelic variant is an IC50 value and the inhibition of expression of the first SCN2A allelic variant is an IC50 value.

[0506] Fl. The method of any one of embodiments E18-E30, comprising determining presence or absence of the pathogenic genetic variant; and if the pathogenic genetic PATENT 7328.158159PCT / NLM-1002-PC variant is present, administering the oligomeric compound, composition or pharmaceutical composition.

[0507] F2. The method of embodiment Fl, comprising: genotyping a genetic variation position and / or a genetic variation site of the MAPK8IP3 / JIP3 nucleic acid, thereby providing a MAPK8IP3 / JIP3 nucleic acid genotype; and determining presence or absence of the pathogenic genetic variant according to the genotype.

[0508] F3. The method of embodiment Fl or F2. wherein the MAPK8IP3 / J1P3 nucleic acid is from a cell or tissue.

[0509] F4. The method of any one of embodiments F1-F3, wherein the MAPK8IP3 / JIP3 nucleic acid is from a subject.

[0510] F5. The method of embodiment F3 or F4. wherein the cell, tissue or subject is a human cell, human tissue or human subject.

[0511] F6. The method of any one of embodiments F1-F5, wherein the MAPK8IP3 / JIP3 nucleic acid is from a subject having a medical condition.

[0512] F7. The method of embodiment F6, wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease, neurodevel opmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0513] F8. The method of any one of embodiments F1 -F7, wherein the MAPK8IP3 / JIP3 nucleic acid is from a cell or cells associated with one or more phenotypes chosen from: increased cell degeneration; reduced cell proliferation; activation of the JNK signaling pathway; enhanced pro-apoptotic signaling via JNK; modification of MAPK8IP3 / JIP3 binding partner interactions; increased MAPK8IP3 / JIP3 expression; reduced JIP4 expression; altered MAPK8IP3 / JIP3 subcellular localization; reduced MAPK8IP3 / JIP3 binding affinity' to JIP4; reduced MAPK8IP3 / JIP3 / JIP4 heterodimer formation; increased MAPK8IP3 / JIP3 binding affinity to KlF5b; decreased axon trafficking; decreased endosome mobility along microtubules in axons; decreased late endosome mobility along microtubules in PATENT

[0514] 7328.158159PCT / NLM-1002-PC axons; and decreased dopamine receptor 1 (DI) signaling; optionally wherein each phenotype is for cells relative to cells not containing a mutant MAPK8IP3 / JIP3.

[0515] F9. The method of embodiment F8, wherein the cell toxicity is neuronal or fibroblast cell toxicity and the cell proliferation is neuronal cell proliferation or fibroblast cell proliferation.

[0516] F10. The method of any one of embodiments F1-F9, wherein determining the presence or absence of the pathogenic genetic variant, and optionally the genotyping, comprises sequencing the MAPK8IP3 / JIP3 nucleic acid.

[0517] Fl l. The method of embodiment F10, wherein the sequencing comprises shortread sequencing, or long-read sequencing, or short-read sequencing and long-read sequencing.

[0518] F12. The method of any one of embodiments E1-E30 and Fl-Fll, comprising: determining presence, absence and / or amount of a MAPK8IP3 / JIP3 level, wherein the MAPK8IP3 / JIP3 level optionally is an elevated level, and optionally wherein the MAPK8IP3 / JIP3 level is a level of a MAPK8IP3 / JIP3 nucleic acid and / or a level of a MAPK8IP3 / JIP3 protein.

[0519] F13. The method of embodiment Fl 2, wherein the MAPK8IP3 / JIP3 level is relative to a control MAPK8IP3 / JIP3 level.

[0520] F14. The method of embodiment F13, wherein the control level is in a cell or cells in which MAPK8IP3 / JIP3 nucleic acid does not contain a pathogenic genetic variant.

[0521] F15. The method of any one of embodiments F 12-F 14. comprising administering an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid if an elevated MAPK8IP3 / JIP3 level is present.

[0522] F16. The method of any one of embodiments F12-F14, wherein presence, absence and / or amount of an elevated MAPK8IP3 / JIP3 level is determined for a sample, a cell, cells, a tissue and / or a subject.

[0523] Fl 7. The method of any one of embodiments F 12-F 14, wherein the MAPK8IP3 / JIP3 level is in blood, or optionally in serum, or optionally in plasma.

[0524] Fl 8. The method of any one of embodiments F 12-F 14, wherein the oligomeric compound targeted to a MAPK8IP3 / J1P3 nucleic acid is administered to a cell, cells, a tissue and / or a subject. PATENT

[0525] 7328.158159PCT / NLM-1002-PC

[0526] Fl 9. The method of any one of embodiments F 12-F18, wherein the MAPK8IP3 / JIP3 nucleic acid is MAPK8IP3 / JIP3 RNA, and optionally the RNA is pre-mRNA and / or mRNA.

[0527] F20. A method for selectively reducing expression of a MAPK8IP3 / JIP3 allelic variant containing a genetic variation site in a cell, tissue or subject, comprising administering to a cell, tissue or subject an oligomeric compound comprising a modified oligonucleotide comprising a nucleobase sequence complementary' to an equal length portion of a genetic variation site of a MAPK8IP3 / JIP3 allelic variant in an amount effective to selectively reduce expression of the MAPK81P3 / J1P3 allelic variant.

[0528] F21. The method of embodiment F20, wherein: the genetic variation site comprises or consists of a differentiating genetic variation site, or optionally comprises a single nucleotide variation site, or optionally comprises a differentiating single nucleotide variation site.

[0529] F22. The method of embodiment F21, wherein: the genetic variation site comprises a genetic variation position and the modified oligonucleotide comprises at least one nucleoside aligned with the genetic variation position; or optionally the single nucleotide variation site comprises a single nucleotide variation position and the modified oligonucleotide comprises a nucleoside aligned with the single nucleotide variation position.

[0530] F23. The method of embodiment F22, wherein: the modified oligonucleotide comprises at least one nucleoside aligned with and complementary to at least one nucleoside at the genetic variation position; or optionally the modified oligonucleotide comprises a nucleoside aligned with and complementary to a nucleoside at the single nucleotide variation position.

[0531] F24. The method of embodiment F23, wherein the MAPK8IP3 / JIP3 allelic variant is a first MAPK8IP3 / JIP3 allelic variant, the modified oligonucleotide comprises: a nucleoside aligned with and complementary' to a first nucleoside at the genetic variation position of the first MAPK8IP3 / JIP3 allelic variant and not complementary to a second nucleoside at the genetic variation position of a second MAPK8IP3 / JIP3 allelic variant; or optionally a nucleoside aligned with and complementary to a first nucleoside at the single nucleotide variation position of the first MAPK8IP3 / JIP3 PATENT

[0532] 7328.158159PCT / NLM-1002-PC allelic variant and not complementary to a second nucleoside at the single nucleotide variation position of a second MAPK8IP3 / JIP3 allelic variant.

[0533] F25. The method of embodiment F24, wherein the modified oligonucleotide is capable of selectively reducing expression of the first MAPK8IP3 / JIP3 allelic variant to a greater extent than expression of the second MAPK8IP3 / JIP3 allelic variant.

[0534] F26. The method of embodiment F25, wherein: the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to selectively reduce expression of the MAPK81P3 / JIP3 allelic variant by at least 2-fold compared to expression of another MAPK8IP3 / JIP3 allelic variant; or optionally the oligomeric compound selectively reduces expression of a first MAPK8IP3 / JIP3 allelic variant according to a selectivity ratio of at least 2 or greater than 2; or optionally the selectivity ratio is (i) inhibition of expression of a second MAPK8IP3 / JIP3 allelic variant to (ii) inhibition of expression of the first MAPK8IP3 / JIP3 allelic variant; or optionally the inhibition of expression of the second SCN2A allelic variant is an IC50 value and the inhibition of expression of the first SCN2A allelic variant is an IC50 value.

[0535] F27. The method of any one of embodiment F22-F26, wherein: the modified oligonucleotide consists of 10-30 linked nucleosides and the nucleoside at position 2, 3. 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. 20. 21, 22, 23, 24, 25, 26, 27, 28 or 29 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with the genetic variation position, or optionally the single nucleotide variation position; or the modified oligonucleotide consists of 18-22 linked nucleosides, or optionally consists of 20 nucleosides, and the nucleoside at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with the genetic variation position, or optionally the single nucleotide variation position.

[0536] F28. The method of any one of embodiments F22-F27, wherein the modified oligonucleotide comprises: a 5’-region consisting of linked 5’-region nucleosides; PATENT

[0537] 7328.158159PCT / NLM-1002-PC a central region consisting of linked central region nucleosides; a 3’-region consisting of linked 3’-region nucleosides; the central region comprises a 5‘ terminus: and the nucleoside at position 1, 2, 3. 4, 5, 6. 7, 8, 9 or 10 of the central region, as counted from the 5' terminus of the central region, aligns with the genetic variation position, or optionally the single nucleotide variation position.

[0538] F29. The method of any one of embodiments F21-F28, wherein the genetic variation site is in: (i) a MAPK8IP3 / JIP3 intron, optionally wherein the intron is chosen from intron 1 or intron 8, or optionally wherein the intron is intron 1 ; or (ii) a MAPK8IP3 / JIP3 exon, optionally wherein the exon is exon 31 or exon 32; (iii) a chromosome 16 portion chosen from: positions 1706658-1724556, 1748721-1758147, 1768477-1768626 or 1768703-1770351; or (iv) a portion of SEQ ID NO:1 chosen from: positions 493-18391, 42556-51982, 62312-62461 or 62538-64186; or (v) a chromosome 16 portion between positions 1706658-1724556; or (vi) a portion of SEQ ID NO: 1 between positions 493-18391.

[0539] F30. The method of any one of embodiments F21-F29, wherein the genetic variation site is:

[0540] (i) rsl7135499, rsl7135500, rsl2922553, rsl l860323, rsl l865685, rs35988159, rs34950492, rsl2930313, rsl2925525, rs8063431, rs9788926, rs2076431 or rs2575329; or

[0541] (ii) rsl7135499, rsl7135500, rs34950492, rs35988159, rs9788926, rs2076431 or rs2575329; or

[0542] (iii) rs34950492 and rs35988159; or

[0543] (iv) rsl7135500.

[0544] F31. The method of any one of embodiments F21-F30, wherein the genetic variation site comprises:

[0545] (i) a chromosome 16 position chosen from: chrl6: 1709793, chrl6: 1709852, chrl 6: 1710090, chrl6: 1714342, chrl6: 1714343, chrl6: 1714886, chrl6: 1714898, chrl6: 1715231, chrl6: 1723913, chrl6: 1754356, chrl 6: 1757779, chrl6: 1768502 or chrl 6: 1769432; or

[0546] (ii) a position in SEQ ID NO: 1 chosen from position: 3628, 3687, 3925, 8177, 8178, 8721, 8733, 9066, 17748, 48191, 51614, 62337 or 63267 ; or

[0547] (iii) chromosome 16 position chrl 6: 1709852; or PATENT

[0548] 7328.158159PCT / NLM-1002-PC

[0549] (iv) SEQ ID NO:1 position 3687.

[0550] F32. The method of any one of embodiments F21-F31, wherein the genetic variation site is within or comprises:

[0551] (i) a chromosome 16 portion chosen from: chrl 6: 1709763-1709823, chrl 6: 1709822- 1709882, chrl6: 1710060-1710120, chrl6: 1714312-1714372, chrl6: 1714313- 1714373, chrl6: 1714856-1714916, chrl6:1714868-1714928, chrl6: 1715201- 1715261, chrl6: 1723883-1723943, chrl6:1754326-1754386, chrl6: 1757749- 1757809. chrl6: 1768472-1768532 or chrl 6: 1769402- 1769462; or

[0552] (ii) a portion of SEQ ID NO: 1 chosen from: 3598-3658, 3657-3717, 3895-3955, 8147-8207, 8148-8208, 8691-8751, 8703-8763, 9036-9096, 17718-17778, 48161- 48221, 51584-51644, 62307-62367 or 63237-63297; or

[0553] (iii) a nucleobase sequence of one of SEQ ID NO:90 to SEQ ID NO: 102; or

[0554] (iv) a chromosome 16 portion between positions 1709822-1709882; or

[0555] (v) a portion of SEQ ID NO: 1 between positions 3657-3717; or

[0556] (vii) a nucleobase sequence of SEQ ID NO:91.

[0557] F33. The method of any one of embodiments F21-F32, wherein the genetic variation site comprises or is within:

[0558] (i) a chromosome 16 portion chosen from: chrl6: 1709785-1709810, chrl 6: 1709840- 1709865, chrl6: 1714873-1714916, chrl 6: 1757763-1757790, chrl6: 1768489- 1768509 or chrl6: 1769422-1769447; or

[0559] (ii) a portion of SEQ ID NO: 1 chosen from positions: 3620-3645. 3675-3700, 8708- 8751. 51598-51625, 62324-62344 or 63257-63282; or

[0560] (iii) a nucleobase sequence of one of SEQ ID NO: 103 to SEQ ID NO: 108; or

[0561] (iv) a chromosome 16 portion between positions 1709840-1709865; or

[0562] (v) a portion of SEQ ID NO: 1 between positions 3675-3700; or

[0563] (vi) a nucleobase sequence of SEQ ID NO: 104.

[0564] F34. The method of any one of embodiments F21-F33, wherein the genetic variation site within or comprises:

[0565] (i) a chromosome 16 portion chosen from: chrl6: 1709844-1709863, chrl6:1714336- 1714355. chrl6: 1754340-1754359, chrl6: 1714892-1714911, chrl6: 1714879- 1714898, chrl6: 1757771-1757790, chrl6: 1768490-1768509, chrl6: 1714888- 1714907, chrl6: 1710085-1710104, chrl6:1709791-1709810, chrl6: 1768489- 1768508, chrl6: 1709841-1709860, chrl6:1709840-1709859, chrl6: 1709785- PATENT

[0566] 7328.158159PCT / NLM-1002-PC

[0567] 1709804, chr 16: 1709846-1709865, chrl6:1714873-1714892, chrl6: 1714884- 1714903, chrl6: 1714891-1714910, chrl6:1714897-1714916, chr!6: 1715217- 1715236, chrl6: 1723903-1723922, chrl6:1757763-1757782, chr 16: 1769422- 1769441. chrl 6: 1714882- 1714901 or chrl 6: 1769428- 1769447; or

[0568] (ii) a portion of SEQ ID NO: 1 chosen from: 3679-3698, 8171-8190, 48175-48194, 8727-8746, 8714-8733, 51606-51625, 62325-62344, 8723-8742, 3920-3939, 3626- 3645, 62324-62343, 3676-3695, 3675-3694, 3620-3639, 3681-3700, 8708-8727, 8719-8738. 8726-8745, 8732-8751, 9052-9071, 17738-17757, 51598-51617, 63257- 63276, 8717-8736 or 63263-63282; or

[0569] (iii) a nucleobase sequence of one of SEQ ID NO:65 to SEQ ID NO: 89; or

[0570] (iv) a chromosome 16 portion between positions 1709844-1709863; or

[0571] (v) a portion of SEQ ID NO: 1 between positions 3679-3698; or

[0572] (vi) a nucleobase sequence of SEQ ID NO:65.

[0573] F35. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO:1; rs!7135499 genetic variation site; chromosome 16 positions 1709763-1709823; positions 3598-3658 of SEQ ID NO: 1; the nucleobase sequence of SEQ ID NO:90; chromosome 16 positions 1709785- 1709810; positions 3620-3645 of SEQ ID NO: 1; a nucleobase sequence of SEQ ID NO: 103; or a nucleobase sequence of SEQ ID NO:78 or SEQ ID NO:74.

[0574] F36. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO:1 ; rsl7135500 genetic variation site; chromosome 16 positions 1709822-1709882; positions 3657-3717 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:91; chromosome 16 positions 1709840-1709865; positions 3675-3700 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 104; nucleobase sequence of SEQ ID NO:77, SEQ ID NO:76, SEQ ID NO:65 or SEQ ID NO:79; or nucleobase sequence of SEQ ID NO:65.

[0575] F37. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO: 1; rs35988159 genetic variation site; chromosome 16 positions 1714856-1714916; positions 8691-8751 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:95; rs34950492 genetic variation site; PATENT

[0576] 7328.158159PCT / NLM-1002-PC chromosome 16 positions 1714868-1714928; positions 8703-8763 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO:96; rs34950492 and rs35988159 genetic variation sites; chromosome 16 positions 1714873-1714916; positions 8708-8751 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 105; or nucleobase sequence of SEQ ID NO:69, SEQ ID NO:88, SEQ ID NO:81, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:68, SEQ ID NO:83 or SEQ ID NO:80.

[0577] F38. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: intron 8; chromosome 16 positions 1748721-1758147; positions 42556-51982 of SEQ ID NO: 1; rs9788926 genetic variation site; chromosome 16 positions 1757749-1757809; positions 51584-51644 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 100; chromosome 16 positions 1757763- 1757790; positions 51598-51625 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 106; or nucleobase sequence of SEQ ID NO: 86 or SEQ ID NO: 70.

[0578] F39. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: exon 31; chromosome 16 positions 1768477-1768626; positions 62312-62461 of SEQ ID NO: 1; rs8063431 genetic variation site; chromosome 16 positions 1754326-1754386; positions 48161-48221 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 99; chromosome 16 positions 1768489- 1768509; positions 62324-62344 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 107; or nucleobase sequence of SEQ ID NO:75 or SEQ ID NO:71.

[0579] F40. The method of any one of embodiments F21-F34, wherein the genetic variation site is within or comprises: exon 32; chromosome 16 positions 1768703-1770351; positions 62538-64186 of SEQ ID NO: 1; rs2575329 genetic variation site; chromosome 16 positions 1769402-1769462; positions 63237-63297 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 102; chromosome 16 positions 1769422- 1769447; positions 63257-63282 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 108; or nucleobase sequence of SEQ ID NO: 87 or SEQ ID NO: 89.

[0580] F41. The method of any one of embodiments F20-F41, wherein the genetic variation site, or optionally the single nucleotide variation site, comprises: (i) a variant at the single nucleotide variation position described in Table D; or (ii) the “vT‘ variant at the genetic variation position described in Table D; or (iii) the ‘‘v2” variant at the genetic variation position described in Table D. PATENT 7328.158159PCT / NLM-1002-PC

[0581] F42. The method of any one of embodiments F20-F41, wherein the modified oligonucleotide comprises or consists of 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleobases of SEQ ID NO: 151 to SEQ ID NO:241.

[0582] F43. The method of any one of embodiments F20-F16, wherein the modified oligonucleotide comprises or consists of 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleobases of:

[0583] (i) SEQ ID NO:40 to SEQ ID NO:64; or

[0584] (ii) SEQ ID NO:40; or

[0585] (hi) SEQ ID NO:53 or SEQ ID NO:49; or

[0586] (iv) SEQ ID NO:52, SEQ ID NO:51, SEQ ID NO 40 or SEQ ID NO:54; or

[0587] (v) SEQ ID NO:44, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:43, SEQ ID NO:58 or SEQ ID NO:55; or

[0588] (vi) SEQ ID NO:61 or SEQ ID NO:45; or

[0589] (vii) SEQ ID NO:50 or SEQ ID NO:46; or

[0590] (viii) SEQ ID NO:62 or SEQ ID NO:64.

[0591] F44. The method of any one of embodiments F20-F43, the modified oligonucleotide comprises or consists of a nucleobase sequence that is at least 85% complementary to, or at least 90% complementary to, or at least 95% complementary, or is 100% complementary to, an equal length portion of the differentiating genetic variation site. F45. The method of any of embodiments F20-F44, wherein the modified oligonucleotide consists of 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50. 15 to 20. 15 to 25. 15 to 30,

[0592] 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 17 to 30,

[0593] 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30, 19 to 50,

[0594] 20 to 25, 20 to 30, or 20 to 50 linked nucleosides.

[0595] F46. The method of any one of embodiments F21-F45, wherein the genetic variation site comprises a synonymous single nucleotide variation.

[0596] F47. The method of any one of embodiments F20-F46, wherein the genetic variation site comprises a genetic variant present in at least 20% of a population, or in at least 25% of a population, or at least 30% of a population, or at least 35% of a population, or at least 40% of a population, or at least 45% of a population, or at least 50% of a population, or at least 55% of a population, or at least 60% of a population, or at least 65% of a population, or at least 70% of a population, or at least 75% of a population, PATENT

[0597] 7328.158159PCT / NLM-1002-PC or at least 80% of a population, or at least 85% of a population, or at least 90% of a population.

[0598] F48. The method of any one of embodiments F20-F47, wherein the MAPK8IP3 / JIP3 allelic variant is a mutant MAPK8IP3 / JIP3 allele associated with a medical condition, or optionally comprises a pathogenic genetic variant associated with a medical condition.

[0599] F49. The method of embodiment F48, wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, which optionally is a neurological medical condition. MAPK81P3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0600] F50. The method of any embodiment F48 or F49, wherein the pathogenic genetic variant is associated with a non-loss of function phenotype.

[0601] F51. The method of embodiment F50, wherein the non-loss of function phenotype is a dominant negative phenotype, a gain of function phenotype or toxic gain of function phenotype.

[0602] F52. The method of any one of embodiments F48-F51, wherein the pathogenic variant is in a pathogenic genetic variation site is a pathogenic single nucleotide variation site. F53. The method of embodiment F52, wherein the pathogenic single nucleotide variation site comprises a non-synonymous single nucleotide variation at a pathogenic genetic variation position.

[0603] F54. The method of any one of embodiments F25-F30, wherein the pathogenic genetic variant:

[0604] (i) is at a rsl567203083, rs770703007, rsl567128142, rsl567214097 or rs 1567198751 pathogenic genetic variation site; or

[0605] (ii) is at a rsl567203083 pathogenic genetic variation site; or

[0606] (iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argl l47Cys. p.Argl l46Cys, p.Argl l40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His. p.Arg521His, p.Arg515His, p.Ala816Glu. p.Ala815Glu, p.Ala809Glu, p.Glu455Gly, p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or PATENT

[0607] 7328.158159PCT / NLM-1002-PC

[0608] (iv) encodes a p.Arg579Cys, p. Arg578Cys or p.Arg572Cys amino acid substitution; or

[0609] (v) encodes a p.Arg579Cys amino acid substitution; or

[0610] (vi) encodes or is C.1735OT, C.1732OT. C.1714OT, c.281A>G, c.l l lOG, c.65del, C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c, 1331T>C, c, 1313T>C, c,1565G>A, C.1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c,1364A>G, c. 1361A>G or c, 1343A>G; or

[0611] (vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or

[0612] (viii) encodes or is c. 1735OT.

[0613] F55. The method of any one of embodiments F48-F54, wherein the equal length portion of the differentiating genetic variation site contains the pathogenic genetic variation position, or contains the pathogenic genetic variation site or portion thereof. F56. The method of any one of embodiments F48-F54, wherein the equal length portion of the differentiating genetic variation site does not contain the pathogenic genetic variation position, or does not contain the pathogenic genetic variation site or portion thereof.

[0614] F57. The method of any one of embodiments F20-F56, wherein the oligomeric compound, composition or pharmaceutical composition is administered in an amount sufficient to selectively reduce expression of the MAPK8IP3 / JIP3 allelic variant by at least 20%.

[0615] F58. The method of any one of embodiments F20-F57, wherein the oligomeric compound is administered in vitro or ex vivo or in vivo.

[0616] F59. The method of any one of embodiments F20-F38, wherein the oligomeric compound is administered to a cell or tissue of a subject in need thereof in an amount sufficient to treat a MAPK8IP3 / JIP3-associated medical condition, which optionally is a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0617] F60. The method of embodiment F59. wherein at least one symptom or hallmark of a MAPK8IP3 / JIP3-associated medical condition is ameliorated, and the symptom or hallmark optionally is one or more of: neurodevelopment impairment, intellectual PATENT

[0618] 7328.158159PCT / NLM-1002-PC disability, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality', physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity, walking difficulties, visual impairment and seizure.

[0619] F61. The method of embodiment F59 or F60, wherein administering the oligomeric compound reduces or delays onset or progression of a MAPK8IP3 / JIP3-associated medical condition.

[0620] F62. The method of any one of embodiments F20-F61, wherein the cell is or the tissue comprises a neuronal cell, fibroblast cell, stem cell-derived neuronal cell or induced pluripotent stem cell (iPSc)-derived neuronal cell.

[0621] F63. The method of any one of embodiments F20-F62, wherein the cell is or the tissue comprises a human cell.

[0622] F64. The method of any of one of embodiments F20-F63, wherein the oligomeric compound, the composition or the pharmaceutical composition is administered to the central nervous system or is administered systemically.

[0623] F65. The method of embodiment F64, wherein the oligomeric compound is administered by intrathecal administration or by intracerebroventricular administration.

[0624] F66. The method of any one of embodiments F20-F65, wherein the subject is human.

[0625] F67. The method of any one of embodiments F20-F66, wherein the oligomeric compound is of any one of embodiments A1-B68. or is in a composition of any one of embodiments C1 -C44, or is in a pharmaceutical composition of any one of embodiments D1-D4.

[0626] F68. A method for administering an oligomeric compound, comprising: determining presence or absence of a differentiating genetic variation site in a MAPK8IP3 / JIP3 nucleic acid; and if a differentiating genetic variation site is present, administering an oligomeric compound targeted to the differentiating genetic variation site.

[0627] F69. The method of embodiment F68, comprising: genotyping a genetic variation site of the MAPK8IP3 / J1P3 nucleic acid. thereby providing a MAPK8IP3 / JIP3 nucleic acid genotype; and PATENT 7328.158159PCT / NLM-1002-PC determining presence or absence of the differentiating genetic variation site according to the genotype.

[0628] F70. A method for administering an oligomeric compound, comprising: determining presence, absence and / or amount of a MAPK8IP3 / JIP3 allele nucleic acid and / or MAPK8IP3 / JIP3 protein expressed from the MAPK8IP3 / JIP3 allele nucleic acid; and administering an oligomeric compound targeted to the MAPK8IP3 / JIP3 allele nucleic acid based on the presence, absence and / or amount of a MAPK81P3 / JIP3 allele nucleic acid and / or MAPK81P3 / J1P3 protein expressed from the MAPK8IP3 / JIP3 allele nucleic acid.

[0629] F71. The method of embodiment F70, wherein the elevated level of the MAPK8IP3 / JIP3 allele nucleic acid or MAPK8IP3 / JIP3 protein is relative to a control level of the MAPK8IP3 / JIP3 allele nucleic acid or MAPK8IP3 / JIP3 protein.

[0630] F72. The method of embodiment F71, wherein the control level is in a cell or cells in which MAPK8IP3 / JIP3 allele nucleic acid does not contain a pathogenic genetic variant.

[0631] F73. The method of any one of embodiments F70-F72, comprising administering an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid if presence of an elevated level of a MAPK8IP3 / JIP3 nucleic acid and / or MAPK8IP3 / JIP3 protein is determined.

[0632] F74. The method of any one of embodiments F68-F73, wherein the MAPK8IP3 / JIP3 nucleic acid is from a cell or tissue.

[0633] F75. The method of any one of embodiments F68-F74, wherein the MAPK8IP3 / JTP3 nucleic acid is from a subject.

[0634] F76. The method of embodiment F74 or F75, wherein the cell, tissue or subject is a human cell, human tissue or human subject.

[0635] F77. The method of any one of embodiments F68-F76, wherein the MAPK8IP3 / JIP3 nucleic acid is from a subject having a medical condition.

[0636] F78. The method of embodiment F77, wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, which optionally is a neurological medical condition. MAPK81P3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease , Parkinson’s disease, PATENT

[0637] 7328.158159PCT / NLM-1002-PC neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly

[0638] F79. The method of any one of embodiments F68-F78, wherein the MAPK8IP3 / JIP3 nucleic acid comprises a mutant MAPK8IP3 / JIP3 allelic variant.

[0639] F80. The method of embodiment F79, wherein a genotype and / or elevated level is determined for the mutant MAPK8IP3 / JIP3 allelic variant.

[0640] F81. The method of embodiment F79 or F80, comprising determining whether the mutant MAPK8IP3 / JIP3 allelic variant comprises a differentiating genetic variant at the genetic variation site, thereby determining presence or absence of a differentiating genetic variant.

[0641] F82. The method of embodiment F81, comprising, if a differentiating genetic variant is present, administering an oligomeric compound targeted to the differentiating genetic variant.

[0642] F83. The method of any one of embodiments G79-G83, comprising characterizing a pathogenic genetic variation site in the mutant MAPK8IP3 / JIP3 allelic variant.

[0643] F84. The method of embodiment F83, wherein the characterizing comprises determining a genotype of the pathogenic genetic variant.

[0644] F85. The method of embodiment F83 or F84, wherein the characterizing comprises determining presence or absence of a non-loss of function genetic variant.

[0645] F86. The method of embodiment F85, wherein the characterizing comprises determining presence or absence of a dominant negative variant, gain of function genetic variant or toxic gain of function genetic variant.

[0646] F87. The method of any one of embodiments F83-F87, wherein the pathogenic genetic variation site:

[0647] (i) is a rsl567203083, rs770703007, rsl567128142, rsl567214097 or rsl567198751 pathogenic genetic variation site; or

[0648] (ii) is a rs 1567203083 pathogenic genetic variation site; or

[0649] (iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argl 147Cys, p.Argll46Cys, p.Argl l40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515His, p.Ala816Glu, p.Ala815Glu, p.Ala809Glu, p.Glu455Gly. p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or PATENT 7328.158159PCT / NLM-1002-PC

[0650] (iv) encodes a p.Arg579Cys, p. Arg578Cys or p.Arg572Cys amino acid substitution; or

[0651] (v) encodes a p.Arg579Cys amino acid substitution; or

[0652] (vi) encodes or is C.1735OT, C.1732OT. C.1714OT, c.281A>G, c.l l lOG, c.65del, C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c, 1331T>C, c, 1313T>C, c,1565G>A, c. l562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c,1364A>G, c. 1361A>G or c, 1343A>G; or

[0653] (vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or

[0654] (viii) encodes or is c. 1735OT.

[0655] F88. The method of any one of embodiments F79-F87, comprising, if presence of the pathogenic genetic variant is determined, or optionally if presence of the non-loss of function genetic variant is determined, administering the oligomeric compound targeted to the differentiating genetic variation site.

[0656] F89. The method of any one of embodiments F68-F88, wherein determining the presence or absence of the differentiating genetic variation site, optionally characterizing the pathogenic genetic variant, and optionally the genotyping, comprises sequencing the MAPK8IP3 / JIP3 nucleic acid.

[0657] F90. The method of embodiment F89, wherein the sequencing comprises short read sequencing, or long read sequencing, or short read sequencing and long read sequencing.

[0658] F91. The method of any one of embodiments F68-F90, wherein the oligomeric compound is of any one of embodiments A1-B68. is in a composition of any one of embodiments C1 -C44, or is in a pharmaceutical composition of any one of embodiments D1-D4.

[0659] F92. The method of any one of embodiments F68-F91, wherein administering the oligomeric compound is according to any one of embodiments E1-E30.

[0660] F93. The method of any one of embodiments F68-G92, wherein the oligomeric compound is targeted to a MAPK8IP3 / JIP3 allelic variant and is capable of selectively reducing expression of the MAPK8IP3 / JIP3 allelic variant.

[0661] F94. The method of any one of embodiments F68-F93, wherein administering the oligomeric compound is according to any one of embodiments F1-F67.

[0662] Gl. An oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C 1 -C44, or a pharmaceutical composition of PATENT

[0663] 7328.158159PCT / NLM-1002-PC any one of embodiments D1 -D4, for reducing MAPK8IP3 / JIP3 expression, and optionally for one or more of: reducing cell toxicity; increasing cell proliferation; increasing axon trafficking; increasing endosome mobility along microtubules in axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling.

[0664] G2. An oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C 1 -C44, or a pharmaceutical composition of any one of embodiments D1-D4. for treating a medical condition.

[0665] G3. Use of an oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C1-C44, or a pharmaceutical composition of any one of embodiments D1-D4, for reducing MAPK8IP3 / JIP3 expression, and optionally for one or more of: reducing cell toxicity; increasing cell proliferation; increasing axon trafficking; increasing endosome mobility along microtubules in axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling.

[0666] G4. Use of an oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C1-C44, or a pharmaceutical composition of any one of embodiments D1-D4, for treating a medical condition.

[0667] G5. Use of oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C 1 -C44, or a pharmaceutical composition of any one of embodiments D1-D4. for the manufacture of a medicament for reducing MAPK8IP3 / JIP3 expression, and optionally for one or more of: reducing cell toxicity; increasing cell proliferation; increasing axon trafficking; increasing endosome mobility along microtubules in axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling.

[0668] G6. Use of oligomeric compound of any one of embodiments A1-B68. a composition of any one of embodiments C1-C44, or a pharmaceutical composition of any one of embodiments D1-D4, for the manufacture of a medicament for treating a medical condition.

[0669] G7. The oligomeric compound, composition, pharmaceutical composition or use of any one of embodiments Gl, G3 or G5. wherein the cell toxicity is neuronal or fibroblast cell toxicity and the cell proliferation is neuronal cell proliferation or fibroblast cell proliferation. PATENT

[0670] 7328.158159PCT / NLM-1002-PC

[0671] G8. The oligomeric compound, composition, pharmaceutical composition or use of any one of embodiments G2, G4 or G6, wherein the medical condition is a MAPK8IP3 / JIP3-associated medical condition, a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease, neurodevel opmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0672] G9. The oligomeric compound, composition, pharmaceutical composition or use of any one of embodiments G1-G8, for administration according to any one of embodiments E1-E30 or F1-F94.

[0673] Hl. A method for inhibiting cell degeneration, comprising administering a composition comprising a c-Jun N-terminal kinase (JNK) signaling pathway inhibitor to cells in an amount effective to inhibit the cell degeneration.

[0674] H2. A method for treating a neurological medical condition in a subject, comprising administering to cells of the subject a composition comprising a JNK signaling pathway inhibitor in an amount effective to treat the neurological medical condition.

[0675] H3. The method of embodiment H2, wherein the medical condition is: a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’s-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

[0676] H4. The method of any one of embodiments Hl -H3, wherein the inhibitor is a c-Jun N-terminal kinase (JNK)-interacting protein 3 (MAPK8IP3 / JIP3) inhibitor.

[0677] H5. The method of any one of embodiments H1-H4, wherein the inhibitor reduces MAPK8IP3 / JIP3 expression.

[0678] H6. A method for reducing MAPK8IP3 / JIP3 expression, comprising administering to cells an inhibitor comprising a modified oligonucleotide targeted to MAPK8IP3 / JIP3 in an amount effective to reduce MAPK8IP3 / JIP3 expression in the cells.

[0679] H7. The method of any one of embodiments H1-H6, wherein the cells are neurons or fibroblasts, and the cell degeneration is neuron degeneration or fibroblast degeneration. PATENT

[0680] 7328.158159PCT / NLM-1002-PC

[0681] H8. The method of any one of embodiments H1 -H7, wherein the cells comprise a mutant MAPK8IP3 / JIP3.

[0682] H9. The method of any one of embodiments H1-H8, wherein the cells comprise a gain of function or toxic gain of function phenotype.

[0683] H10. The method of any one of embodiments H1-H9, wherein the cells comprise one or more phenotypes chosen from: increased cell degeneration; reduced cell proliferation; activation of the JNK signaling pathway; enhanced pro-apoptotic signaling via JNK; modification of MAPK8IP3 / JIP3 binding partner interactions; increased MAPK8IP3 / J1P3 expression; reduced J1P4 expression; and altered MAPK8IP3 / JIP3 subcellular localization.

[0684] HIT The method of embodiment H10, wherein the cells comprise one or more phenotypes chosen from: reduced MAPK8IP3 / JIP3 binding affinity to JIP4, reduced MAPK8IP3 / JIP3 / JIP4 heterodimer formation, and increased MAPK8IP3 / JIP3 binding affinity to KIF5b.

[0685] H12. The method of any one of embodiments H1-H10, wherein the cells and / or cells of the subject comprise one or more phenotypes chosen from: decreased axon trafficking; decreased endosome mobility along microtubules in axons; decreased late endosome mobility along microtubules in axons; and decreased dopamine receptor 1 (DI) signaling.

[0686] Hl 3. The method of embodiment Hl 2, wherein the cells and / or cells of the subject do not comprise one or both phenotypes chosen from: decreased dopamine receptor 2 (D2) signaling and decreased lysosomal mobility along microtubules in axons.

[0687] H13.1. The method of any one of embodiments H10-H13, wherein each phenotype is relative to cells not containing a mutant MAPK8IP3 / JIP3.

[0688] H14. The method of any one of embodiments H8-H13. 1. wherein the mutant MAPK8IP3 / JIP3 comprises a MAPK8IP3 / JIP3 pathogenic genetic variant.

[0689] H15. The method of embodiment H14, wherein the pathogenic genetic variant is a non-synonymous single nucleoside variant at a pathogenic genetic variation position.

[0690] H16. The method of embodiment H14 or H15, wherein: PATENT 7328.158159PCT / NLM-1002-PC the pathogenic genetic variant is selected from: c. 1735OT, c. 1732OT, c.281 A>G, c.1714 C>T, c.ClllG, c57C>G, c.65delG, C.C3436T, C.C1732T, C.CT1331C, C.1544G>A, c.2447OA and c,1364A>G; or the pathogenic genetic variant:

[0691] (i) is at a rs 1567203083, rs770703007, rsl567128142, rsl567214097 or rs!567198751 pathogenic genetic variation site; or

[0692] (ii) is at a rs!567203083 pathogenic genetic variation site; or

[0693] (iii) encodes a p.Arg579Cys. p.Arg578Cys, p.Arg572Cys. p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3. p.Argl!47Cys. p.Arg! 146Cys. p.Arg! 140Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515His, p.Ala816Glu, р.Ala815Glu, p.Ala809Glu, p.Glu455Gly, p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or

[0694] (iv) encodes a p.Arg579Cys. p.Arg578Cys or p.Arg572Cys amino acid substitution; or

[0695] (v) encodes a p.Arg579Cys amino acid substitution; or

[0696] (vi) encodes or is C.1735OT, C.1732OT, C.1714OT, c.281A>G, c.lllOG, c.65del, C.3439OT, C.3436OT, C.3418OT. c, 1334T>C, c, 1331T>C. c,1313T>C, с, 1565G>A, C.1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c,1364A>G, C.1361A>G or c, 1343A>G; or

[0697] (vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or

[0698] (viii) encodes or is C.1735OT.

[0699] H17. The method of any one of embodiments H14-H16, wherein the pathogenic genetic variant is selected from: p. Arg579Cys, p.Glu455Gly and p.Tyr94Cys.

[0700] H17.1. The method of embodiment H17, wherein the MAPK8IP3 / JIP3 nucleic acid comprises a c. 1735OT pathogenic genetic variant and / or results in a p.Arg579Cys variant in a MAPK8IP3 / JIP3 protein.

[0701] H18. The method of any one of embodiments H1-H17.1, wherein the inhibitor: reduces cell death and / or cell apoptosis; increases cell proliferation; and / or reduces activation of the JNK signaling pathway.

[0702] H19. The method of any one of embodiments H5-H18. wherein the inhibitor reduces JIP4 expression less than it reduces MAPK8IP3 / JIP3 expression or does not reduce JIP4 expression. PATENT

[0703] 7328.158159PCT / NLM-1002-PC

[0704] H20. The method of any one of embodiments H8-H19, wherein the inhibitor is not allele selective.

[0705] H21. The method of embodiment H20, wherein the mutant MAPK8IP3 / JIP3 expression and the wild-type MAPK8IP3 / JIP3 expression differ by less than 2-fold in the presence of the inhibitor, and optionally the mutant MAPK8IP3 / JIP3 expression and the wild-type MAPK8IP3 / JIP3 expression differ by less than 2-fold in the presence of the inhibitor at the IC50 concentration of the inhibitor for the wild-type protein.

[0706] H22. The method of embodiment H20 or H21, wherein the inhibitor reduces expression of mutant MAPK8IP3 / JIP3 by about 50% to about 95% or by about 80% to about 90%, optionally at the ICso concentration of the inhibitor.

[0707] H23. The method of any one of embodiments H20-H22, wherein the inhibitor reduces expression of wild-type MAPK8IP3 / JIP3 by about 50% to about 80% or about 60% to about 70%, and optionally at the IC50 concentration of the inhibitor.

[0708] H24. The method of any one of embodiments H20-H23, wherein the mutant MAPK8IP3 / JIP3 comprises a pathogenic genetic variant that encodes or is c. 1735OT or p.(Arg579Cys).

[0709] H25. The method of any one of embodiments H6-H24, wherein the modified oligonucleotide comprises a nucleobase sequence at least 80% complementary to an equal length portion of a MAPK8IP3 / JIP3 nucleobase sequence.

[0710] H26. The method of embodiment H25, wherein the modified oligonucleotide consists of a nucleobase sequence at least 80% complementary to an equal length portion of a MAPK8IP3 / JIP3 nucleic acid nucleobase sequence.

[0711] H27. The method of embodiment H25 or H26, wherein the nucleobase sequence of the modified oligonucleotide is not complementary to an equal length portion of a JIP4 nucleic acid nucleobase sequence.

[0712] H28. The method of any one of embodiments H1-H27, wherein the inhibitor is administered in vitro or ex vivo.

[0713] H29. The method of any one of embodiments H1-H27, wherein the inhibitor is administered in vivo.

[0714] H30. The method of any one of embodiments H1-H29. wherein the cells are human cells and / or the MAPK8IP3 / JIP3 is a human MAPK8IP3 / JIP3. PATENT

[0715] 7328.158159PCT / NLM-1002-PC

[0716] H31 . The method of any one of embodiments H2-H30, wherein the subject is a human subject.

[0717] H32. The method of any one of embodiments H2-H31, wherein at least one symptom or hallmark of the neurological medical condition is ameliorated.

[0718] H33. The method of embodiment H32, wherein the symptom or hallmark is one or more of: neurodevelopment impairment, intellectual disability, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality, physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity7, walking difficulties, visual impairment and seizure.

[0719] H34. The method of any one of embodiments H6-H31, wherein the inhibitor is an oligomeric compound of any one of embodiments A1-B68, a composition of any one of embodiments C 1 -C44, or a pharmaceutical composition of any one of embodiments D1-D4, or optionally wherein the inhibitor is administered according to any one of embodiments E1-E30 or F1-F94.

[0720] H35. The method of any one of embodiments H8-H34, comprising determining presence or absence of the MAPK8IP3 / JIP3 mutant or one or more phenotypes of any one of embodiments H8-H17; and if the MAPK8IP3 / JIP3 mutant or one or more phenoty pes is present, administering the inhibitor.

[0721] H36. The method of embodiment H35, comprising: genotyping a genetic variation position and / or a genetic variation site of the MAPK8IP3 / JIP3 nucleic acid, thereby' providing a MAPK8IP3 / JIP3 nucleic acid genotype; and determining presence or absence of the MAPK8IP3 / JIP3 mutant according to the genotype.

[0722] H37. The method of embodiment H35 or H36, wherein the MAPK8IP3 / JIP3 nucleic acid is from a cell or tissue.

[0723] H38. The method of any one of embodiments H35-H37, wherein the MAPK8IP3 / JIP3 nucleic acid is from a subject.

[0724] H39. The method of embodiment H37 or H38, wherein the cell, tissue or subject is a human cell, human tissue or human subject. PATENT 7328.158159PCT / NLM-1002-PC

[0725] H40. The method of any one of embodiments H35-H39, wherein the MAPK8IP3 / JIP3 nucleic acid is from a subject having a medical condition.

[0726] H41. The method of embodiment H40, wherein the medical condition is a neurological medical condition, and optionally a medical condition of embodiment H3.

[0727] H42. The method of any one of embodiments H35-H41, wherein determining the presence or absence of the pathogenic genetic variant, and optionally the genotyping, comprises sequencing the MAPK8IP3 / JIP3 nucleic acid.

[0728] H43. The method of embodiment H42, wherein the sequencing comprises short-read sequencing, or long-read sequencing, or short-read sequencing and long- read sequencing.

[0729] Exemplar}' Oli gon ucl eo li d es

[0730] In certain embodiments, provided are oligomeric compounds comprising oligonucleotides that consist of linked nucleosides. Oligonucleotides can be unmodified oligonucleotides (RNA or DNA) or can be modi fied oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DN A Modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and / or a modified nucleobase) and / or at least one modified internucleoside linkage. Certain modified nucleosides and modified intemucleoside linkages suitable for use in modified oligonucleotides are described.

[0731] 1: wuipkm Modified Nucleosides

[0732] Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase. In certain embodiments, modified nucleosides comprising the following modified sugar moieties and / or the following modified nucleobases can be incorporated into antisense oligonucleotides.

[0733] Exemplary Sugar Moieties

[0734] In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding io those of other types of modified sugar moieties. PATENT 7328.158159PCT / NLM-1002-PC

[0735] In certain embodiments, modified sugar moieties are non-bicyclic modified furanosyl sugar moieties comprising one or more acyclic substituent, including, but not limited to, substituents at the 2’, 3'. 4’, and / or 5' positions. In certain embodiments, the furanosyl sugar moiety is a ribosyl sugar moiety. In certain embodiments, one or more acyclic substituent of non-bicyclic modified sugar moieties is branched

[0736] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 2’-position, referred to as 2’ -substituted sugar moieties. Examples of substituent groups suitable for the Imposition of modified sugar moieties include but are not limited to: -F, -OCH3 COMe” or “O-methyT’ or “methoxy’’), and - OCH2CH2OCH3 (“MOE” or "‘O-methoxy ethyl"’). In certain embodiments, 2‘- substituent groups are selected from among' halo, allyl, amino, azido, SH, CN, OCN, CFs, OCF3. O-CI-CJO alkoxy, O-C1-C10 substituted alkoxy, O-Ci-Cto alkyl, O-Cj-Cio substituted alkyl, S-alkyl, N(Rm)-alkyl, O-alkenyl, S-alkenyl, N(Rm)-alkenyk O- alkynyl, S-alkynyL N(Rm)-alkynyl, O-alkylenyl-O-alkyl, alkynyl. alkaryl, aralkyl, O- alkatyl, CUaralkyl, OCClhhSCH?, O(CH2)2ON(Rm)(Rn) or OCH2C(===O)-N(Rm)(Ra), where each Rmand 1U, is, independently, hydrogen, an ammo protecting group, or substituted or unsubstitutedCi-Cio alkyl, -OtCHifiONfCHs)?. (“DMAOE”), 2“- ()(CH2)2O(CH2)2N(CH3)?. (“DMAEOE”), and the 2 '-substituent groups described in Cook et al.. U.S. 6.531,584; Cook et al. U.S. 5,859,221 ; and Cook et al., U.S. 6,005,087. Certain embodiments of these 2’ -substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl. halogen, alkyl, aryl, alkenyl and aikynyl.

[0737] In certain embodiments, a 2 ’-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridgmg 2" -substituent group selected from: F, NH?„ N3, OCF3, QClb, 0(CN2)?NH2, CH2CH-CH2, OCFI2CIT-CTI2, OCH2CH2OCH3 (“MOE”). O(C H O2SCH3, O(CH2)2ON(R^)(RA.

[0738] O(CH?.)2O(CH2)2N(CH3)2, and N -substituted acetamide (OCH2C(=O)-N(R1„)(RJI)), where each Rmand R» is, independently, hydrogen, an amino protecting group, or substituted or unsubstituted Ci-Cio alkyl

[0739] In certain embodiments, a 2'-substituted non-bicyclic modified nucleoside comprises a sugar moiety7comprising a non-bridgmg 2 '-substituent group selected from: F, PATENT

[0740] 7328.158159PCT / NLM-1002-PC

[0741] (M m . OCT I 3. OCH2CH2OCH3, O(CH 2)2SCH3. O(C H 2) OXf CH 3)2, OlCI I.WH 1 NCI i fo O(CH2)2ON(CH3)2 f’DMAOE”), O(CH2)2.O(CH2)2N(CH3)?. (“DMAEOE”), and OCH?.C(===O)-N(H)CH5(“NMA”).

[0742] In certain embodiments, a 2 ’-substituted non-bicy die modified nucleoside comprises a sugar moiety comprising a non-bridging 2 ’-substituent group selected from: F, OCH3, OCH2CH2OCH3. OiCHmSCI E. O(CH2)2ON(CH3)2.

[0743] O(CHO?.O(CH2)2N(CH3)2, and OC I h( 'C ==O)-N(I I)C C'NMAfi.

[0744] In certain embodiments, a 2 ’-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2’ -substituent group selected from: F, (M H... and 0CH2CH2OCH3.

[0745] In certain embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by isomeric configuration. For example, a 2’-deoxyfuranosyl sugar moiety can be in seven isomeric configurations other than the naturally occurring beta-D-deoxyribosyi configuration. Such modified sugar moieties are described in, for example,

[0746] WO2019 / 157531. A 2'-modified sugar moiety has an additional stereocenter at the 2’- position relative to a 2‘-deoxyfuranosy1 sugar moiety: therefore, such sugar moieties have a total of sixteen possible isomeric configurations. 2‘ -modified sugar moieties described herein are in the beta-D-ribosyl isomeric configuration unless otherwise specified.

[0747] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 4 ’-position. Examples of substituent groups suitable for the 4 ’-position of modified sugar moieties include but are not limited to alkoxy (for example, methoxy), alkyl, and those described in Manoharan et al.. WO2015 / 106128.

[0748] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 3 ’-position. Examples of substituent groups suitable for the deposition of modified sugar moieties include, but are not limited to, alkoxy (for example, methoxy) and alkyl (for example, methyl, ethyl).

[0749] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 5 ’-position. Examples of substituent groups suitable for ihe 5 ’-position of modified sugar moieties include, but are not limited to, vinyl, alkoxy (for example, methoxy), and alkyl (e g.. methyl (R or S). ethyl). PATENT

[0750] 7328.158159PCT / NLM-1002-PC

[0751] In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non- bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., W02008 / 101157 and Rajeev et al., US2013 / 0203836).

[0752] In naturally occurring (unmodified) nucleic acids, sugars are linked to one another 3' to 57 In certain embodiments, (oligonucleotides include one or more nucleoside or sugar moiety linked at an alternative position, for example at the 2’ position or inverted 5’ to 3’. For example, where the linkage is at the 2' position, the 2'- substituent groups may instead be at the 3 '-position.

[0753] Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. In certain embodiments, the bicyclic sugar moiety comprises a bridge between the 4’ and the 2' furanose ring atoms. Examples of such 4' to 2’ bridging sugar substituents include, but are not limited to: 4'-CH2-2', 4'-(CH2)2-2!, 4!-(CH2)s-2!, 4'-CH?.-O-2!(“LN A”), 4'- CH2-S-2’. 4!-(CH2)2-O-2* (“ENA”), 4'-CFT(CH3)-O-2’ (referred to as “cons trained ethyl" or “cEU), 4’-CH2-O-CH2-2', 4'-CH2-N(R)-2\ 4'-CH(CH2OCHs)-O-2‘ (‘■constrained MOE” or “cMOE”) and analogs thereof (see. for example, Seth et al , U.S. 7,399,845, Bhat et al„ U.S. 7,569,686, Swayze et al., U.S. 7,741.457, and Swayze et ah, U.S. 8,022,193). 4'-C(CH3)(CH3)-O-2’ and analogs thereof (see, for example, Seth et ai., U S. 8,278,283). 4'-CH2-N(OCH3)-2' and analogs thereof (see. for example, Prakash et al.. U.S. 8.278,425), 4'-CH2-O-N(CH3>2' (see. for example. Allerson et al., U.S. 7,696,345 and Allerson et al., U.S. 8,124,745), 4’-CH?.- C(H)(CH3)-2' (see. for example, Zhou, et al., J. Org Chem. .2009, 74. 11 8-134), 4‘- CH2-C(=CH2)-2’ and analogs thereof (see for example,. Seth et al., U.S. 8.278,426), 4’-C(RaRb)-N(R>()-2’, 4’-C(RaRt>)-O-N(R)-2’, 4'-CTl?-O-N(R)-2; and 4'-C ’H ?,-N( R)- O-2‘, where each R, R;i, and Rt, is, independently, hydrogen, a protecting group, or C1-C12 alkyl (see, for example Imanishi et al , U.S. 7,427,672).

[0754] In certain embodiments, such 4’ to 2‘ bridges independently comprise from 1 to 4 linked groups independently selected from; -[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]n-O-, - CXRa)-C(Rb)-, -C(Ra)-N-, -C(=NRa)-, -CfoO)-, -C(-S)-, -O-, -Si(Ra)2-. -S(-O)x-, and -N(Ra)-; where: x is 0, I. or 2; n is 1. 2, 3, or 4: each Raand Rt. is. independently, hydrogen, a protecting group, hydroxyl, Ci-Ci?, alkyl, substituted Ct-Cr?. alkyl, C?.- PATENT 7328.158159PCT / NLM-1002-PC

[0755] C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJi. NJ1J2, SJi, Ns. COOJi, acyl (C(:::O)-H), substituted acyl, CN, sulfonyl (S(=O)2-Jf ). or sulfbxyl (S(=O)-Ji): and each Ji and J2 is, independently, hydrogen. CJ-C12 alkyd, substituted C1-C12 alkyl, CWCi?. alkenyl, substituted C2-C12 alkenyl, Cz-Cii alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, acyl (C(=O)-H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl. substituted Cj-Crz aminoalkyl, or a protecting group.

[0756] Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research. 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem , 2006. 71, 7731-7740, Singh et al , Chem. Commun., 1998, 4, 455-456; Koshkin et al.. Tetrahedron, 1998. 54. 3607-3630; Wahlestedt et al.. Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 5633-5638; Kumar et al , Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org Chem , 1998. 63. 10035-10039; Srivastava et al., J Am. Chem. Soc., 2007. 129, 8362-8379; Elayadi et al., Curr. Opinion Inverts. Drugs, 2001, 2, 558-561 ; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum et al., Curr. Opinion Mok Then. 2001 , 3, 239-243; Wengel et al., U.S. 7.053,207, Imanishi et al., U.S

[0757] 6,268.490. Imanishi et al U S. 6.770.748, Imanishi et ai., U.S RE44.779; Wengel et al., U.S. 6,794,499, Wengel et al., U.S. 6,670,461 ; Wengel et al., U.S. 7,034, 133, Wengel et al., U.S. 8,080,644; Wengel et al., U.S. 8,034,909; Wengel et al., U.S.

[0758] 8.153,365; Wengel et al., U.S. 7.572,582; and Ramasamy et al.. U.S. 6.525, 191 , Torsten et ah. WO 2004 / 106356. Wengel et al., WO 1999 / 014226; Set et al. W'O 2007 / 134181 ; Seth et al., U.S. 7,547,684, Seth et al., U.S. 7.666,854; Seth et al„ U.S. 8,088,746; Seth et al., U.S. 7,750,131; Seth et al., U.S 8.030,467; Seth et al.. U.S. 8,268,980; Seth et al., U.S. 8,546,556: Seth et al., U.S. 8,530,640; Migawa et al., U.S. 9,012.421 ; Seth et al., U S. 8,501,805; Allerson et al.. US2008 / 0039618; and Migawa et al , US2015 / 0191727

[0759] In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LN.A nucleoside (described herein) can be in the alpha-L configuration or in the beta- D configuration. PATENT

[0760] 7328.158159PCT / NLM-1002-PC

[0761] LNA (beta-D-coiifiguration) alpha-L-LNA (alpha-L-coiifiguration) bridge - WI H M bridge:::4'*CIb.-O“2'

[0762] Alpha-L-metityleneoxy (4’-CH2-O-2’) or alpha-L-LNA bicyclic nucleosides have been incoiporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research. 2003. 21. 6365-6372). The addition of locked nucleic acids to siRNAs has been shown to increase si RNA stability in serum, and to reduce off- target effects (Elmen, J et al., (2005) Nucleic Acids Research 33(l)’439-447; Mook. OR. et al.. (2007) Mai Cane Thor 6(3):833-843; Grunweller, A. el al ., (2003) Nucleic Acids Research 31(12):3185-3193). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (for example, LNA or cEt) are identified in embodiments herein, they' are in the beta-D configuration, unless otherwise specified

[0763] In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (for example, 5’- substituted and 4'-2' bridged sugars).

[0764] In certain embodiments, modified sugar moieties are sugar surrogates. Tn certain such embodiments, the oxygen atom of the sugar moiety is replaced, for example, with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and / or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4’-sulfur atom and a substitution at the 2'-position (see, for example. Bhat et al.. U.S. 7,875,733 and Bhat et al., U.S. 7,939,677) and / or the 5’ position

[0765] In certain embodiments, sugar surrogates comprise rings having other titan 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran CTHP”). Such tetrahydropyrans can be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (‘ANA”), mannitol PATENT

[0766] 7328.158159PCT / NLM-1002-PC nucleic acid f‘MNA”) (see, for example. Leumann, CJ Bioorg. & Med Chero. 2002.

[0767] 10, 841-854), fluoro HNA:

[0768] (“F-HNA”, see for example, Swayze et al.. U.S. 8,088,904; Swayze el al., U.S.

[0769] 8,440,803; Swayze et al., U.S. 8.796,437; and Swayze et al.. U.S. 9.005.906; F-HNA can also be referred to as a F-THP or 3’-tluoro tetrahydropyran)- and nucleosides comprising additional modified HIP compounds having the formula: where, independently, for each of the modified HIP nucleoside:

[0770] Bx is a nucleobase moiety;

[0771] Ts and Id each, independently, is an mlemucleoside linking group linking the modified TUP nucleoside io the remainder of an oligonucleotide or one of T? and Ti is an internucleoside linking group finking the modified HIP nucleoside to the remainder of an oligonucleotide and the other of Ts and Th is hydrogen, a hydroxyl protecting group, a linked conjugate group, or a 5' or 3'-ternnnaI group; qi, qs, qs. qp qs. qs and q? are each, independently, hydrogen, Ci-Cr alkyl, substituted Ci-Cs alkyl, Ci-Cr alkenyl, substituted C2-C0 alkenyl. Cc-Cs alkynyl. or substituted Cr-Cr alkynyl; and each of Ri and R.a is independently selected from among hydrogen, halogen, substituted or unsubstituted alkoxy, NJ1J2, SJn Ns, OC(:::X)J], OC(:::X)NJ]J?., NJ3C(:::X)NJIJ2, and CN, where X is 0, S or NJi and each ,h. Jc, and Js is, independently, hydrogen or Ci-Cs alkyl.

[0772] In certain embodiments, modified TH? nucleosides are provided where qi, qs, qs. qv q5, qs and q? each is hydrogen. In certain embodiments, at least one of qi. q?, qs, cp, qi, qs and q? is other than hydrogen. In certain embodiments, at least one of qi, q?., qs. PATENT

[0773] 7328.158159PCT / NLM-1002-PC qi, qs. qs and q? is methyl. In certain embodiments, modified THP nucleosides are provided where one of Rt and R? is fluorine. In certain embodiments, Rt is fluorine and R?. is hydrogen, in certain embodiments. Rj is methoxy and R? is hydrogen, and in certain embodiments, Ri is methoxyethoxy and Rc is hydrogen.

[0774] In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, for example. Braasch et al . Biochemistry, 2002, 41, 4503-4510 and Summerton et at.. U.S. 5.698,685, Summerton et al.. U.S. 5.166.315, Summerton el al., U.S. 5,185,444; and Summerton et al., U.S. 5,034,506). As used here, the term “morpholino” means a sugar surrogate that can be in a nucleoside having the following structure, where Bx is a nucleobase moiety:

[0775] In certain embodiments, morpholinos can be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

[0776] In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include, but are not limited to. peptide nucleic acid CTNA'’). acyclic butyl nucleic acid (see. for example, Kumar et al., Org. Biomol Chem., 2013. H. 5853-5865), and nucleosides and oligonucleotides described in Manoliaran et al., WO2011 / 133876. In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include, but are not limited to. peptide nucleic acid (“PNA”). acyclic butyl nucleic acid (see. for example, Kumar et al., Org. Biomol. Client., 2013, 11, 5853-5865). and nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U S. Patent Nos. 5,539.082; 5,714,331; and 5.719,262 Additional PATENT 7328.158159PCT / NLM-1002-PC

[0777] PNA compounds suitable for use in the oligonucleotides of the invention are described in, for example, in Nielsen et al . Science, 1991, 254, 1497-1500,

[0778] In certain embodiments, sugar surrogates are the “unlocked"’ sugar structure of UNA (unlocked nucleic acid) nucleosides. UNA is an unlocked acyclic nucleic acid, where any of the bonds of the sugar has been removed, fonning an unlocked sugar surrogate. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, US Patent No 8,314,227; and US Patent Publication Nos.

[0779] 2013 / 0096289; 2013 / 001 1922; and 2011 / 0313020.

[0780] In certain embodiments, a sugar surrogate is a glycerol as found in GN A (glycol nucleic acid) nucleosides as depicted below:

[0781] (S)-GNA where Bx represents a nucleobase moiety.

[0782] Many other bicyclic and tricyclic sugar and sugar surrogates are known in the art that can be used in modified nucleosides.

[0783] Exemplary Modified Nucleobases

[0784] In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside. In certain embodiments, modified oligonucleotides comprise one or more inosine nucleosides (i.e , nucleosides comprising a hypoxanthine nucleobase).

[0785] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain PATENT

[0786] 7328.158159PCT / NLM-1002-PC embodiments, modified nucieobases are selected from: 5-msthylcytosine, 2- aminopropyladenine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2- aminoadenine, 6-N-methy {guanine, 6-N-methyladenine, 2-propyladenine, 2- thiouracil. 2-thiothymine and 2-thiocytosine, 5-propynyl (-OC-CH3) uracil, 5- propynylcytosine, 6-azouracil, 6-a.zocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thioL 8~thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluorometliyl, 5- halouracil, and 5-halocytosine. 7-me thyl guanine, 7-methyladenine, 2-F-adenine, 2- aminoadenine. 7-deazaguamne, 7-deazaadenine, 3-deazaguanine, 3-deazaadenme, 6- N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyI 4-N-benzoylcytosine, 5-rnethyl 4-N-benzoyl uracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases Further modified nucieobases include tricyclic pyrimidines, such as 1.3- diazaphenoxazine-2-one, 1 ,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy )- 1 ,3- diazaphenoxazine- 2-one (G-clamp). Modified nucieobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenme, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucieobases include those disclosed in Merigan et al. U.S. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, K,roschwitz, J. I, Ed., John Wiley & Sons, 1990. 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, Crooke, S.T. and Lebien, B.. Eds . CRC Press, 1993. 273-288; and those disclosed in Chapters 6 and 5, Antisense Drug Technology, Crooke S T., Ed , CRC Press. 2008, 163-166 and 442-443.

[0787] Publications that teach the preparation of certain of the abo ve noted modified nucieobases as well as other modified nucieobases include without limitation, Manoharan et al., US 2003 / 0158403; Manoharan et al., US 2003 / 0175906; Dinh et al., U.S 4,845.205, Spielvogel ei al, U.S. 5, 130,302; Rogers ei al. U.S. 5.134,066; Bischofberger et al. , U S 5, 175,273; Urdea et al., U S. 5,367.066; Benner et al . U.S. 5.432,272; Matteucci et al.. U.S. 5,434.257; Gmeiner et al.. U.S 5,457.187; Cook et al., U.S. 5,459,255; Froehler et al.. U.S. 5,484.908; Matteucci et al.. U.S. 5,502,177; Hawkins et al. U.S. 5,525.71 1 ; Flaralambidis et al.. U.S. 5,552.540; Cook et al, U.S. 5,587,469; Froehler et al, U S 5,594, 121 ; Switzer et al , U.S. 5.596,091 ; Cook et al , PATENT

[0788] 7328.158159PCT / NLM-1002-PC

[0789] U S .5,614.617; Froehler et al., U.S. 5.645,985; Cook et al, U.S. 5,681 ,941; Cook et al., U.S. 5,811,534; Cook et al., U S. 5,750,692; Cook et al., U.S. 5,948,903; Cook et al., U.S. 5,587,470; Cook et al., U.S. 5,457,191 ; Matteucci et al.. U.S. 5,763,588;

[0790] Froehler et al.. U.S 5,830.653; Cook et al, U.S. 5.808,027; Cook et al, U.S. 6,166.199; and Maiteucci et al, U.S. 6.005,096

[0791] Exemplary Modified Intemucleoside Linkages

[0792] The naturally occurring intemucleoside linkage of RNA and DNA is a 3' to 5’ phosphodiester linkage. In certain embodiments, nucleosides of modified oligonucleotides can be linked together using one or more modified intemucleoside linkages. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing intemucleoside linkages include, but are not limited to, phosphodi esters, which contain a phosphodiester bond C;P=O’ ) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, phosphoroihioates (“P::::S”), and phosphorodi thioates f‘HS-P:::S”) Representative non-phosphorus containing intemucleoside linking groups include, but are not limited to. methylenemethylimmo )••(>•( 'H.-- g tlnodiester. thionocarbamate (-0-

[0793] C(:::;O)(NH)-S-), siloxane (-O-Silh-O-): and N,N'-dimethylhydrazine (-CH?.-N(CHs)- N(CHj)-). Modified intemucleoside linkages, compared to naturally occurring phosphodiester intemucleoside linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, intemucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non- phosphorous-containing intemucleoside linkages are well known to those skilled in the art.

[0794] In certain embodiments, a modified intemucleoside linkage is any of those described in WO 2021 / 030778 in certain embodiments, a modified intemucleoside linkage comprises the formula: PATENT

[0795] 7328.158159PCT / NLM- 1002-PC where independently for each intemudeoside linking group of the modified oligonucleotide:

[0796] X is selected from O or S;

[0797] Ri is selected from hydrogen, Ci-Cs alkyl, and substituted C1-C.5 alkyl, and

[0798] T is selected from SO2R2, C(::::O)R3, and P(:::O)foR5. where:

[0799] Re is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a Ci-G> alkoxy, Ci-G> alkyl, Ci-C-6 alkenyl. Ci-Cr alky ny 1, substituted Ci-Ce alkyl, substituted Ci-Cs alkenyl substituted Ci-Ce alkynyl, and a conj ugate group;

[0800] Rs is selected from an aryl, a substituted aryl, CH.% N(CH:;)2, OCHs and a conjugate group;

[0801] R.J is selected from OCH3, OH. Ci-Ce alkyl, substituted Ci-Ce alkyd and a conjugate group; and

[0802] Rs is selected from OCH3, OH, Ci-Ck alkyl, and substituted Cf-Cs alkyl

[0803] In certain embodiments, a modified intemudeoside linkage comprises a mesyl phosphoramidate linking group having a formula:

[0804] In certain embodiments, a mesyl phosphoramidate intemudeoside linkage may comprise a chiral center. In certain embodiments, modified oligonucleotides comprising (Rp) and / or (Sp) mesyl phosphoramidates comprise one or more of the following formulas, respectively, where “B*’ indicates a nucleobase: PATENT

[0805] 7328.158159PCT / NLM- 1002-PC

[0806] In certain embodiments, a modified internucleoside linkage comprises a busyl phosphoramidate linking group having a formula.

[0807] A busy! phosphorami date internucleoside linkage may comprise a chiral center In certain embodiments, a modified oligonucleotide can include (Rp) and / or (Sp) busyl phosphorami dates having structures corresponding to those shown for (Rp) or (Sp) mesyl phosphoramidaies, respectively.

[0808] Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates, phosphoramidaies, and phosphorothioates. Modified oligonucleotides comprising mtemucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereo-random internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages where all of the phosphorothioate internucleoside linkages arc stereo-random. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereo-configuration In certain embodiments, populations of modified oligonucleotides are enriched for modified PATENT

[0809] 7328.158159PCT / NLM-1002-PC oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration.

[0810] In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present m at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present m at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules m the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, for example, methods described in Oka et al., JACS 125, 830 / (.2003), Wan et al Nuc. Acid Res. 42, 13456 (2014), and WO 2017 / 015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched tor modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and / or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, where “B” indicates a nucleobase:

[0811] Unless otherwise indicated, chiral internucleoside linkages of modi fied oligonucleotides described herein can be stereo-random or in a particular stereochemi cal confi duration. PATENT

[0812] 7328.158159PCT / NLM-1002-PC

[0813] Neutral intern ucleoside linkages include, without limitation, phosphotriesters, alkylphosphoiiates, methylphosphonates, MMI (3’-CH?-N(CH3)-O-5'), amide- 3 (3'~ amide-4 (3'-CH2-N(H)-C(-O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl (MOP), and thioformacetal (3 -S-CH2-O-5'). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in .Antisense Research’, Y.S. Sanghvi and P.O. Cook. Eds.. ACS Symposium Series 580: Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, 0, S and CH?. component parts. In certain embodiments, modified oligonucleotides comprise one or more inverted nucleoside, as shown below: where each Bx independently represents any nucieobase.

[0814] In certain embodiments, an inverted nucleoside is terminal (i.e., the last nucleoside on one end of an oligonucleotide) and so only one in tern ucleoside linkage depicted above will be present. In certain such embodiments, additional features (such as a conjugate group) can be attached to the inverted nucleoside. Such terminal inverted nucleosides can be attached to ei liter or both ends of an oligonucleotide

[0815] In certain embodiments, such groups lack a nucleohase and are referred to herein as inverted sugar moi eties. In certain embodiments, an inverted sugar moiety is terminal PATENT

[0816] 7328.158159PCT / NLM-1002-PC

[0817] (i.e . attached to the last nucleoside on one end of an oligonucleotide) and so only one intemucleoside linkage above will be present. In certain such embodiments, additional features (such as a conjugate group) can be attached to the inverted sugar moiety.

[0818] Such terminal inverted sugar moieties can be attached to either or both ends of an oligonucleotide

[0819] In certain embodiments, nucleic acids can be linked 27to 5’ rather than the standard 3' to 5’ linkage Such a linkage is illustrated below, where each Bx represents any nucleobase:

[0820] Exemplary Motifs

[0821] In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified intemucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties. nucleobases, and / or intemucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties. nucleobases, and intemucleoside linkages are each independent of one another. Thus, a modified oligonucleotide can be described by its sugar motif, nucleobase motif and / or intemucleoside linkage motif (as used herein, nucleobase moti f describes the modifications to the nucleobases independent of the sequence of nucleobases).

[0822] Exemplary Sugar Motifs in certain embodiments, oligonucleotides comprise one or more type of modified sugar and / or unmodified sugar moiety arranged along the oligonucleotide or region PATENT

[0823] 7328.158159PCT / NLM-1002-PC thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited io any of the sugar modifications described herein.

[0824] In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which is defined by two external regions or "wings" and a central or internal region or “gap." The three regions of a gapmer motif (the 5’-wing, the central region (or gap), and the 3 ’-wing) form a contiguous sequence of nucleosides where at least some of the sugar moi eties of the nucleosides of each of the wings differ from at least some of the sugar moi eties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3’-most nucleoside of the 5'-wing and the 5’-most nucleoside of the 3’-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i e., the wing / gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5'-wmg differs from the sugar motif of the 3’ -wing (asymmetric gapmer)

[0825] In certain embodiments, the wings of a gapmer comprise 1 -6 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least two nucleosides of each wing of a gapmer comprises a modified sugar moiety In certain embodiments, at least three nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least four nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least five nucleosides of each wing of a gapmer comprises a modified sugar moiety.

[0826] In certain embodiments, the central region (or gap) of a gapmer comprises 7-12 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2’-beia-D-deoxy ribosyl sugar moiety. In certain embodiments, at least three nucleosides, which sometimes are at least three contiguous nucleosides, of the central region of a gapmer comprise a 2 ’-beta-D-deoxy ribosyl sugar moiety'. In certain PATENT

[0827] 7328.158159PCT / NLM-1002-PC embodiments, 3, 4, 5, 6, 7. 8. 9, 10, 1 1 or 12 nucleosides, or 3, 4, 5. 6. 7, 8, 9, 10, 11 or 12 contiguous nucleosides, m a central region each comprise a 2’-beta-D- deoxyribosyl sugar moiety. In certain embodiments, at least one nucleoside of the central region of a gapmer comprises a modified sugar moiety. In certain embodiments, one or two nucleosides of the central region of a gapmer comprises a modified sugar moietys Certain embodiments in which a central region includes at least one nucleoside comprising a modified sugar moiety and / or at least one modified intemucleoside linkage are described herein.

[0828] In certain embodiments, the gapmer is a deoxy gapmer. In certain embodiments, the nucleosides on the gap side of each wing / gap junction comprise 2'-beta-D- deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing / gap junction comprise modified sugar moieties. In certain embodiments, each nucleoside of the gap comprises a 2:-beta-D-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a 2’-0Me sugar moiety or 2* -MOE sugar moiety.

[0829] In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif. Tn such embodiments, each nucleoside of the fully modified portion of the modified oligonucleotide comprises a modified sugar moietys In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif, where each nucleoside within the fully modified portion comprises the same modified sugar moiety, referred to as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly- modified oligonucleotide comprises the same 2 ‘-modification. l ierein, the lengths (number of nucleosides) of the three regions of a gapmer can be provided using the notation [# of nucleosides in the 5'-wing] - [H of nucleosides in the gap] - [# of nucleosides in the 3 ’-wing], 'Thus, a 3-10-3 gapmer consists of 3 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such PATENT

[0830] 7328.158159PCT / NLM-1002-PC nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprise 2’- beta-D-deoxy ribosyl sugar moieties. Thus, a 5-10-5 MOE gapmer consists of 5 linked 2 '-MOE nucleosides in the 5'-wing, 10 linked 2'-beta-D-deoxynucleosides in the gap, and 5 linked 2’-MOE nucleosides in the 3 ’-wing. A 3-10-3 cEt gapmer consists of 3 linked cEt nucleosides in the 5 ’-wing, 10 linked 2’-beta-D-deoxynucleosides in the gap, and 3 linked cEt nucleosides in the 3 ‘-wing. A 5-8-5 gapmer consists of 5 linked nucleosides comprising a modified sugar moiety in the 5'-wing, 8 linked 2'-beta-D- deoxynucleosides in the gap, and 5 linked nucleosides comprising a modified sugar moiety in the 3’-wing. A 5-8-5 mixed gapmer has at least two different modified sugar moieties in the 5 ’-wing and / or the 3’-wing.

[0831] In certain embodiments, modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 BNA gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 cEt gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 LN A gapmers

[0832] In certain embodiments, modified oligonucleotides have a sugar motif of 5’- eeeeeddddddddddeeeee-3’, where each "d " represents a 2 '-beta-D-deoxy ribosyl sugar moiety, each “e” represents a 2 ’-MOE sugar moiety.

[0833] Exemplary Nucleobase Motifs

[0834] In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along die oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-melhylcytosines. In certain embodiments, ail of the cytosine nucleobases are 5-methylcytosines and all of the oilier nucleobases of the modified oligonucleotide are unmodified nucleobases In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3’-end of the PATENT

[0835] 7328.158159PCT / NLM-1002-PC oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3’- end of the oligonucleotide. In certain embodiments, the block is at the 5 ’-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the S'- end of the oligonucleotide

[0836] In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. in certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2’-beta-D-deoxyribosyl sugar moiety, in certain embodiments, the modified nucleobase is selected from a 2-thiopyrmndine and a 5- propy n epy ri rm di n e.

[0837] Exemplary intemucleoside Linkage Motifs

[0838] In certain embodiments, oligonucleotides comprise modified and / or unmodified mtemucieoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each intemucleoside linking group is a phosphodi ester internucleoside linkage (P:::O). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide is a phosphorothioale intemucleoside linkage (P=S). In certain embodiments, each intemucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioale intemucleoside linkage and phosphodiester intemucleoside linkage. In certain embodiments, each phosphorothioale intemucleoside linkage is independently selected from a stereo-random phosphorothioale a (Sp) phosphorothioate, and a (Rp) phosphorothioale.

[0839] In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the intemucleoside linkages within the gap are all modified. In certain embodiments, some or all of the intemucleoside linkages in the wings are unmodified phosphodi ester intemucleoside linkages. In certain embodiments, the terminal mtemucieoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the intemucleoside linkage motif comprises at least one ph osphod tester intemucleoside linkage in at least one wing, where die at least one phosphodies ter linkage is not a terminal intemucleoside linkage, and the remaining intemucleoside linkages are phosphorothioate PATENT

[0840] 7328.158159PCT / NLM-1002-PC intemucleoside linkages In certain such embodiments, all of the phosphorothioate linkages are stereo-random. In certain embodiments, all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, or Rp motif In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such intemucleoside linkage motifs.

[0841] In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of (from 5’ to 3’) soooossssssssssooss, sososssssssssssooss or sooosssssssssssooss, where each “s'” represents a phosphorothioate intemucleoside linkage and each W’ represents a phosphodiester intemucleoside linkage.

[0842] In certain embodiments, modified oligonucleotides have an intemucleoside linkage motif comprising one or more mesyl phosphoramidate intemucleoside linkages in certain embodiments, one or more phosphorothioate intemucleoside linkages or one or more phosphodi ester intemucleoside linkages of the intemucleoside linkage motifs herein is substituted with a mesyl phosphoramidate intemucleoside linkage.

[0843] Exempl ary I. ength s

[0844] It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a scries of oligonucleotides 13-25 nucleobases m length were tested for their ability to induce cleavage of a target RNA in an oocy te injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides w ere able to direct specific cleavage of the target RNA. albeit io a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nudeobase oligonucleotides, including those with 1 or 3 mismatches.

[0845] In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10. 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44. 45. 46, 47, 48, 49, and .50: provided that PATENT

[0846] 7328.158159PCT / NLM-1002-PC

[0847] X<¥. For example, in certain embodiments, oligonucleotides consist of 12 to 13. 12 to 14, 12 to 15, 12 io 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22. 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to IS. 13 to 19, 13 to 20, 13 to 21 , 13 to 22, 13 to 23. 13 to 24, 13 to 25, 13 to 26, 13 to 27. 13 to 28, 13 to 29, 13 to 30, 14 to 15. 14 to 16. 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25. 14 to 26, 14 to 27, 14 to 28. 14 to 29, 14 io 30, 15 to 16, 15 to 17, 15 to 18. 15 to 19, 15 to 20. 15 to 21. 15 to 22, 15 to 23, 15 to 24, 15 to 2.5. 15 to 26. 1.5 to 27, 15 to 28. 15 to 29. 15 to 30. 16 to 17, 16 to 18, 16 to 19, 16 to 20. 16 to 21, 16 to 22, 16 to 23. 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 1 7 to 18, 17 to 19, 17 to 20, 17 io 21 , 17 to 22, 17 to 23. 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28. 17 to 29. 17 io 30, 18 to 19, 1 8 to 20. 18 to 21 , 18 to 22, 18 io 23, 18 to 24, 18 to 25. 18 io 26. 18 to 27. 18 to 28. 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23. 19 to 24, 19 to 25, 19 to 26. 19 to 27, 19 to 28, 19 to 29, 19 to 30. 20 to 21. 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28. 20 to 29, 20 to 30, 21 to 22, 21 to 23. 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28. 21 to 29, 21 to 30, 22 to 23. 22 to 24, 22 to 25. 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25. 23 to 2b, 23 to 27, 23 to 28, 23 to 29. 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27. 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28. 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

[0848] In certain embodiments, oligonucleotides (including modified oligonucleotides) consist of 16 linked nucleosides. In certain embodiments, oligonucleotides (including modified oligonucleotides) consist of 17 linked nucleosides. In certain embodiments, oligonucleotides (including modified oligonucleotides) consist of 18 linked nucleosides. In certain embodiments, oligonucleotides (including modified oligonucleotides) consist of 19 linked nucleosides, in certain embodiments, oligonucleotides (including modified oligonucleotides) consist of 20 linked nucleosides.

[0849] Exemplary Modified Oligonucleotides

[0850] In certain embodiments, the above modifications (sugar, nucleobase, imemucleoside linkage) are incorporated into a modified oligonucleotide In certain embodiments. PATENT

[0851] 7328.158159PCT / NLM-1002-PC modified oligonucleotides are characterized by their modification motifs and overall lengths In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each intern ucleoside linkage of an oligonucleotide having a gapmer sugar motif can be modi fied or unmodi fied and may or may not follow the gapmer modification pattern of the sugar modifications For example, the intemucleoside linkages within the wing regions of a sugar gapmer can be the same or different from one another and can be the same or different from the intemucleoside linkages of the gap region of the sugar motif. Likewise, such sugar gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent ofnucleoba.se sequence.

[0852] Certain oligonucleotide modifications can enhance antisense activity. An oligonucleotide may include one or more modifications described in Shen et al., Nature Biotechnology 640(37): 640—650 (2019); Migawa et al.. Nucleic Acids Research 47( 1 1 ): 5465—5479 (2019); Anderson et al. , Nucleic Acids Research 49(16): 9026-9041 (2021 ) and Vasquez et al.. Nucleic Acids Research 49(4)' 1828-1839 (2021).

[0853] In certain embodiments, an oligomeric compound comprises a central region, and the central region comprises 1 to 5 (1, 2, 3, 4 or 5 for example) mesyl phosphoramidite and / or busyl phosphoramidite intemucleoside linkages. In certain embodiments, the central region comprises a 5’ terminus, and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a mesyl phosphoramidite and / or a busyl phosphoramidite intemucleoside linkage. In certain embodiments, the central region comprises a 5’ terminus, and position 2. or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a mesyl phosphoramidite intemucleoside linkage.

[0854] In certain embodiments, an oligomeric compound comprises a central region, and the central region comprises 1 to 5 alkyd phosphonate intemucleoside linkages. In certain embodiments, the central region comprises a 5’ terminus; and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises an alkylphosphonate intemucleoside PATENT

[0855] 7328.158159PCT / NLM-1002-PC linkage. In certain embodiments, the central region comprises a 5’ terminus, and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a mesyl phosphoramidite and / or a busyl phosphoramidite intemucleoside linkage. In certain embodiments, the alkylphosphonate intemucleoside linkage comprises methoxypropyl (MOP). In certain embodiments, the alkylphosphonates intemucleoside linkage comprises methyl.

[0856] In certain embodiments, an oligomeric compound comprises a central region, and the central region comprises 1 to 5 (1, 2, 3, 4 or 5 for example) modified sugar moieties. In certain embodiments, each of the 1 to 5 modified sugar moieties independently is a non-bicyclic modified sugar moiety. In certain embodiments, each of the 1 to 5 modified sugar moieties independently is a bicyclic modified sugar moiety. In certain embodiments, a modified sugar moiety comprises a 2’ substituent, and in certain instances is a 2’-OMe modified sugar moiety. In certain embodiments, a modified sugar moiety comprises a 5’ substituent, and in certain instances is a 5’-methyl or 5’- ethyl modified sugar moiety.

[0857] In certain embodiments, the central region comprises a 5’ terminus, and position 2, or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety. In certain embodiments, position 2. or position 3, or positions 2 and 3 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety comprising a 2’ substituent. In certain embodiments, the modified sugar moiety independently is a 2’-OMe modified sugar moiety.

[0858] In certain embodiments, an oligomeric compound comprises a central region, the central region comprises a 5' terminus; and position 3, or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central region, each independently comprises a modified sugar moiety. In certain embodiments, position 3, or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central region, each independently comprises modified sugar moiety comprising a 5‘ substituent. In certain embodiments, position 3. or position 4, or positions 3 and 4 of the central region, as counted from the 5' terminus of the central PATENT

[0859] 7328.158159PCT / NLM-1002-PC region, each independently comprises a 5 ’-methyl modified sugar moiety. In certain embodiments, the 5 ’-methyl modified sugar moiety independently is a R-5’ -methyl modified sugar moiety or a S-5’-methyl modified sugar moiety.

[0860] Exemplary Populations of Modified Oligonucleotides

[0861] Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chiraliy enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereo-random in a stereo-random population. In a chiraliy enriched population, at least one particular chiral center is not stereo-random in the modified oligonucleotides of the population, in certain embodiments, the modified oligonucleotides of a chiraliy enriched population are enriched for beta-D ribosyl sugar rnoielies. and all of the phosphorothioate intemucleoside linkages are stereo-random. In certain embodiments, the modified oligonucleotides of a chiraliy enriched population are enriched for both beta-D ribosyl sugar moieties and at least one, particular phosphorothioate intemucleoside linkage in a particular stereochemical configuration.

[0862] Nficleobase.Seguence

[0863] In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further described by their nucleobase sequence. In certain embodiments oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid In certain such embodiments, a region of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain embodiments, the nucleobase sequence of a region or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.

[0864] Exemplary Oligomeric Compounds

[0865] In certain embodiments, provided are oligomeric compounds, which consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and / or terminal groups Conjugate groups consist of one or more conjugate PATENT

[0866] 7328.158159PCT / NLM-1002-PC moiety and a conjugate linker which links the conjugate moiety’ to the oligonucleotide. Conjugate groups can be attached to either or both ends of an oligonucleotide and / or at any internal position. In certain embodiments, conjugate groups are atached to the Imposition of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that, are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are atached at the 3’ and / or 5 ’-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3‘-end of oligonucleotides, in certain embodiments, conjugate groups are attached near the o’end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are atached at the 5 ’-end of oligonucleotides In certain embodiments, conjugate groups are attached near the 5 '-end of oligonucleotides. Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties. protecting groups, modified or unmodified nucleosides, and two or more nucleosides that arc independently modified or unmodified.

[0867] Exemplary C.onj.ugate.Groups

[0868] In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the atached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.

[0869] In certain embodiments, conjugation of one or more carbohydrate moi eties to a modified oligonucleotide can optimize one or more properties of the modified oligonucleotide. In certain embodiments, the carbohydrate moiety is atached to a modified subunit of the modified oligonucleotide. For example, the ribose sugar of one or more ribonucleotide subunits of a modified oligonucleotide can be replaced with another moiety, for example, a non-carbohydrate (preferably cyclic) earner to which is attached a carbohydrate ligand. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred to herein as a ribose replacement modification subunit (RRMS), which is a modified sugar moiety. A cyclic carrier can be a carbocyclic ring system, i.e.. one or more ring atoms can be a heteroatom, for example, nitrogen, oxygen, sulfur. The cyclic carrier can be a monocyclic ring PATENT

[0870] 7328.158159PCT / NLM-1002-PC system, or may contain two or more rings, for example, fused rings The cyclic earner can be a fully saturated ring system, or it may contain one or more double bonds In certain embodiments, the modified oligonucleotide is a gapmer.

[0871] In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, for example, fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al.. Proc Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et ah. Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a ihioether, for example. hexyl-S-tritylthioi (Manoharan et al., Ann. A. Y. Acad. Sci., 1992. 660, 306-309; Manoharan et al., Bioorg Med. Chem. Lett, 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al . Nucl. Acids Res., 1992. 20, 533-538), an aliphatic chain, for example, do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al.. FEES Lett., 1990, 259, 327-330; Svinarchuk et al., Biochtmie, 1993, 75, 49-54), a phospholipid, for example, di-hexadecyl-rac-glycerol or tri ethylammonium l,2-di-O-hexadecyl-rac-g!ycero-3-H-phosphonate (Manoharan et al. , Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990. 18, 3777- 3783), a poly amine or a polyethylene glycol chain (Manoharan el al., Nucleosides & Nucleotides, 1995. 14. 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta. 1995, 1264, 229-237), an octadecyl amine or hexylamino-carbonyl-oxycholesterol moiety (Crooks et al., J. Pharmacol. Exp. Then, 1996, 277, 923-937). a tocopherol group (Nishina et al.. Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al ., Molecular Therapy. 2008, 16, 734-740). or a GalNAc cluster (for example, WO2014 / 179620).

[0872] In certain embodiments, conjugate groups can be selected from any of a C22 alkyl. C20 alkyl, C16 alkyl, CIO alkyl, C21 alkyl. C l 9 alkyl. C l 8 alkyl, C17 alkyl, C 15 alkyl, C 14 alky], C13 alky], C12 alky]. CH alkyl, C9 alkyl, C8 alkyl, Cl alky], C6 alkyd, C5 alkyd. C22 alkenyl, C20 alkenyl, C16 alkenyl, CIO alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C17 alkenyl, C15 alkenyl, C 14 alkenyl, C13 alkenyl, C 12 alkenyl. Cl I alkenyl, C9 alkenyl. C8 alkenyl. Cl alkenyl. C6 alkenyl, or C5 alkenyl, in certain embodiments, conjugate groups can be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, CIO alkyl, C21 alkyl, C19 alkyl, C18 alkyl. C17 alkyl. C15 alky l. PATENT

[0873] 7328.158159PCT / NLM-1002-PC

[0874] Cl 4 alkyl. Cl 3 alkyl. Cl 2 alkyl. CH alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, where the alkyd chain has one or more unsaturated bonds.

[0875] In certain embodiments, a conjugate group is a lipid having the following structure:

[0876] Exemplary Conjugate Moieties

[0877] Conjugate moieties include, without limitation, intercalates, reporter molecules, polyamines, polyamides, peptides, carbohydrates (e g,, GalNAc), antibodies, vitamin moieties. polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotm, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes

[0878] In certain embodiments, a conjugate moiety comprises an active drug substance, tor example, aspirin, warfarm, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-( -)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-iriiodobenzoic acid, fingolimod. flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepme, mdo-niethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

[0879] Exemplary Conjugate Linkers

[0880] Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain oligomeric compounds, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units

[0881] In certain embodiments, a conjugate linker comprises pyrrolidine In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo. amide, disulfide, polyethylene glycol, ether, ihioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups PATENT

[0882] 7328.158159PCT / NLM-1002-PC selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises al least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

[0883] In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, for example, those known in the aid to be useful for attaching conjugate groups to compounds, such as the oligonucleotides provided. In general, a bifunctional linking moiety comprises al least two functional groups. One of the functional groups is selected to bind to a particular site on a compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups, in certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, ally 1. alkenyl, and alkynyl.

[0884] Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6- dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomelhyl) cyclohexane- 1 - carboxylate (SMCC ) and 6-ammohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstiluted Cl-Cl 0 alkyl, substituted or unsubstiluted C2-CI 0 alkenyl or substituted or unsubstituted C2-C10 alkynyl, where a nonlimitmg list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

[0885] In certain embodiments, conjugate linkers comprise 1 -10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. in certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker- nucleosides comprise a modified sugar moiety. In certain embodiments, linker- PATENT 7328.158159PCT / NLM-1002-PC nucleosides are unmodified. In certain embodiments, link er-nucleosi des comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine. 5- methylcytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine. guanine and 2-N-isobutyryiguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds, hi certain embodiments, such cleavable bonds are phosphodiester bonds.

[0886] Herein, linker-nucleosides are not considered to be part oft.be oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and / or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides. those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1 ) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising I -10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker- nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than I linker-nucleoside.

[0887] In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds PATENT

[0888] 7328.158159PCT / NLM-1002-PC comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. Tn certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety' is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds In certain embodiments, a cleavable moiety' is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases

[0889] In certain embodiments, a cleavable bond is selected from among an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a conjugate moiety7or conjugate group.

[0890] In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nuc-leosides. In certain such embodiments, the one or more linker-nucleosides are linked to one another and / or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2'- deoxynucleoside that is attached to either the 3' or 5'-terminal nucleoside of an oligonucleotide by a phosphate iiiiermicleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage In certain such embodiments, the cleavable moiety is 2’- deoxy adenosine.

[0891] Exemplary7Cell- Moieties

[0892] In certain embodiments, a conjugate group comprises a cell-targeting moiety. In certain embodiments, a conjugate group has the general formula: PATENT

[0893] 7328.158159PCT / NLM-1002-PC

[0894] [Ligand — Tetheij— [Branching group ]— [Linker Moiety ]- — | Cleavable ] 1 k

[0895] Cell-targeting moiety Conjugate Linker where n is from I to about 3, m is 0 when n is 1, m is 1 when n is 2 or greater, j is 1 or 0. and k is 1 or 0. In certain embodiments, n is I , J is I and k is 0. In certain embodiments, n is 1, j is 0 and k is 1. In certain embodiments, n is 1, j is I and k is 1. In certain embodiments, n is 2, j is I and k is 0. In certain embodiments, n is 2, j is 0 and k is 1. In certain embodiments, n is 2, j is 1 and k is 1. In certain embodiments, n is 3, j is 1 and k is 0. In certain embodiments, n is 3. j is 0 and k is I. In certain embodiments, n is 3 , j is 1 and k is I .

[0896] In certain embodiments, conjugate groups comprise cell-targeting moieties that have at least one tethered ligand In certain embodiments, cell-targeting moieties comprise two tethered ligands covalently attached to a branching group in certain embodiments, cell-targeting moieties comprise three tethered ligands covalently attached to a branching group.

[0897] In certain embodiments, each ligand of a cell -targeting moiety has an affinity for at least one type of receptor on a target cell. In certain embodiments, each ligand has an affinity for at least one type of receptor on the surface of a mammalian liver cell. In certain embodiments, each ligand has an affinity for the hepatic asialoglycoprotein receptor (ASGP-R). In certain embodiments, each ligand is a carbohydrate. In certain embodiments, a conjugate group comprises a cell-targeting conjugate moiety. In certain embodiments, a conjugate group has the general formula:

[0898] Cell-targeting conjugate moiety Conjugate Linker where n is from 1 to about 3, m is 0 when n is 1 , m is 1 when n is 2 or greater, j is 1 or 0, and k is 1 or 0. In certain embodiments, n is 1, j is 1 and k is 0. In certain embodiments, n is 1. j is 0 and k is I . In certain embodiments, n is 1 , j is I and k is I . In certain embodiments, n is 2, j is I and k is 0. In certain embodiments, n is 2, j is 0 and k is 1 . In certain embodiments, n is 2, j is 1 and k is 1 In certain embodiments, n PATENT

[0899] 7328.158159PCT / NLM-1002-PC is 3, j is 1 and k is 0. In certain embodiments, n is 3. j is 0 and k is 1. In certain embodiments, n is 3, j is 1 and k is 1.

[0900] In certain embodiments, conjugate groups comprise cell-targeting moieties that have at least one tethered ligand. In certain embodiments, cell-targeting moieties comprise two tethered ligands covalently attached to a branching group. In certain embodiments, cell-targeting moieties comprise three tethered ligands covalently attached to a branching group.

[0901] In certain embodiments, the cell-targeting moiety targets neurons. Tn certain embodiments, the cell-targeting moiety targets a neurotransmiter receptor. In certain embodiments, the cell targeting moiety targets a neurotransmitter transporter. In certain embodiments, the cell targeting moiety targets a GABA transporter. See for example. WO 201 1 / 131693. WO 2014 / 064257.

[0902] In certain embodiments, conjugate groups comprise cell-targeting moieties that have affinities for transferrin receptor (TfR) (also referred to herein as TfRl and CD71). In certain embodiments, a conjugate group described herein comprises an anti-TfRl antibody or fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfRl. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfRl. In certain embodiments, the anti-TfRl antibody or fragment thereof can be any known in the art including but not 1 inn ted to those described i n WO1991 / 004753 ; W02013 / 103800: W 02014 / 144060: WO2016 / 081643;

[0903] WO2016 / 179257; WO2016 / 207240; WO2017 / 221883; WO2018 / 129384;

[0904] WO2018 / 124121 ; WO2019 / 151539; WO2020 / 132584; W02020 / 028864; US 7.208,174; US 9.034,329: and US 10.550, 188. In certain embodiments, a fragment of an anti-TfR.1 antibody is F(ab')2. Fab, Fab', Fw or scFv

[0905] In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR l . In certain embodiments, the protein or peptide capable of binding TfR 1 can be any known in the art including but not limited to those described in W02019 / 140050; W02020 / 037150; W02020 / 124032; and US 10.138,483.

[0906] In certain embodiments, the conjugate group comprises an aptamer capable of binding TfRl . Tn certain embodiments, the aptamer capable of binding TfRl can be any PATENT

[0907] 7328.158159PCT / NLM-1002-PC known in the art including but not limited to those described in WO2013 / 163303; WO2019 / 033051; and WO2020 / 245198.

[0908] Exemplary Terminal Groups

[0909] In certain embodiments, oligomeric compounds comprise one or more terminal groups. In certain such embodiments, oligomeric compounds comprise a stabilized 5’- phosphate. Stabilized 5 '-phospha les include, but are not limited to 5 ’-phosphonates, including, but not limited to 5’-vinylphosphonates. In certain embodiments, terminal groups comprise one or more abasic sugar moieties and / or inverted nucleosides. In certain embodiments, terminal groups comprise one or more 2 ’-linked nucleosides or sugar moieties. In certain such embodiments, the 2 '-linked group is an abasic sugar moiety .

[0910] Exemplary' Anti sense Activity

[0911] In certain embodiments, oligomeric compounds and oligomeric duplexes are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity and such oligomeric compounds and oligomeric duplexes are referred to as “antisense compounds.” In certain embodiments, antisense compounds have antisense activity when they reduce or inhibit the amount or activity of a target nucleic acid by 25% or more in the standard in vitro assay In certain embodiments, antisense compounds selecti vely affect one or more target nucleic acid. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity, and does not hybridize to one or more non- target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity. The standard in vitro assay is described in Example I .

[0912] For certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid For example, certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RN A:DNA duplex need not be unmodified DNA and can include modified oligonucleotide of antisense compounds. In certain embodiments, antisense compounds are sufficiently “DNA-Iike” to elicit PATENT

[0913] 7328.158159PCT / NLM-1002-PC

[0914] RNase H activity. In certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

[0915] For certain antisense activities, an antisense compound or a portion of an antisense compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid For example, certain antisense compounds result in cleavage of the target nucleic acid by Argonaute. Antisense compounds that are loaded into RISC are RNAi agents RNAi agents can be doublestranded (siRNA or dsRNAi) or single-stranded (ssRNAi).

[0916] In certain embodiments, hybridization of an antisense compound to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain embodiments, hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in alteration of translation of the target nucleic acid

[0917] An antisense activity can be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein and / or a phenotypic change in a cell or subject.

[0918] Exemplary Target Nucleic Acids

[0919] In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein In certain such embodiments, the target nucleic acid is selected from: a mature mRNA and a pre- mRNA, including intromc, exonic and untranslated regions. In certain embodiments, the target RNA is a mature mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron / exon junction. Tn certain embodiments, the target region is at least 50% within an intron. In certain PATENT

[0920] 7328.158159PCT / NLM-1002-PC embodiments, the target nucleic acid is the RNA transcriptional product of a retrogene. In certain embodiments, the target nucleic acid is a non-coding RNA. In certain embodiments, the target non-coding RNA is selected from, a long non-coding RNA, a short non-coding RNA, an intronic RNA molecule.

[0921] Complementauty / Mismatches to Target Nucleic Acid and Duplex Complementarity

[0922] In certain embodiments, oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%. 90%, 85%, or 80% complementary to the target nucleic acid In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a region that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the region of full complementarity' is from 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.

[0923] It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al. (J. Natl. Cancer Inst. 93:463-471. March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xl.. in vitro and in vivo Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358. 1988) tested a series of tandem 14 nucleobase oligonucleotides, and 28 and 42 nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 n ud eobase ol igonucleotides .

[0924] In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid, hi certain embodiments, antisense activity against the target is reduced by such mismatch, but activity- against anon- target is reduced by a greater amount. Thus, in certain embodiments selectivity of the oligonucleotide is improved.

[0925] In certain embodiments, a mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position I , 2, 3, 4, 5, 6, 7, or 8 from the 5 ’-end of the gap region (central region). In PATENT

[0926] 7328.158159PCT / NLM-1002-PC certain embodiments, the mismatch is at position 9, 8, 7, 6, 5. 4. 3, 2, 1 from the 3’- end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5 ‘-end of the wing region. In certain embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3 ’-end of the wing region

[0927] Exemplary JNK signaling pathway members

[0928] The c-Jun N-terminal kinase (JNK) signaling pathway plays a role in cell death, and specifically neuronal cell death. There are three JNK genes in mammals, Jnkl, Jnk2, and Jnk3 on three different chromosomes, each in alternative spliced forms resulting in at least ten different JNK proteins. JNK can phosphorylate the N-terminal transactivation domain of c-Jun and thereby enhance its ability7to transactivate related gene expression. JNK also can phosphorylate transcription factors such as JunB, JunD, c-Fos, and ATF. These transcription factors, together with c-Jun, constitute activator protein- 1 transcription factors, which can regulate the expression of several stress-responsive genes. There are other transcription factors such as E1K1, NFAT, and p53 that can also be phosphory lated by JNK. JNK is able to phosphorylate both pro- and anti-apoptotic proteins. For example, JNK can phosphorylate Bcl-2 and Bcl-xL and diminish their anti-apoptotic activity7. JNK can also phosphorylate the pro- apoptotic protein Bim and Bmf. The JNK signaling pathway involved in neuronal cell death includes activated Racl / Cdc42, mixed-lineage kinases (MLK), ASK1, MKK4, MKK7 and JNK. Other components in activation of the JNK signaling pathway include SH3 (POSH) and JNK interacting proteins (JIP) serving as a scaffold to form a multiprotein complex with other JNK signaling pathway members. JNK signaling pathway members include, for example, (i) a JNK protein; (ii) a protein phosphorylated by a JNK protein; (iii) a protein that phosphorylates a JNK protein; (iv) a protein that interacts with (i), (ii) or (iii); (v) a protein forming a scaffold with a JNK signaling pathway member (a JIP protein for example); and (vi) a DNA or RNA encoding a JNK signaling pathway member protein. A JNK signaling pathway member is MAPK8IP3 / JIP3 in certain embodiments.

[0929] MAPK8IP3 / JIP3

[0930] The term “MAPK8IP3 / JIP3” collectively refers to MAPK8IP3 nucleic acid, including genomic chromosome, pre-mRNA and mRNA nucleic acid, and encoded JIP3 protein. When referring to a nucleic acid, the term “MAPK8IP3 / JIP3” ty pically refers to a PATENT

[0931] 7328.158159PCT / NLM-1002-PC modified (for example, mutant) or wild-type MAPK8IP3 nucleic acid. When referring to a protein, the term “MAPK8IP3 / JIP3” typically refers to a modified (for example, mutant) or wild-type JIP3 protein. The term “MAPK8IP3 / JIP3’' typically refers to MAPK8IP3 nucleic acid and JIP3 protein, or MAPK8IP3 nucleic acid or JIP3 protein. The term ‘MAPK8IP3 / JIP3” can refer to MAPK8IP3 nucleic acid and JIP3 protein, or MAPK8IP3 nucleic acid or JIP3 protein, in the context of reducing MAPK8IP3 / JIP3 expression or treating a MAPK8IP3 / JIP3-associated medical condition, for example. A “MAPK8IP3 / JIP3 allele” typically refers to a MAPK8IP3 nucleic acid allele. An oligomeric compound typically is targeted to a MAPK81P3 nucleic acid, and can reduce expression of a MAPK8IP3 nucleic acid and / or JIP3 protein.

[0932] In certain embodiments, a MAPK8IP3 / JIP3 is a human MAPK8IP3 / JIP3, and can be a human mutant MAPK8IP3 / JIP3 or human wild-type MAPK8IP3 / JIP3 nucleic acid (RNA for example) or protein. Human MAPK8IP3 / JIP3 genomic nucleic acid is located on human chromosome 16 and starts on chromosome 16 position 1706166 and ends on chromosome 16 position 1770351. Table A provides access information for a representative human MAPK8IP3 / JIP3 chromosome genomic reference sequence (SEQ ID NO: 1 herein), representative human MAPK8IP3 / JIP3 complementary DNA (cDNA) sequence (SEQ ID NO:2 herein) and representative human MAPK8IP3 / JIP3 protein sequence (SEQ ID NO:39). A representative MAPK8IP3 / JIP3 coding sequence (CDS) is provided as SEQ ID NO:38 herein. Table A also provides access information for representative human JIP4 nucleic acid and protein sequences. Each MAPK8IP3 / JIP3 and JIP4 sequence can be accessed at World Wide Web address URL useast.ensembl.org, and each is according to the Ensembl vll2 release and GRCh38.pl4 genome assembly.

[0933] Table A: MAPK8IP3 / JIP3 and JIP4 sequences PATENT

[0934] 7328.158159PCT / NLM-1002-PC

[0935] Table B provides boundaries for certain introns within the MAPK8IP3 reference genomic sequence. The second column and third column provide the chromosome 16 start and end position, respectively, within the MAPK8IP3 genomic nucleic acid for each intron defined in the first column. The fourth column and fifth column provide the start and end position, respectively, of each intron within SEQ ID NO: 1, that corresponds to the chromosome 16 position provided in the second column and third column, respectively. The sixth column of Table B provides a designation for a pathogenic genetic variation site in MAPK8IP3 exon 16, which is described in greater detail herein. The sixth column of Table B also provides designations for non- pathogenic genetic variation sites within MAPK8IP3 introns 1 and 8 and exons 31 and 32 targeted by certain oligomeric compounds described herein (in Example 4 for example). The genetic variation site designations in the sixth column of Table B are according to World Wide Web Address URL ncbi.nlm.nih.gov / snp / .

[0936] Table B: Boundaries for certain MAPK8IP3 / JIP3 introns and exons PATENT

[0937] 7328.158159PCT / NLM-1002-PC

[0938] * chromosome 16 start position and end position for each listed MAPK8IP3 / JIP3 intron and exon

[0939] ** start position and end position in SEQ ID NO: 1 (SID1) corresponding to chromosome 16 start position and end position in preceding columns

[0940] In certain embodiments, a composition comprises a c-Jun N-terminal kinase (JNK) signaling pathway inhibitor. In certain embodiments, a JNK inhibitor can inhibit a protein participating in the JNK signaling pathway, and in certain embodiments, a JNK inhibitor can reduce expression of a protein participating in the JNK signaling pathway. In certain embodiments, a JNK inhibitor is an oligomeric compound containing an oligonucleotide complementary to a nucleic acid encoding a protein participating in the JNK signaling pathway that is capable of reducing expression of the protein. In certain embodiments, a JNK signaling pathway inhibitor is used in a method for inhibiting cell degeneration. In certain embodiments, a method includes administering a composition comprising a JNK signaling pathway inhibitor to cells in an amount effective to inhibit the cell degeneration. In certain embodiments, a JNK signaling pathway inhibitor is a MAPK8IP3 / JIP3 inhibitor.

[0941] In certain embodiments, a composition comprises an inhibitor of a MAPK8IP3 / JIP3 nucleic acid or MAPK8IP3 / JIP3 protein. In certain embodiments, an inhibitor reduces expression of a MAPK8IP3 / JIP3 nucleic acid or protein, and in certain embodiments, the inhibitor can reduce expression of the MAPK8IP3 / JIP3 nucleic acid or protein in a cell in vitro or in vivo. In certain embodiments, an inhibitor is an oligomeric compound comprising an oligonucleotide complementary to portion of a MAPK8IP3 / JIP3 nucleic acid. In certain embodiments, a MAPK8IP3 / JIP3 nucleic acid is a mutant MAPK8IP3 / JIP3 nucleic acid or a wild t pe MAPK8IP3 / JIP3 nucleic acid, and in certain embodiments, a MAPK8IP3 / JIP3 protein is a mutant MAPK8IP3 / JIP3 protein or wild-ty pe MAPK8IP3 / JIP3 protein.

[0942] In certain embodiments, a mutant MAPK8IP3 / JIP3 nucleic acid or mutant MAPK8IP3 / JIP3 protein contains a pathogenic genetic variant at a pathogenic variation site, such as a pathogenic genetic variant described herein for example. In PATENT

[0943] 7328.158159PCT / NLM-1002-PC certain embodiments, the pathogenic genetic variant is associated with a gain of function phenotype or toxic gain of function phenotype.

[0944] In certain embodiments, the pathogenic genetic variant is associated with one or more phenotypes chosen from: increased cell degeneration; reduced cell proliferation; activation of the JNK signaling pathway; enhanced pro-apoptotic signaling via JNK; modification of MAPK81P3 / J1P3 binding partner interactions; increased MAPK8IP3 / JIP3 expression; reduced JIP4 expression; altered MAPK8IP3 / JIP3 subcellular localization; reduced MAPK8IP3 / JIP3 binding affinity to JIP4; reduced MAPK8IP3 / JIP3 / JIP4 heterodimer formation; increased MAPK8IP3 / JIP3 binding affinity to KIF5b; decreased axon trafficking; decreased endosome mobility along microtubules in axons; decreased late endosome mobility along microtubules in axons; and decreased dopamine receptor 1 (DI) signaling. In certain embodiments, the phenotype is in neuronal cell(s) or fibroblast cell(s). In certain embodiments, the pathogenic genetic variant is not associated with one or both phenotypes chosen from: decreased dopamine receptor 2 (D2) signaling and decreased lysosomal mobility along microtubules in axons. Each of the foregoing phenoty pes can be determined by an applicable method provided in Example 2 and / or Example 3 herein. In certain embodiments, each phenotype is relative to cells containing the wild-type MAPK8IP3 / JIP3 nucleic acid and / or wild-type MAPK8IP3 / JIP3 protein, and not containing a mutant MAPK8IP3 / JIP3 nucleic acid and / or MAPK8IP3 / JIP3 protein containing a pathogenic genetic variant (cells homozy gous for the wild-type MAPK8IP3 / JIP3 allele for example).

[0945] In certain embodiments, a target region in a MAPK8IP3 / JIP3 nucleic acid to which an oligomeric compound is targeted is 100% identical to an equal length portion in a MAPK8IP3 / JIP3 reference genomic sequence (SEQ ID NO: 1) or MAPK8IP3 / JIP3 CDS sequence (SEQ ID NO:38). In certain embodiments, a MAPK8IP3 / JIP3 target region to which an oligomeric compound is targeted is at least 80% identical to, or at least 85% identical to, or at least 90% identical to. or at least 95% identical to, an equal length portion in the MAPK8IP3 / JIP3 reference genomic sequence (SEQ ID NO: 1) or MAPK8IP3 / JIP3 CDS sequence (SEQ ID NO:38). In certain embodiments, a target region to which an oligomeric compound is targeted is identical to an equal length portion in the MAPK8IP3 / JIP3 reference genomic sequence (SEQ ID NO: 1) or MAPK8IP3 / JIP3 CDS sequence (SEQ ID NO:38) except for a one-nucleobase PATENT

[0946] 7328.158159PCT / NLM-1002-PC mismatch. In certain embodiments, an oligomeric compound oligonucleotide comprises or consists of a nucleobase sequence that is 100% complementary to the target region.

[0947] In certain embodiments, (i) a target region to which an oligomeric compound is targeted is 100%, or in certain embodiments is at least 85% identical to, or at least 90% identical to. or at least 95% identical to, an equal length portion in a MAPK8IP3 / JIP3 allele nucleic acid, and (ii) the oligonucleotide of the oligomeric compound is 100% complementary to the target region. In certain embodiments, a mutant MAPK8IP3 / JIP3 allele is targeted that comprises a pathogenic genetic variant associated with a medical condition. In certain embodiments, the medical condition is a MAPK8IP3 / JIP3 -associated medical condition. In certain instances, a pathogenic genetic variation is a single nucleotide variation (SNV) at a pathogenic genetic variation position, and sometimes is a non-synonymous SNV located in an exon of a mutant MAPK8IP3 / JIP3 nucleic acid.

[0948] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 allelic variant containing pathogenic genetic variant. In certain embodiments, the equal length portion comprises a genetic variation site, which often is a not a pathogenic genetic variation site. In certain embodiments, the equal length portion comprises a pathogenic genetic variation site. In certain embodiments, the oligomeric compound is allele selective, and selectively inhibits expression of a mutant MAPK.8IP3 / JIP3 allelic variant.

[0949] In certain embodiments, a pathogenic genetic variant in a mutant MAPK8IP3 / JIP nucleic acid is in an exon. In certain embodiments, a pathogenic genetic variant in a mutant MAPK8IP3 / JIP nucleic acid is in exon 16. In certain embodiments, a mutant MAPK8IP3 / JIP3 nucleic acid contains pathogenic genetic variant that encodes or is a c. 1735OT pathogenic genetic variant and / or a genetic variant resulting in a p.Arg579Cys variant in a MAPK8IP3 / JIP3 protein. In certain embodiments, a mutant MAPK8IP3 / JIP3 protein contains a pathogenic genetic variant that encodes or is p.Arg579Cys variant. A c. l735C>T pathogenic genetic variant ty pically is at a position corresponding to chromosome position Chrl6: 1762843 and / or position 56678 in SEQ ID NO: 1, a wild-type allele typically includes a cytosine (C) at the PATENT

[0950] 7328.158159PCT / NLM-1002-PC position, and a mutant allele typically includes a thymine (T) or uracil (U) at this position.

[0951] Additional information concerning the C.1735OT pathogenic genetic variation site and position is provided in Example 4. The c. 1735OT pathogenic genetic variant and other pathogenic genetic variants in the canonical MAPK8IP3 / JIP transcript are provided with corresponding positions in other MAPK8IP3 / J1P isoforms in Table C. The first column provides a reference for the pathogenic genetic variant in the database located at World Wide Web Address URL ncbi.nlm.nih.gov / snp / . The second column provides the corresponding chromosome 16 position of the pathogenic genetic variant in genomic nucleic acid (World Wide Web address URL useast.ensembl.org, according to the Ensembl vl 12 release and GRCh38.pl4 genome assembly), and the third column provides the corresponding position of the pathogenic genetic variant in the reference MAPK8IP3 / JIP nucleic acid sequence of SEQ ID NO: 1. In Table C, (i) entries in columns 7-9 are for proteins translated from the transcripts referenced in columns 4-6, respectively, (ii) the transcripts referenced in columns 4-6 are for different MAPK8IP3 / JIP3 isoforms, and (iii) the entries in columns 4-9 are from the same genome release (World Wide Web address URL useast.ensembl.org, according to the Ensembl v!12 release and GRCh38.pl4 genome assembly). The fourth column of Table C provides pathogenic genetic variants in the MAPK8IP3 / JIP canonical transcript. The c. 1735OT pathogenic genetic variant in the canonical transcript corresponds to C.1732OT in the transcript designated in the fifth column of Table C and corresponds to c,1714C>T in the transcript designated in the sixth column of Table C. The seventh column of Table C designates the protein translated from the canonical transcript and the p.Arg579Cys variant therein corresponds to the p.Arg578Cys variant in the protein isoform designated in the eighth column of Table C. The C.3436OT and c. 1331T>C variants in the transcript provided in the fifth column of Table C correspond to the C.3439OT and c. 1334T>C variants, respectively, in the canonical transcript designated in the fourth column of Table C. The c. 1544G>A variant in the transcript designated in the sixth column of Table C corresponds to the c. 1565G>A variant in the canonical transcript designated in the fourth column of Table C. PATENT

[0952] 7328.158159PCT / NLM- 1002-PC

[0953] Table C: Pathogenic variants

[0954] PATENT

[0955] 7328.158159PCT / NLM-1002-PC

[0956] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant in exon 16, a pathogenic genetic variant at a rs 1567203083 polymorphic site, optionally a pathogenic genetic variant at chromosome 16 position 1762843, optionally a pathogenic genetic variant at position 56678 of SEQ ID NO: 1, optionally a C.1735OT pathogenic genetic variant, optionally a C.1732OT pathogenic genetic variant, optionally a c. 1714OT pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p. Arg579Cys substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p. Arg578Cys substitution in a JIP3 protein or optionally a pathogenic genetic variant encoding a p.Arg572Cys amino acid substitution in a JIP3 protein.

[0957] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at chromosome 16 position 1706620, optionally a pathogenic genetic variant at position 455 of SEQ ID NO: 1, optionally a c.281A>G pathogenic genetic variant, or optionally a pathogenic genetic variant encoding a p.Tyr94Cys amino acid substitution in a JIP3 protein.

[0958] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at a rs770703007 polymorphic site, optionally a pathogenic genetic variant at chromosome 16 position 1706450, optionally a pathogenic genetic variant at position 285 of SEQ ID NO:1, optionally a c. ll lOG pathogenic genetic variant, or optionally a pathogenic genetic variant encoding a p.Tyr37Ter modification of a JIP3 protein, where ‘‘Ter” is a termination (stop) codon (TGA, TAG or TAA for example).

[0959] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at a rsl567128142 polymorphic site, optionally a pathogenic genetic variant at chromosome 16 position 1706404, optionally a pathogenic genetic variant at position 239 of SEQ ID NO: 1, optionally a c.65del pathogenic genetic variant, or optionally a pathogenic genetic variant encoding a p.Gly22AlafsTer3 modification a JIP3 protein. For the term “AlafsTer3,” “Ala” PATENT

[0960] 7328.158159PCT / NLM-1002-PC signifies that the first affected amino acid in the protein sequence is alanine, ‘"fs” signifies a frameshift mutation, and “Ter3” signifies the premature termination of protein translation after the incorporation of three amino acids within the new reading frame generated by the frameshift, according to Human Genome Variation Society (HGVS) nomenclature.

[0961] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at a rsl567214097 polymorphic site, optionally a pathogenic genetic variant at chromosome 16 position 1767834, optionally a pathogenic genetic variant at position 61669 of SEQ ID NO: 1, optionally a C.3439OT pathogenic genetic variant, optionally a C.3436OT pathogenic genetic variant, optionally a C.3418OT pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p.Argll47Cys substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p. Argl 146Cys substitution in a JIP3 protein, or optionally a pathogenic genetic variant encoding a p.Argl 140Cys amino acid substitution in a JIP3 protein.

[0962] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at a rs 1567198751 polymorphic site, optionally a pathogenic genetic variant at chromosome 16 position 1760409, optionally a pathogenic genetic variant at position 54244 of SEQ ID NO: 1, optionally a c,1334T>C pathogenic genetic variant, optionally a c, 1331T>C pathogenic genetic variant, optionally a C.1313T>C pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p.Leu445Pro substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p.Leu444Pro substitution in a JIP3 protein, or optionally a pathogenic genetic variant encoding a p.Leu438Pro amino acid substitution in a JIP3 protein.

[0963] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at chromosome 16 position 1762376, optionally a pathogenic genetic variant at position 56211 of SEQ ID NO: 1, optionally a c.1565G>A pathogenic genetic variant, optionally a c.1562G>A pathogenic genetic PATENT

[0964] 7328.158159PCT / NLM-1002-PC variant, optionally a c. 1544G>A pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p.Arg522His substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p.Arg521His substitution in a JIP3 protein, or optionally a pathogenic genetic variant encoding a p.Arg515His amino acid substitution in a JIP3 protein.

[0965] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at chromosome 16 position 1765960, optionally a pathogenic genetic variant at position 59795 of SEQ ID NO: 1, optionally a C.2447OA pathogenic genetic variant, optionally a C.2444OA pathogenic genetic variant, optionally a C.2426OA pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p.Ala816Glu substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p.Ala815Glu substitution in a JIP3 protein, or optionally a pathogenic genetic variant encoding a p. Ala809Glu amino acid substitution in a JIP3 protein.

[0966] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising: a pathogenic genetic variant at chromosome 16 position 1760439, optionally a pathogenic genetic variant at position 54274 of SEQ ID NO: 1, optionally a c. 1364A>G pathogenic genetic variant, optionally a c. 1361A>G pathogenic genetic variant, optionally a c. 1343A>G pathogenic genetic variant, optionally a pathogenic genetic variant encoding a p.Glu455Gly substitution in a JIP3 protein, optionally a pathogenic genetic variant encoding a p.Glu454Gly substitution in a JIP3 protein, or optionally a pathogenic genetic variant encoding a p.Glu448Gly amino acid substitution in a JIP3 protein.

[0967] In certain embodiments, an oligomeric compound oligonucleotide is complementary to an equal length portion of a mutant MAPK8IP3 / JIP3 nucleic acid comprising a pathogenetic variant:

[0968] (i) is at a rs!567203083, rs770703007, rs!567128142, rs!567214097 or rs!567198751 pathogenic genetic variation site; or

[0969] (ii) is at a rs!567203083 pathogenic genetic variation site; or PATENT 7328.158159PCT / NLM-1002-PC

[0970] (iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argll47Cys, p.Argll46Cys, p.Argll40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515His, p.Ala816Glu, р.Ala815Glu, p.Ala809Glu, p.Glu455Gly. p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or

[0971] (iv) encodes a p.Arg579Cys, p. Arg578Cys or p.Arg572Cys amino acid substitution; or

[0972] (v) encodes a p.Arg579Cys amino acid substitution; or

[0973] (vi) encodes or is C.1735OT, C.1732OT. C.1714OT, c.281A>G, c.lllOG, c.65del. C.3439OT, C.3436OT, C.3418OT, c,1334T>C, c,1331T>C, c,1313T>C, с,1565G>A, c.!562G>A, c,1544G>A, C.2447OA, C.2444OA, C.2426OA, c.!364A>G, c.1361A>G or c,1343A>G: or

[0974] (vii) encodes or is c.1735OT. C.1732OT or c.1714OT; or

[0975] (viii) encodes or is c.1735OT

[0976] In certain embodiments, an oligomeric compound oligonucleotide is 100% complementary to a portion of a mutant MAPK8IP3 / JIP3 nucleic acid containing the pathogenic genetic variation position. In certain embodiments, an oligomeric compound oligonucleotide is 100% complementary to a portion of a mutant MAPK8IP3 / JIP3 nucleic acid containing a pathogenic genetic variant that encodes or is the C.1735OT genetic variant, which can be in SEQ ID NO:38 for example. In certain embodiments, an oligomeric compound oligonucleotide is complementary to a portion of a MAPK8IP3 / JIP3 nucleic acid not containing the pathogenic genetic variation position.

[0977] In certain embodiments, an inhibitor is capable of eliciting one or more of the following activities (cellular activities for example) after in vitro or in vivo administration: reducing cell toxicity; increasing cell proliferation; reducing cell death; reducing cell apoptosis; increasing cell proliferation; and reducing activation of the JNK signaling pathway. In certain embodiments, the cell toxicity, cell proliferation, cell death, cell apoptosis and / or cell proliferation is of neuronal cell(s) or fibroblast cell(s). In certain embodiments, an inhibitor is capable of reducing JIP4 expression less than reducing MAPK8IP3 / JIP3 expression or not reducing JIP4 expression. In certain embodiments, an inhibitor is capable of one or more of the following activities: increasing axon trafficking; increasing endosome mobility along PATENT

[0978] 7328.158159PCT / NLM-1002-PC microtubules in axons; increasing late endosome mobility along microtubules in axons; and increasing dopamine receptor 1 (DI) signaling. Each of the foregoing activities can be assessed by an applicable method described in Example 1, Example 2 and / or Example 3 herein.

[0979] In certain embodiments, oligomeric compounds reduce MAPK8IP3 / JIP3 expression. In certam embodiments, an oligomeric compound comprises or consists of an oligonucleotide comprising a region that is complementary to a target region in a MAPK8IP3 / JIP3 nucleic acid, and thereby targets the MAPK8IP3 / JIP3 nucleic acid.

[0980] In certain embodiments, contacting a ceh with an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid target region reduces the amount of MAPK8IP3 / JIP3 RNA, and in certain embodiments reduces the amount of MAPK8IP3 / JIP3 protein. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide and a conjugate group.

[0981] In certain embodiments, contacting a cell with an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid target region reduces the amount of MAPK8IP3 / JIP3 RNA in a cell. In certain embodiments, contacting a cell with an oligomeric compound targeted to a MAPK8IP3 / J1P3 nucleic acid target region reduces the amount of MAPK8IP3 / JIP3 protein in the cell In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in a subject. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certam embodiments, contacting a ceil in a subject with an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid target region ameliorates one or more symptoms or hallmarks of a MAPK8IP3 / JIP3 -associated medical condition In certain embodiments, the medical condition is a MAPK8IP3 / JIP3-associated medical condition, a neurological medical condition. MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3- associated neurodegenerative medical condition, Parkinson’ s-like disease, Parkinson’s disease and / or microencephaly. In certain embodiments, the medical condition is neurodevelopmental disorder with or without variable brain abnormalities (NEDBA), which can be assessed according to the Gross Motor Function Classification System, and which can be according to a level (Level 1 to Level 4 for example). PATENT

[0982] 7328.158159PCT / NLM-1002-PC

[0983] In certain embodiments, an oligomeric compound targeted to a MAPK8IP3 / JIP3 nudeic acid target region is capable of reducing the amount of MAPK8IP3 / JIP3 RNA in vitro by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. at least 70%, at least 80%, or at least 90% when administered according to the standard in vitro assay. In certain embodiments, an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid target region is capable of reducing the amount of MAPK.8IP3 / JIP3 RNA in vivo by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. at least 70%, at least 80%, or at least 90% when administered according to a standard in vivo assay. In certain embodiments, an oligomeric compound targeted to a MAPK8IP3 / JIP3 nucleic acid target region ...

Claims

PATENT7328.158159PCT / NLM-1002-PCWHAT TS CLAIMED IS:

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides, wherein: the modified oligonucleotide comprises or consists of a nucleobase sequence that is at least 80% complementary to an equal length portion of a genetic variation site of a MAPK81P3 / J1P3 nucleic acid; the equal length portion of the genetic variation site contains a differentiating genetic variation; and the modified oligonucleotide comprises a modified nucleoside, or a modified intemucleoside linkage, or a modified nucleoside and a modified intemucleoside linkage.

2. The oligomeric compound of embodiment A20. which is capable of selectively reducing expression of a MAPK8IP3 / JIP3 allelic variant.

3. The oligomeric compound of claim 1 or claim 2, wherein: the genetic variation site comprises a substitution, deletion or insertion, or optionally the genetic variation site is a single nucleotide variation site, or optionally wherein the single nucleotide variation site comprises a synonymous single nucleotide variation.

4. The oligomeric compound of claim 3, wherein: the genetic variation site comprises a genetic variation position and the modified oligonucleotide comprises at least one nucleoside aligned with the genetic variation position; or optionally the single nucleotide variation site comprises a single nucleotide variation position and the modified oligonucleotide comprises a nucleoside aligned with the single nucleotide variation position.

5. The oligomeric compound of claim 4, wherein: the modified oligonucleotide comprises at least one nucleoside aligned with and complementary to a first nucleoside at the genetic variation position of a first MAPK8IP3 / JIP3 allelic variant and not complementary to a second nucleoside at the genetic variation position of a second MAPK8IP3 / JIP3 allelic variant; or optionally the modified oligonucleotide comprises a nucleoside aligned with and complementary to a first nucleoside at the single nucleotide variation position of a first MAPK8IP3 / JIP3 allelic variant and notPATENT7328.158159PCT / NLM-1002-PC complementary to a second nucleoside at the single nucleotide variation position of a second MAPK8IP3 / JIP3 allelic variant.

6. The oligomeric compound of claim 5, wherein: the modified oligonucleotide is capable of selectively reducing expression of the first MAPK8IP3 / JIP3 allelic variant by at least 2-fold compared to expression of the second MAPK81P3 / JIP3 allelic variant; or optionally the oligomeric compound selectively reduces expression of the first MAPK8IP3 / JIP3 allelic variant according to a selectivity ratio of at least 2 or greater than 2; or optionally the selectivity ratio is (i) inhibition of expression of the secondMAPK8IP3 / JIP3 allelic variant to (ii) inhibition of expression of the firstMAPK8IP3 / JIP3 allelic variant; or optionally the inhibition of expression of the second SCN2A allelic variant is an IC50 value and the inhibition of expression of the first SCN2A allelic variant is an IC50 value.

7. The oligomeric compound of claim 5 or 6, wherein: the modified oligonucleotide consists of 10-30 linked nucleosides and the nucleoside at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with a nucleoside in the genetic variation position, or optionally aligns with the single nucleotide variation position; or the modified oligonucleotide consists of 18-22 linked nucleosides, or optionally 20 linked nucleosides, and the nucleoside at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 of the modified oligonucleotide, as counted from the 5' terminus of the modified oligonucleotide, aligns with a nucleoside in the genetic variation position.

8. The oligomeric compound of any one of claims 5-7, wherein the modified oligonucleotide consists of 18-22 linked nucleosides, or optionally 20 linked nucleosides, and comprises: a 5'-region consisting of linked 5’-region nucleosides; a central region consisting of linked central region nucleosides; a 3’-region consisting of linked 3’-region nucleosides;PATENT 7328.158159PCT / NLM-1002-PC the central region comprises a 5’ terminus; and the nucleoside at position 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the central region, as counted from the 5' terminus of the central region, aligns with a nucleoside in the genetic variation position.

9. The oligomeric compound of any one of claims 1-8, wherein the modified oligonucleotide comprises or consists of anucleobase sequence containing at least 8. at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site in: (i) a MAPK8IP3 / JIP3 intron, optionally wherein the intron is chosen from intron 1 or intron 8, or optionally wherein the intron is intron 1; or (ii) a MAPK8IP3 / JIP3 exon, optionally wherein the exon is exon 31 or exon 32.

10. The oligomeric compound of any one of claims 1-9, wherein the modified oligonucleotide comprises or consists of a nucleobase sequence containing at least 8, at least 9. at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site chosen from:(i) rsl7135499. rsl7135500, rsl2922553, rsl 1860323, rsl 1865685, rs35988159, rs34950492, rsl2930313, rsl2925525. rs8063431, rs9788926, rs2076431 or rs2575329; or(ii) rsl7135499, rsl7135500, rs34950492, rs35988159, rs9788926, rs2076431 or rs2575329; or(iii) rs34950492 and rs35988159; or(iv) rs 17135500.

11. The oligomeric compound of any one of claims 1-10, wherein the modified oligonucleotide comprises or consists of anucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site comprising:PATENT7328.158159PCT / NLM-1002-PC(i) a chromosome 16 position chosen from: chrl6:1709793, chrl6: 1709852, chrl 6: 1710090, chrl6:1714342, chrl6: 1714343, chrl 6: 1714886, chrl6: 1714898, chrl6: 1715231, chrl6: 1723913, chrl6: 1754356, chrl 6: 1757779, chrl6: 1768502 or chrl 6: 1769432; or(ii) a position in SEQ ID NO: 1 chosen from position: 3628, 3687, 3925, 8177, 8178, 8721, 8733, 9066, 17748, 48191, 51614, 62337 or 63267 ; or(iii) chromosome 16 position chrl 6: 1709852; or(iv) SEQ ID NO: 1 position 3687.

12. The oligomeric compound of any one of claims 1-11, wherein the modified oligonucleotide comprises or consists of anucleobase sequence containing at least 8. at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases within a MAPK8IP3 / JIP3 nucleic acid genetic variation site chosen from:(i) a nucleobase sequence of one of SEQ ID NO:90 to SEQ ID NO: 102; or(ii) a nucleobase sequence of SEQ ID NO:91; or(iii) a nucleobase sequence of one of SEQ ID NO: 103 to SEQ ID NO: 108; or(iv) a nucleobase sequence of SEQ ID NO: 104; or(v) a nucleobase sequence of one of SEQ ID NO:65 to SEQ ID NO:89; or(vi) anucleobase sequence of SEQ ID NO:65.

13. The oligomeric compound of any one of claims 1-12, wherein the modified oligonucleotide comprises or consists of anucleobase sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of contiguous nucleobases within: intron 1; chromosome 16 positions 1706658-1724556; positions 493-18391 of SEQ ID NO: 1 ; rsl7135500 genetic variation site; chromosome 16 positions 1709822-1709882; positions 3657- 3717 of SEQ ID NO:1; nucleobase sequence of SEQ ID NO:91; chromosome 16 positions 1709840-1709865; positions 3675-3700 of SEQ ID NO: 1; nucleobase sequence of SEQ ID NO: 104; nucleobase sequence of SEQ ID NO:77, SEQ ID NO:76, SEQ ID NO:65 or SEQ ID NO:79; or nucleobase sequence of SEQ ID NO:65.PATENT 7328.I58I59PCT / NLM-I002-PC14. The oligomeric compound of any one of claims 1-13, wherein the modified oligonucleotide comprises or consists of 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleobases of:(i) SEQ ID NO:40 to SEQ ID NO:64; or(ii) SEQ ID NO:40; or(iii) SEQ ID NO:53 or SEQ ID NO:49; or(iv) SEQ ID NO:52, SEQ ID NO:51, SEQ ID NO 40 or SEQ ID NO:54; or(v) SEQ ID NO:44, SEQ ID NO 53, SEQ ID NO:56, SEQ ID NO:

47. SEQ ID NO:57, SEQ ID NO:43, SEQ ID NO:58 or SEQ ID NO:55; or(vi) SEQ ID NO:61 or SEQ ID NO:45; or(vii) SEQ ID NO:50 or SEQ ID NO:46; or(viii) SEQ ID NO:62 or SEQ ID NO:64.

15. The oligomeric compound of any one of claims 1-14, the modified oligonucleotide comprises or consists of anucleobase sequence that is at least 85% complementary to, or at least 90% complementary to, or at least 95% complementary, or is 100% complementary7to, an equal length portion of the genetic variation site.

16. The oligomeric compound of any of claims 1-14, wherein the modified oligonucleotide consists of 12 to 20, 12 to 25, 12 to 30, 13 to 20, 13 to 25, 13 to 30, 14 to 20, 14 to 25, 14 to 30, 15 to 20, 15 to 25, 15 to 30. 16 to 18, 16 to 20, 16 to 25, 16 to 30, 17 to 20, 17 to 25, 17 to 30, 18 to 20, 18 to 25. 18 to 30. 19 to 20, 19 to 25, 19 to 30, 20 to 25, 20 to 30 linked nucleosides; or consists of 18-22 linked nucleosides, 19-21 linked nucleosides or 20 linked nucleosides.

17. The oligomeric compound of any one of claims 2-15, wherein: the MAPK8IP3 / JIP3 allelic variant is a mutant MAPK8IP3 / JIP3 allelic variant associated with a medical condition; optionally the mutant MAPK8IP3 / JIP3 allelic variant comprises a pathogenic genetic variant associated with a medical condition; and optionally the medical condition is a MAPK8IP3 / JIP3-associated medical condition, which optionally is a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’s-like disease, Parkinson’sPATENT 7328.158159PCT / NLM-1002-PC disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

18. The oligomeric compound of claim 17, wherein: the pathogenic genetic variant is associated with anon-loss of function phenotype; or optionally the non-loss of function phenotype is a dominant negative phenotype, a gain of function phenotype or toxic gain of function phenoty pe.

19. The oligomeric compound of claim 17 or 18, wherein the pathogenic genetic variant:(i) is at a rsl567203083, rs770703007, rsl567128142, rsl567214097 or rs 1567198751 pathogenic genetic variation site; or(ii) is at a rsl567203083 pathogenic genetic variation site; or(iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argll47Cys, p.Argll46Cys, p.Argll40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His, p.Arg521His, p.Arg515I4is, p.Ala816Glu, р.Ala815Glu, p.Ala809Glu, p.Glu455Gly. p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or(iv) encodes a p.Arg579Cys, p. Arg578Cys or p.Arg572Cys amino acid substitution; or(v) encodes a p.Arg579Cys amino acid substitution; or(vi) encodes or is C.1735OT, C.1732OT, C.1714OT, c.281A>G, c. lllOG, c.65del, C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c,1331T>C, c,1313T>C,С.1565G>A, C.1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c,1364A>G, c, 1361A>G or c, 1343A>G: or(vii) encodes or is c. 1735OT. C.1732OT or c. 1714OT; or(viii) encodes or is c. 1735OT.

20. The oligomeric compound of any one of claims 17-19, wherein: the equal length portion of the genetic variation site contains the pathogenic genetic variation position, or contains the pathogenic genetic variation site or portion thereof: orPATENT 7328.158159PCT / NLM-1002-PC the equal length portion of the genetic variation site does not contain the pathogenic genetic variation position, or does not contain the pathogenic genetic variation site or portion thereof.

21. The oligomeric compound of any one of claims 1-20, wherein: the modified oligonucleotide comprises at least one modified intemucleoside linkage; or optionally the at least one modified intemucleoside linkage is a phosphorothioate intemucleoside linkage.

22. The oligomeric compound of claim 21, wherein the modified oligonucleotide comprises an intemucleoside linkage motif (from 5' to 3’) selected from sososssssssssssooss, sooosssssssssssooss and soooossssssssssooss, wherein eachL‘s” represents a phosphorothioate intemucleoside linkage and each “o” represents a phosphodiester intemucleoside linkage, and optionally each “s” represents a (S)- phosphorothioate intemucleoside linkage.

23. The oligomeric compound of any one of claims 1-22, wherein: the modified oligonucleotide comprises at least one modified nucleoside; or optionally the at least one modified nucleoside comprises a modified sugar; or optionally the at least one modified nucleoside is a 2’ -substituted sugar moiety; or optionally the 2’-substitued sugar moiety is a 2'-MOE sugar moiety.

24. The oligomeric compound of claim 23, wherein the modified oligonucleotide comprises a sugar motif of 5’-eeeeeddddddddddeeeee-3’, wherein each "d " represents a 2'-beta-D-deoxyribosyl sugar moiety, each “e'’ represents a 2 -MOE sugar moiety.

25. The oligomeric compound of any one of claims claim 21-24, wherein the modified oligonucleotide: (i) consists of 20 linked nucleosides; (ii) consists of a sugar motif (from 5' to 3'): eeeeeddddddddddeeeee, wherein each "e" represents a 2' -MOE ribosyl sugar moiety, and each "d" represents a 2’-deoxyribosyl sugar moiety; (iii) consists of a nucleoside linkage motif (from 5' to 3 '): soooossssssssssooss, wherein each "s" represents a (S)-phosphorothioate intemucleoside linkage, and each "o" represents a phosphodiester intemucleoside linkage; and (iv) each “C” nucleoside is a 5-methylcytosine.PATENT 7328.158159PCT / NLM-1002-PC26. The oligomeric compound of any one of claims 1-25, wherein the modified oligonucleotide comprises: a 5'-region consisting of 1-6 linked 5’-region nucleosides: a central region consisting of 6-10 linked central region nucleosides; and a 3’-region consisting of 1-6 linked 3’-region nucleosides; wherein: each of the 5 ’-region nucleosides and each of the 3 ’-region nucleosides comprises a modified sugar moiety , and three or more of the central region nucleosides comprise a 2’ -beta-D-deoxy ribosyl sugar moiety.

27. The oligomeric compound of any one of claims 1-26, wherein the modified oligonucleotide comprises: a 5’-region consisting of 5 linked 5’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3’-region consisting of 5 linked 3’-region nucleosides; wherein: each of the 5 ’-region nucleosides and each of the 3 ’-region nucleosides comprises a modified sugar moiety, and three or more of the central region nucleosides comprise a 2’-beta-deoxyribosyl sugar moiety.

28. The oligomeric compound of any one of claims 1-27, comprising or consisting of:5'-A-mC-mU-A-A-T-A-T-T-mC-A-mC-A-T-G-mU-mC-A-mU-mC-3' (SEO ID NO: 116) , wherein: “m” is methyl; each of the underlined nucleosides is a modified nucleoside comprising a 2’- MOE sugar moiety; optionally each of the nucleosides not underlined comprises a 2’-beta-deoxyribosyl sugar moiety; optionally each mil is a 5-methyluridine; or optionally each mC is a 5 -methylcytidine.

29. The oligomeric compound of any one of claims 1-28, comprising or consisting of (SEQ ID NO: 117):2'-0-(2-methoxyethyl)-adenosine-(3'-0-2'-0-(2-methoxyethyl)-5-methylcytidine-( 2'-0-(2-methoxyethyl)-5-methyluridine-(3 2'-0-(2-methoxyethyl)-adenosine-(3'-0- 2'-0-(2-methoxyethyl)-adenosine-(3'-0-2 -0-(2-deoxy)-thymidine-(3'-0^5'-0)- 2 -0-(2-deoxy)-adenosine-(3'-0->5'-0)-PATENT7328.158159PCT / NLM- 1002-PC2'-0-(2-deoxy)-thymidine-(3'-0^5'-0)-2 -0-(2-deoxy)-thymidine-(3'-0^5'-0)-2 -0-(2-deoxy)-5-methylcytidine -(3'-O-»5'-O)-2 -0-(2-deoxy)-adenosine-(3'-0->5'-0)- 2'-0-(2-deoxy)-5-methylcytidine -(3'-O->5'-O)-2'-0-(2-deoxy)-adenosine-(3'-0->5'-0)-2'-0-(2-deoxy)-thymidine-(3'-0^5'-0)-2 -0-(2-deoxy)-guanosine-(3'-0— >5'-O)2 -0-(2-methoxyethyl)-5-methyluridine- 2'-O-(2-methoxyethyl)-5-methylcytidine )-2 -0-(2-methoxyethyl)-adenosine-(3'-02 -0-(2-methoxyethyl)-5-methyluridine-2'-0-(2-methoxyethyl)-5-methylcytidine)-nonadecasodium salt (SEQ ID NO:117).

30. The oligomeric compound of any one of claims 1-29, comprising or consisting of:

31. A composition, comprising an oligomeric compound of any one of claims 1-30; or a pharmaceutical composition comprising an oligomeric compound of any one of claims 1-30 and a pharmaceutically acceptable diluent.PATENT 7328.158159PCT / NLM-1002-PC32. An oligomeric compound of any one of claims 1-30, or a composition or a pharmaceutical composition of claim 31, for reducing MAPK8IP3 / JIP3 expression, and optionally for selectively reducing expression of a MAPK8IP3 / JIP3 allelic variant.

33. An oligomeric compound of any one of claims 1-30, a composition or a pharmaceutical composition of claim 31, for treating a MAPK8IP3 / JlP3-associated medical condition; wherein the MAPK8IP3 / JIP3-associated medical condition optionally is a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3-associated neurodegenerative medical condition, Parkinson’s-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

34. The oligomeric compound, composition or pharmaceutical composition of claim 33, wherein at least one symptom or hallmark of the medical condition is ameliorated, and optionally wherein the symptom or hallmark is one or more of: neurodevelopment impairment, intellectual disability, intellectual impairment, impaired intellectual development, developmental delay, global developmental delay, severe global developmental delay, gross motor delay, poor speech, absent speech, brain abnormality', physical impairment, muscle tone impairment, movement disorder, ataxia, tremor, autism, dystonia, hypertonia, hypotonia, spasticity, walking difficulties, visual impairment and seizure.

35. The oligomeric compound, composition or pharmaceutical composition of any one of claims 31-34, comprising: determining presence or absence of a differentiating genetic variation site in a MAPK8IP3 / JIP3 nucleic acid; and if a differentiating genetic variation site is present, administering an oligomeric compound targeted to the differentiating genetic variation site.

36. The oligomeric compound, composition or pharmaceutical composition of claim 35, wherein the MAPK8IP3 / JIP3 nucleic acid comprises a mutant MAPK8IP3 / JIP3 allelic variant, and optionally characterizing a pathogenic genetic variation site in the mutant MAPK8IP3 / JIP3 allelic variant.PATENT7328.158159PCT / NLM-1002-PC37. The oligomeric compound, composition or pharmaceutical composition of any one of claims 31-36, wherein: the MAPK8IP3 / JIP3 nucleic acid is a mutant MAPK8IP3 / JIP3 nucleic acid and the MAPK8IP3 / JIP3 allelic variant is a mutant MAPK8IP3 / JIP3 allelic variant, each comprising a pathogenic genetic variant associated with a medical condition; or optionally the medical condition is a MAPK8IP3 / JIP3-associated medical condition; or optionally the MAPK81P3 / JIP3-associated medical condition is a neurological medical condition, MAPK8IP3 / JIP3-associated neurological medical condition, a neurodegenerative medical condition, a MAPK8IP3 / JIP3- associated neurodegenerative medical condition, Parkinson's-like disease, Parkinson’s disease, neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) or microencephaly.

38. The oligomeric compound, composition or pharmaceutical composition of claim 37, wherein the pathogenic genetic variant:(i) is at a rsl567203083, rs770703007, rs!567128142, rs!567214097 or rs 1567198751 pathogenic genetic variation site; or(ii) is at a rsl567203083 pathogenic genetic variation site; or(iii) encodes a p.Arg579Cys, p.Arg578Cys, p.Arg572Cys, p.Tyr94Cys, p.Tyr37Ter, p.Gly22AlafsTer3, p.Argl l47Cys, p.Argll46Cys. p.Argll40Cys, p.Leu445Pro, p.Leu444Pro, p.Leu438Pro, p.Arg522His. p.Arg521His, p.Arg515His, p.Ala816Glu. р.Ala815Glu, p.Ala809Glu, p.Glu455Gly, p.Glu454Gly or p.Glu448Gly amino acid modification or substitution; or(iv) encodes a p.Arg579Cys, p.Arg578Cys or p.Arg572Cys amino acid substitution; or(v) encodes a p.Arg579Cys amino acid substitution; or(vi) encodes or is C.1735OT, C.1732OT, C.1714OT, c.281A>G, c.lllOG, c.65del, C.3439OT, C.3436OT, C.3418OT, c, 1334T>C, c,1331T>C, c,1313T>C, с, 1565G>A, c, 1562G>A, c, 1544G>A, C.2447OA, C.2444OA, C.2426OA, c, 1364A>G, c, 1361A>G or c, 1343A>G: or(vii) encodes or is c. 1735OT, C.1732OT or c. 1714OT; or(viii) encodes or is C.1735OT.

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