Antisense thiomorpholino oligonucleotides for the inhibition of peg10 ribosomal frameshifting

Abstract

Composition and methods for treating neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman's Syndrome (AS), the compositions specifically including antisense oligonucleotides (ASOs) containing thiomorpholino nucleotides configured to inhibit ribosomal frameshifting of paternally expressed gene 10 (PEG 10) mRNA during translation, thereby inhibiting the formation of the long form gag-pol protein.

Description

[0001]ANTISENSE THIOMORPHOLINO OLIGONUCLEOTIDES FOR THE INHIBITION OF PEG10 RIBOSOMAL FRAMESHIFTING CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 673,046, filed July 18, 2024. The entire specification and figures of the above-referenced application are hereby incorporated, in their entirety by reference. SEQUENCE LISTING The instant application contains contents of the electronic sequence listing (90245.01251- Sequence-Listing.xml; Size: 23,803 bytes; and Date of Creation: July 18, 2025) is herein incorporated by reference in its entirety. TECHNICAL FIELD The present disclosure relates generally to the field of improved methods for treating neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS). It also provides compositions to inhibit frameshifting in a target mRNA during translation, and preferably the translational frameshifting of Human Paternally Expressed Gene 10 (PEG10) mRNA. BACKGROUND ALS is a fatal neuromuscular disorder characterized by progressive paralysis that affects upwards of 30,000 Americans. It is a devastating disease that afflicts people, primarily in the fifth to sixth decade of life, and typically kills within 3-5 years of diagnosis. There is no cure for ALS, and there are no reliable biomarkers for the disease and few treatment options—none of which significantly prolong lifespan. Two leading therapeutics for ALS are Riluzole and Edaravone, which have shown limited therapeutic success. Both work by inhibiting excitotoxic glutamatergic signaling and oxidative stress, respectively. However, these drugs have shown limited benefit in reducing symptoms and do not significantly lengthen lifespan. There is a significant unmet medical need for novel ALS therapeutics. One of the major roadblocks to developing ALS therapies is that very little is known about the molecular mechanism of disease. In general, ALS shares a few key molecular perturbations. ALS patient tissues exhibit protein accumulation and aggregation, which is thought to contribute to neuronal dysfunction. However, the specifics of how aggregates lead to neuronal dysfunction are poorly understood. There are multiple genes that have been identified as risk factors for a familial form of ALS (fALS), which accounts for approximately 10% of total ALS cases; the other cases are considered sporadic (sALS), with no known genetic etiology. While there are multiple unique genetic mutations that can lead to fALS, each genetic mutation is unique, current treatment options therapeutically target downstream effects that are shared amongst familial and sporadic ALS. UBQLN2 is a known genetic risk factor for ALS. Mutations in UBQLN2 cause approximately 2% of familial ALS cases, but the mechanism of disease was not known and may be shared broadly amongst other forms of ALS. Normally, UBQLN2 degrades PEG10 protein. In some forms of ALS and FTD, UBQLN2 is mutated and PEG10 accumulates. Notably, translation of PEG10 is unique because it uses the ribosome to frameshift halfway through protein synthesis forming two distinct proteins namely short form protein, referred to as gag, and a long-from protein gag-pol. More specifically, the formation of gag-pol is the result of ribosomal frameshifting where the ribosome sees a “knot” in the PEG10 mRNA and pauses, right on top of a slippery stretch of RNA. That causes the ribosome to slip backwards by just one base altering the reading frame. The knot eventually resolves; however, the new reading frame produces gag-pol instead of recognizing the now out of frame stop codon shortly thereafter. Notably, UBQLN2 only regulates gag-pol, and not the short form gag protein. The formation gag-pol resulting from this ribosomal frameshift accumulates in cells of patients exhibiting neurodegenerative diseases, such as ALS, FTD, and AS. Based on this insight, the present disclosure describes the discovery of antisense oligonucleotide approach that inhibits PEG10 frameshifting in vivo by disrupting or preventing formation of the secondary mRNA “knot” structure. This novel antisense approach is applicable for all type of chemistries and oligonucleotide constructs that do not involve RNase H activation properties. Examples of applicable chemistries include PS-RNA (Phosphorothioate-modified RNA), PS-2´-OMe (Phosphorothioate-modified 2’-O-Methyl RNA), PS--MOE (Phosphorothioate-modified 2’-O- Methoxyethyl RNA), PS-LNA (Phosphorothioate-linked locked nucleic acid), and TMO (Thiomorpholino oligonucleotide) modifications, showing all regulation effect, with strong outperform of TMO modified sequences. These antisense oligonucleotides (ASOs) can further be applied as a therapeutic intervention for neurodegenerative diseases implicating the accumulation of gag-pol, such as UBQLN2-mediated ALS. SUMMARY OF THE INVENTION In one aspect, the present Applicants have developed antisense oligonucleotides (AOs or ASOs) containing one or more chemical modifications to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. In another aspect, the present Applicants have developed thiomorpholino (TMO) ASOs to inhibits ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. In another aspect, the present Applicants have developed phosphorothioate locked nucleic acids (PS-LNA) ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. In another aspect, the present Applicants have developed phosphorothioate RNA (PS- RNA) ASOs to decrease PEG10 mRNA. In another aspect, the present Applicants have developed Phosphorothioate-modified 2’- O-Methyl (PS-OMe) ASOs to decrease PEG10 mRNA. In another aspect, the present Applicants have developed Phosphorothioate-modified 2’- O- Methoxyethyl (PS-MOE) ASOs to decrease PEG10 mRNA. According to one aspect of the invention, there is provided an isolated or purified chemically modified AOs for inhibiting ribosomal frameshifting of the PEG10 gene transcript or part thereof. Preferably, there is provided an isolated or purified antisense oligomer for inducing ribosomal frameshifting modulation, especially inhibiting ribosomal frameshifting of the PEG10 mRNA leading to preferential translation of the shortform gag protein, and conversely a reduction of the of long form gag-pol protein. In another aspect, the antisense oligomer(s) of the disclosure targets a pseudoknot structure of the PEG10 mRNA and preferably loop 1 of the predicted pseudoknot structure of the PEG10 mRNA. In this aspect the antisense oligomer breaks the Watson-Crick base pairing in Stem one, and stabilizes loop 2 of a pseudoknot formed by the PEG10 mRNA such that the ribosome during translation does not stall at this position thereby inhibiting the translational frameshift resulting in preferential production of gag. In another aspect, the antisense oligomer(s) of the disclosure targets a pseudoknot structure of the PEG10 mRNA and preferably loop 1 of the predicted pseudoknot structure of the PEG10 mRNA. In this aspect the antisense oligomer sterically interferes with the formation of the pseudoknot generally shaped by the PEG10 mRNA such that the ribosome during translation thereby inhibiting the translational frameshift resulting in preferential production of gag. In another aspect, the antisense oligomer having one or more chemical modifications is selected from the group SEQ ID NO. 6 or 7. The disclosure further extends, according to a still further aspect thereof, to cDNA or cloned copies of the antisense oligomer sequences of the disclosure, as well as to vectors containing the antisense oligomer sequences that are unmodified and can be expressed in vivo are described herein. The disclosure extends further also to cells containing such sequences and / or vectors. The disclosure extends further also to methods of synthesizing the antisense oligomers having one or more chemical modifications of the present disclosure. In another aspect, the disclosure provides for methods and compositions for modulating the ribosomal frameshifting of the PEG10 mRNA during translation by providing providing one or more of the antisense oligomers as described herein and allowing the oligomer(s) to bind to a target nucleic acid site, which can preferably occur in the nucleus. In another aspect, the disclosure provides pharmaceutical, prophylactic, or therapeutic compositions to treat, prevent or ameliorate the effects of a disease associated with the PEG10 in a subject in need thereof, and in particular the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation in a subject, the composition comprising: one or more antisense oligomers as described herein, and one or more pharmaceutically acceptable carriers. Preferably the disease is a neurodegenerative disease, and even more preferably a neurodegenerative disease selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS). The subject or patient with a neurodegenerative disease may be a mammal, and preferably a human. In another aspect, the disclosure provides a method to treat, prevent or ameliorate the effects of a disease associated with the PEG10 in a subject in need thereof, and in particular the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation in a subject, comprising the step of administering to the subject a therapeutically effective amount of one or more antisense oligomers or pharmaceutical compositions comprising one or more antisense oligomers as described herein. In another aspect, the disclosure provides for the use of purified and isolated antisense oligomers as described herein, for the manufacture of a medicament to treat, prevent or ameliorate the effects of a disease associated with the PEG10, and in particular the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation in a subject. In another aspect, the disclosure provides a kit to treat, prevent, or ameliorate the effects of a disease associated with the PEG10, and in particular the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation in a subject, which kit comprises at least an antisense oligomer as described herein and combinations or cocktails thereof, packaged in a suitable container, together with instructions for its use. In a preferred aspect, disease associated with the PEG10 can be selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS). Additional aspects of the embodiments of the disclosure will now be described with reference to the accompanying non-limiting examples, specification, claims, and figures. BRIEF DESCRIPTION OF THE FIGURES FIG. 1A-C: PEG10 mRNA to protein schematic and design of ASOs. a) Schematic of PEG10 pseudoknot. Stop codons are shown with stop signs. mRNA generates two protein products: gag and gag-pol. Note that base pairs are not to scale. b) close-up of pseudoknot structure from Manktelow et al.2005. Base pairs are not to scale. c) Regions of pseudoknot used to generate morpholinos H1, H2, H3, and H4. Base pairs are not to scale. FIG. 2A-D: Human PEG10-targeting thiomorpholino H3 and H4 prohibit production of PEG10 gag-pol protein. a) Western blot of HEK cells 48 hr after transfection with increasing doses of morpholino. Cells were transfected using Lipofectamine 2000 with either 0, 50, 100, or 200 nM ASO. PEG10 was blotted with polyclonal antibody. b) Quantification of gag protein levels normalized to Tubulin for each ASO. Note that H1 and H2 have a mild dose-dependent effect on gag, but H3 and H4 do not. c) Quantification of gag-pol protein levels normalized to Tubulin for each ASO. Note that H3 and H4, but especially H3, have a dose-dependent effect on gag-pol, while H1 and H2 do not. d) Ratio of gag-pol:gag protein levels of PEG10 for each ASO. H1 and H2 have no effect on the ratio or slightly increase gag-pol frameshifting efficiency. H3 and H4, but especially H3, considerably diminish gag-pol frameshifting. e) Model of how H3 ASO melts out pseudoknot to allow ribosome to complete translation of gag mRNA without pause and -1 frameshift. W-C: Watson-Crick pairing. FIG.3A-B: Dual fluorescence reporter shows that H3 and H4 limit production of gag-pol protein. a) Top: schematic of frameshift reporter with N-terminal mCherry and C-terminal eGFP. Bottom: flow cytometric analysis showing cells express more eGFP when transfected with “forced frameshift” construct. b) Representative microscopy of cells co-transfected with reporters and ASOs (bottom, labeled in white). Only H3 and H4 cotransfection result in a demonstrable loss of green signal. FIG.4A-D: Murine Peg10-targeting thiomorpholino limits production of gag-pol protein. a) Western blot of murine 3T3 cells 72 hr after transfection with increasing doses of morpholino along with HA-tagged murine Peg10 construct. Cells were transfected using Lipofectamine 2000 with either 0, 50, 100, or 200 nM ASO. Peg10 was blotted with HA antibody. Star denotes nonspecific band. n = 2 representative experiments. b) Ratio of gag-pol:gag protein levels of Peg10 for each ASO. M2 has no obvious effect; M4 has a minor effect, and M3 has a major effect even at 50 nM. n = 2 representative experiments. c) Schematic of Peg10 protein with peptides detected by LC-MS.3T3 cells were transfected with ASO or HA-PEG10 and harvested for proteomics 72 hr later. d) Ratio of peptides from pol region of Peg10 (blue) versus gag region of Peg10 (pink) from (c). Only M3 has an apparent decrease in the pol: gag ratio. FIG.5A-B: exemplary (a) hybrid murine / human (M / H) and murine (M) anti-PEG10 TMO sequences M1 / H1, M2, Me and M4; (b) human (H) anti-PEG10 TMO sequences H2, H3 and H4. (Legend: RED: Thiomorpholino nucleotides and BLACK 2’-deoxynucleoside at the 3’-end). FIG.6A-C: Overview of different chemistries and their effect on gag and gag-pol protein production by targeting the PEG10 pseudoknot with the most potent candidate sequence, H3.; a. Overview of the chemistries used.; b. Western blot results showing protein production.; c. Quantification of Western blot analysis for gag and gag-pol protein levels. FIG. 7A-B: Thermal stability study of all tested chemistries with complementary sense RNA. a. Melting curves of individual sequences measured in triplicate and averaged automatically; Tm₅₀ values were calculated by first derivative analysis. b. Graph showing the increase in thermal stability based on the chemistry used. * Thermal stability values exceeding measurable limits (100^°C) were estimated based on the extrapolated trend of the sigmoid curve. FIG.8A-F: Intracellular localization study of labeled sequences using Fluorescein (FAM) and Cyanine-5 (Cy-5) attached to the 5′ end of sequences, analyzed by confocal microscopy. a. Schematic representation of the experiment to determine nuclear or cytoplasmic localization of the sequences. b. Fully TMO-modified H3 sequence labeled with FAM, confirming its localization in the nucleus (visualized with DAPI). c. PS-RNA sense strand labeled with Cy-5, showing localization in the cytoplasm and endoplasmic reticulum. d. Introduction of a double-stranded system, showing non-nuclear localization of the Cy-5–labeled PS-RNA sense strand. e. Imaging of the same area using the FAM wavelength to confirm non-nuclear localization of the fully TMO- modified H3 sequence. f. Merged image of both wavelengths (FAM and Cy-5), showing colocalization and confirming that the double-stranded system is localized outside the nucleus. FIG.9A-C: Validation of the localization of the observed effect. a. Experimental design using RNase H1–active and –inactive constructs in single-stranded and double-stranded systems: a fully TMO-modified variant of the H3 sequence (RNase H1–inactive), and a Cap-gap construct (TMO modifications in the cap regions and PS-DNA in the gap region; RNase H1–active). b. Western blot analysis of gag and gag-pol protein expression in cells treated with single-stranded and double-stranded systems. c. Quantification of Western blot data showing gag and gag-pol protein levels. FIG. 10A-C: Hypothesized pseudoknot structural alternatives. a. Originally proposed pseudoknot structure as described by Manktelow et al. b. AlphaFold server–predicted structure of the PEG10 pseudoknot. c. Proposed model of pseudoknot folding highlighting the potential effect of alternative binding sites within higher-order mRNA structures. DETAILED DESCRIPTION OF THE INVENTION Features of the present disclosure are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad summary, disclosure or description of the invention as set out above. PEG10 is one of a family of domesticated retrotransposon genes derived from the Sushi- ichi lineage of Ty3 / Gypsy LTR retrotransposons and codes for both gag and pol domains separated by a programmed ribosome frameshifting site (PEG 10 includes a protein sequence according to SEQ ID NO 1, an mRNA sequence according to SEQ ID NO. 2 or 3). Use of the ribosomal frameshift occurs with high efficiency, resulting in two forms of PEG10 proteins: gag, and gag-pol. PEG10 has been implicated in neurodegenerative diseases due to its ability to accumulate the long form gag-pol protein in the absence of functional UBQLN2, leading to changes in the expression of neuronal genes. Without being held to any theory, the present invention is based on the understanding that, the translational frame switching of PEG10 resulting in the production of gag-pol protein has clinical implications in the treatment of neurodegenerative diseases, such as ALS, FTD, and AS. A such, present disclosure seeks to provide a composition and method to treat neurodegenerative diseases, such as ALS that currently lack a commercially and clinically viable treatment. One possible treatment is the use of ASOs to inhibit frame shifting during translation of PEG10. The three main chemistries that are widely used in frameshifting applications are phosphorodiamidate morpholino oligomer (PMO), 2’-O-Methyl (2’-OMe) and 2’-O- Methoxyethyl (2’-MOE) (See i.e., Figure 22 of PCT / US2023 / 079495, incorporated herein by reference). However, these chemistries are associated with significant limitations such as toxicity in the case of 2’-OMe and 2’-MOE, while PMO is challenging to synthesize on a scale large enough for use as therapeutic drugs despite its excellent safety profile. In addition, PMOs are known to be rapidly excreted after administration in vivo and thereby require high dosages that could subsequently contribute to the cost of treatment. Another limitation of PMOs is their inability to form complexes with commercial transfection reagents which obstructs the rapid evaluation of any PMO drug in an in vitro system. To overcome the limitations in traditional ASO application described above, the present Applicants have developed novel chemically modified ASO to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. In one embodiment, the disclosure provides ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having thiomorpholino nucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. In one embodiment, the disclosure provides thiomorpholino (TMO) ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having thiomorpholino nucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. Examples of TMOs and their synthesis a described by Caruthers et al., in U.S. Pat No.11230565B, which is incorporated herein by reference. In another embodiment, the disclosure provides PS-LNA ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having phosphorothioate locked nucleic acids nucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. In another embodiment, the disclosure provides PS-MOE ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having phosphorothioate-modified 2’-O- Methoxyethyl nucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. In another embodiment, the disclosure provides PS-OMe ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having phosphorothioate-modified 2’-O- Methyl nucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. In another embodiment, the disclosure provides PS-RNA ASOs to inhibit ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein. Towards this purpose, various frame shift inhibiting ASOs having phosphorothioate-modified ribonucleotides have been designed, synthesized, and evaluated in in vitro, as well as in vivo model systems. As used herein, reference to an antisense oligomer includes both unmodified forms of that ASO, as well as chemically modified forms, and preferably TMO, PS-RNA, PS-OMe, PS-MOE, and PS-LNA antisense oligomers. Moreover, reference to a specific or group of ASOs by SEQ ID NO, explicitly both unmodified forms of that SEQ ID NO, as well chemically modified forms, and preferably as SEQ ID NO. having a chemically modified form selected from: a TMO, a PS-RNA, a PS-OMe, a PS-MOE, and a PS-LNA. The antisense oligomer induced inhibition of frame shifting of the present disclosure need not completely or even substantially ablate the function of the PEG10 protein. Preferably, inhibiting the frame shifting process results in a reduced or compromised functionality of the differentially expressed gag-pol protein subunit in a cell. In contrast to other antisense oligomer-based therapies, the present invention does not induce increased degradation of mRNA via recruitment of RNase H, wherein the RNase H preferentially recognize, binds and degrades mRNA in duplex with DNA and DNA like sequence (for example PS-DNA) forming A-form of duplex with mRNA of the PEG10 gene. Nor does it rely on hybridization of the antisense oligomer to the PEG10 genomic DNA or the binding of antisense oligomers to mRNA to modulate the amount of PEG10 protein produced by interfering with normal functions such as replication, transcription, translocation, and translation. Rather, the antisense oligomers are used to modify the translation process to preferentially produce the gag protein subunit by inhibiting the frame shifting of the PEG10 mRNA. Preferably, the present invention leads to the preferential production of the gag protein and a reduction in the gag-pol protein. According to a first aspect of the invention, there is provided antisense oligomers capable of binding to a selected target on a PEG10 mRNA to inhibit ribosomal frameshifting during translation, thereby inhibiting the formation of a long form gag-pol protein, and thereby preferentially producing a short form gag protein. Preferably the antisense oligomers of the disclosure target a pseudoknot structure of the PEG10 mRNA and loop 1 of the pseudoknot structure of the PEG10 mRNA (SEQ ID NO.3). Preferably, the antisense oligomer is selected from the SEQ ID NO. 6 or 7, which are configured to target loop 1 of the pseudoknot structure of the PEG10 mRNA. Additional examples of variants include antisense oligomers having about or at least about 70% sequence identity or homology, e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity or homology, over the entire length of any of SEQ ID NO.6 or 7. In a preferred embodiment, the ASO of SEQ ID NO.6 or 7 comprises a TMO. In another preferred embodiment, the ASO of SEQ ID NO. 6 or 7 comprises an ASO containing at least one PS, and at least one MOE modification (PS-MOE). In another preferred embodiment, the ASO of SEQ ID NO. 6 or 7 comprises an ASO containing at least one PS, and at least one LNA modification. In another preferred embodiment, the ASO of SEQ ID NO. 6 or 7 comprises an ASO containing at least one PS, and at least one OMe modification (PS-OMe). In another preferred embodiment, the ASO of SEQ ID NO.6 or 7 comprises an ASO containing at least one PS, and at least one RNA. In certain embodiments, the degree of complementarity between the target sequence and antisense oligomer is sufficient to form a stable duplex. The region of complementarity of the antisense oligomers with the target RNA sequence may be as short as 8-11 bases, but can be 12-15 bases or more, e.g., 10-50 bases, 10-40 bases, 12- 30 bases, 12-25 bases, 15-25 bases, 12-20 bases, or 15-20 bases, including all integers in between these ranges. An antisense oligomer of about 16-17 bases is generally long enough to have a unique complementary sequence. In certain embodiments, a minimum length of complementary bases may be required to achieve the requisite binding Tm, as discussed herein. The stability of the duplex formed between an antisense oligomer and a target sequence is a function of the binding Tm and the susceptibility of the duplex to cellular enzymatic cleavage. The Tm of an oligonucleotide with respect to complementary-sequence RNA may be measured by conventional methods, such as those described by Hames et al., Nucleic Acid Hybridization, IRL Press, 1985, pp.107-108 or as described in Miyada C. G. and Wallace R. B., 1987, Oligonucleotide Hybridization Techniques, Methods Enzymol. Vol. 154 pp. 94-107. In certain embodiments, antisense oligomers may have a binding Tm, with respect to a complementary-sequence RNA, of greater than body temperature and preferably greater than about 45°C or 50°C. Tm’s in the range 60-80°C or greater are also included. In certain embodiments, oligonucleotides as long as 50 bases may be suitable, where at least a minimum number of bases, e.g., 10-12 bases, are complementary to the target sequence. In general, however, facilitated, or active uptake in cells is optimized at oligonucleotide lengths of less than about 30 bases. Included are antisense oligomers that consist of about 10, 11, 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 or 50 bases. In certain embodiments, antisense oligomers may be 100% complementary to the target sequence, or may include mismatches, e.g., to accommodate variants, as long as a heteroduplex formed between the antisense oligomer and target sequence is sufficiently stable to withstand the action of cellular nucleases and other modes of degradation which may occur in vivo. Hence, certain oligonucleotides may have about or at least about 70% sequence complementarity, e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence complementarity, between the oligonucleotide and the target sequence. Mismatches, if present, are typically less destabilizing toward the end regions of the hybrid duplex than in the middle. The number of mismatches allowed will depend on the length of the antisense oligomer, the percentage of G:C base pairs in the duplex, and the position of the mismatch(es) in the duplex, according to well understood principles of duplex stability. Although such an antisense oligomer is not necessarily 100% complementary to the target sequence, it is effective to bind to the target sequence stably and specifically, such that ribosomal frame shifting of the target mRNA is modulated. The terms “complementary” and “complementarity” refer to polynucleotides (i.e., a sequence of nucleotides) related by base-pairing rules. For example, the sequence “T-G-A (5’- 3’),” is complementary to the sequence “T-C-A (5’-3’).” Complementarity may be “partial,” in which only some of the nucleic acids” bases are matched according to base pairing rules. Or there may be “complete” or “total” complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. While perfect complementarity is often desired, some embodiments can include one or more but preferably 6, 5, 4, 3, 2, or 1 mismatches with respect to the target RNA. Variations at any location within the oligomer are included. In certain embodiments, variations in sequence near the termini of an oligomer are generally preferable to variations in the interior, and if present are typically within about 6, 5, 4, 3, 2, or 1 nucleotides of the 5’ and / or 3’ terminus. Exemplary embodiments of the invention relate to morpholino oligonucleotides having thiomorpholino-containing internucleotide linkages, i.e. TMOs. Efficient methods of making such thiomorpholino oligonucleotides, including antisense oligonucleotides, are detailed, for example, in co-owned Application No. PCT / US17 / 51839, filed September 15, 2017, which is expressly incorporated by reference herein. Important properties of the thiomorpholino-based subunits include: 1) the ability to be linked in a oligomeric form with 2’-deoxyribonucleosides; 2) the ability to support a nucleotide base (e.g. adenine, cytosine, guanine, thymidine, uracil and inosine) such that the polymer formed can hybridize with a complementary-base target nucleic acid, including target RNA, Tm values above about 50 °C in relatively short oligonucleotides (e.g., 8-15 bases); 3) the ability of the oligonucleotide to be actively or passively transported into mammalian cells; and 4) longer half- life (i.e., slower excretion) than PMOs; 6) a charged backbone that increases their ability to complex with currently available transfection agents for rapid in vitro cellular uptake. Exemplary backbone structures for antisense thiomorpholino oligonucleotides of this disclosure include the thiomorpholino subunit types shown in FIGS. 1A and 1B of PCT / US2017 / 051839, linked by a phosphorothioate-containing internucleotide linkages, sometimes abbreviated as PS, or having at least one PS modification. In certain embodiments, the antisense compounds can be prepared by stepwise solid-phase synthesis, employing methods detailed in Application No. PCT / US17 / 51839, as well as U.S. Provisional Application No.63 / 818,566, with respect to the synthesis of oligonucleotides having a mixture of uncharged and cationic backbone linkages. In some cases, it may be desirable to add additional chemical moieties to the antisense compound, e.g., to enhance pharmacokinetics or to facilitate capture or detection of the compound. Such a moiety may be covalently attached, according to standard synthetic methods. For example, addition of a moiety to enhance cellular uptake (such as TAT), or an Fc binding immunoglobulin subunit, or a saccharide (such as a disaccharide, such as lactose), or a polyethylene glycol moiety or other hydrophilic polymer, e.g., one having 1-100 monomeric subunits, may be useful in enhancing solubility, increasing cellular uptake, or prolonging serum half-life, and the like. A reporter moiety, such as fluorescein or a radiolabeled group, may be attached for purposes of detection. Alternatively, the reporter label attached to the oligomer may be a ligand, such as an antigen or biotin, capable of binding a labeled antibody or streptavidin. In selecting a moiety for attachment or modification of an antisense compound, it is desirable to select chemical compounds of groups that are biocompatible and likely to be tolerated by a subject without undesirable side effects. Oligomers useful in the antisense applications of this disclosure generally range in length from about 8 to about 50 nucleotide residues, more preferably about 8 to 30 nucleotides, and typically 10-25 bases. Each thiomorpholino (TMO) ring structure supports a base pairing moiety, to form a sequence of base pairing moieties which is typically designed to hybridize to a selected antisense target in a cell or in a subject being treated. The base pairing moiety may be a purine or pyrimidine found in native DNA or RNA (e.g., the bases Adenine (A), Guanine (G), Cytosine (C), Thymine (T) or Uracil (U)) or an analog, such as hypoxanthine (the base component of the nucleoside inosine), or 5-methyl cytosine. As noted above, embodiments include antisense oligomers comprising novel internucleotide linkages, including TMO-X oligomers and those having modified terminal groups. These oligomers may have higher affinity for DNA and RNA than do the corresponding unmodified oligomers and demonstrate improved cell delivery, potency, and / or tissue distribution properties compared to oligomers having other internucleotide linkages. The structural features and properties of the various linkage types and oligomers are described in more detail in the following discussion. The synthesis of these and related oligomers is described in co-owned Application No. PCT / US17 / 51839, as well as U.S. Provisional Application No.63 / 818,566, which are incorporated herein by reference in its entirety. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense molecule need not be 100% complementary to that of its target sequence to be specifically hybridizable. An antisense molecule is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of utility, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed. The most common method for producing antisense molecules is the methylation of the 2’ hydroxyribose position, and the incorporation of a phosphorothioate backbone produces molecules that superficially resemble RNA but that are much more resistant to nuclease degradation. To avoid degradation of pre-mRNA during duplex formation with the antisense molecules, the antisense molecules used in these methods may be adapted to minimize or prevent cleavage by endogenous RNase H. This property is highly preferred as the treatment of the RNA with the unmethylated oligonucleotides either intracellularly or in crude extracts that contain RNase H leads to degradation of the pre-mRNA-antisense oligonucleotide duplexes. Any form of modified antisense molecules that is capable of by-passing or not inducing such degradation may be used in the present methods. An example of antisense molecules, which when duplexed with RNA, are not cleaved by cellular RNase H is 2’-O-methyl derivatives.2’-O-methyl-oligoribonucleotides are very stable in a cellular environment and in animal tissues, and their duplexes with RNA have higher Tm values than their ribo- or deoxyribo-counterparts. While antisense oligonucleotides are a preferred form of the antisense molecules, this disclosure comprehends other oligomeric antisense molecules, including but not limited to oligonucleotide mimetics. Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural inter-nucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorothioate in the backbone and those that do not have a phosphorothioate in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorothioate in their inter-nucleoside backbone can also be considered to be oligonucleosides. Modified oligonucleotides may also contain one or more substituted sugar moieties. Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. Certain nucleo-bases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2- aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2 °C and are presently preferred base substitutions, even more particularly when combined with 2’-O-methoxyethyl sugar modifications. Another modification of the oligonucleotides of this disclosure involves chemically linking to the oligonucleotide one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a saccharide, such as the disaccharide lactose, a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-5-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O- hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl- oxycholesterol moiety. Additional chemical conjugates can include Vitamin E, Cholesterol, and / or N- Acetylgalactosamine (GalNAc). It is not necessary for all positions in a compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. This disclosure also includes antisense compounds that are chimeric compounds. “Chimeric” antisense compounds or “chimeras” are antisense molecules, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified to confer increased resistance to nuclease degradation, increased cellular uptake, and / or an additional region for increased binding affinity for the target nucleic acid. The antisense oligonucleotides of this disclosure may include oligonucleotide moieties conjugated to a CPP, preferably an arginine-rich peptide transport moiety effective to enhance transport of the compound into cells. The transport moiety is preferably attached to a terminus of the oligomer. The peptides have the capability of inducing cell penetration within 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of cells of a given cell culture population, including all integers in between, and allow macromolecular translocation within multiple tissues in vivo upon systemic administration. In one embodiment, the cell-penetrating peptide may be an arginine-rich peptide transporter. In another embodiment, the cell-penetrating peptide may be Penetratin or the TAT peptide. These peptides are well known in the art and are disclosed, for example, in US Patent Publication No. 2010 / 0016215, incorporated herein by reference in its entirety. A particularly preferred approach to conjugation of peptides to antisense oligonucleotides can be found in PCT Publication No. WO2012 / 150960, which is incorporated herein by reference in its entirety. A preferred embodiment of a peptide conjugated oligonucleotides of this disclosure utilizes glycine as the linker between the CPP and the antisense oligonucleotide. For example, a preferred peptide conjugated PMO consists of R6-G-TMO. These transport moieties have been shown to greatly enhance cell entry of attached oligomers, relative to uptake of the oligomer in the absence of the attached transport moiety. Uptake is preferably enhanced at least ten-fold, and more preferably twenty-fold, relative to the unconjugated compound. The use of arginine-rich peptide transporters (i.e., cell-penetrating peptides) are particularly useful in the compositions and methods of this disclosure. Certain peptide transporters have been shown to be highly effective at delivery of antisense compounds into primary cells including muscle cells (Marshall, Oda et al.2007; Jearawiriyapaisarn, Moulton et al.2008; Wu, Moulton et al.2008). Furthermore, compared to other known peptide transporters, such as Penetratin and the TAT peptide, the peptide transporters described herein, when conjugated to an antisense TMO, demonstrate an enhanced ability to alter splicing of several gene transcripts (Marshall, Oda et al. 2007). In one embodiment, the modified antisense oligomers of the invention are synthesised in vitro and do not include antisense compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of antisense oligomers. The molecules of the invention may also be mixed, encapsulated, conjugated, or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor targeted molecules, oral, rectal, topical, or other formulations, for assisting in uptake, distribution and / or absorption. In one embodiment, the antisense oligomers of the invention can be administered via a pharmaceutical composition. As used herein, “pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of the disclosed compound(s) together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition). Pharmaceutical formulations and delivery systems appropriate for the compositions and methods of the disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20.sup.th ed., Mack Publishing Co., Easton, Pa.; Remington's Pharmaceutical Sciences (1990) 18.sup.th ed., Mack Publishing Co., Easton, Pa.; The Merck Index (1996) 12.sup.th ed., Merck Publishing Group, Whitehouse, N.J.; Pharmaceutical Principles of Solid Dosage Forms (1993), Technonic Publishing Co., Inc., Lancaster, Pa.; Ansel and Stoklosa, Pharmaceutical Calculations (2001) 11.sup.th ed., Lippincott Williams & Wilkins, Baltimore, Md.; and Poznansky et al., Drug Delivery Systems (1980), R. L. Juliano, ed., Oxford, N.Y., pp.253-315). This disclosure also provides formulations or compositions suitable for the therapeutic delivery of antisense oligomers to a subject. These compositions may be pharmaceutically acceptable compositions that comprise a therapeutically-effective amount of one or more of the oligomers described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. While it is possible for an oligomer of this disclosure to be administered alone, it is preferable to administer the compound as a pharmaceutical composition. Methods for the delivery of nucleic acid molecules are described, for example, in Akhtar et al., 1992, Trends Cell Bio., 2:139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar; Sullivan et al., PCT WO 94 / 02595. These and other protocols can be utilized for the delivery of virtually any nucleic acid molecule, including the isolated oligomers of the present invention. As detailed below, the pharmaceutical compositions of this disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) (intra)ocularly; (7) transdermally; or (8) nasally. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of materials that can serve as pharmaceutically-acceptable carriers include, without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Additional non-limiting examples of agents suitable for formulation with the antisense oligomers of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues; biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al., 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of mesoporus silica, or polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). These compositions may also comprise liposomes or lipoplexes, including surface- modified liposomes / lipoplexes containing saccharides and / or poly(ethylene glycol) lipids (PEG- modified, branched and unbranched or combinations thereof, or long-circulating liposomes or stealth liposomes). Oligomers of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug. Such liposomes / lipoplexes have been shown to accumulate selectively in tumors. The long-circulating liposomes / lipoplexes may enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes. Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. Methods of preparing Lipid nanoparticles (LNPs) and encapsulating polypeptides and nucleic acids in LNPs are described in, e.g., Methods and Protocols, Volume 1: Pharmaceutical Nanocarriers: Methods and Protocols. (ed. Weissig). Humana Press, 2009 and Heyes et al. (2005) J Controlled Release 107:276-87. Methods of preparing microparticles and encapsulating polypeptides and nucleic acids are described in, e.g., Functional Polymer Colloids and Microparticles volume 4 (Microspheres, microcapsules & liposomes). (eds. Arshady & Guyot). Citus Books, 2002 and Microparticulate Systems for the Delivery of Proteins and Vaccines. (eds. Cohen & Bernstein). CRC Press, 1996. This disclosure includes oligomer compositions prepared for delivery as described in U.S. Pat. Nos.6,692,911, 7,163,695 and 7,070,807. Thus, this disclosure provides an oligomer of this disclosure in a composition comprising copolymers of lysine and histidine (HK) (as described in U.S. Pat. Nos.7,163,695; 7,070,807; and 6,692,911) either alone or in combination with PEG (e.g., branched or unbranched PEG or a mixture of both), in combination with PEG and a targeting moiety or any of the foregoing in combination with a crosslinking agent. This disclosure also provides antisense oligomers in compositions comprising gluconic-acid-modified polyhistidine or gluconylated-polyhistidine / transferrin-polylysine. Amino acids with properties similar to His and Lys may be substituted within the composition. The oligomers described herein may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term “pharmaceutically acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. The pharmaceutically acceptable salts of the subject oligomers include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. The oligomers of this disclosure may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically acceptable salts” in these instances refer to the relatively non- toxic, inorganic and organic base addition salts of the TMO compounds of this disclosure. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, e.g., Berge et al., supra). Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in these compositions. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Useful formulations of this disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. A formulation of this disclosure may comprise an excipient selected from cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an oligomer of the present invention, that may render orally bioavailable an oligomer of this disclosure. Methods of preparing these formulations or compositions include the step of bringing into association an oligomer of this disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of this disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. The formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of this disclosure as an active ingredient. An oligomer of this disclosure may also be administered as a bolus, electuary or paste. In these solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active TMO therapeutic ingredient may be mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (e.g., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical- formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Formulations or dosage forms for the topical or transdermal administration of an oligomer as provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active oligomers may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an oligomer of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of an oligomer of this disclosure to the body. Such dosage forms can be made by dissolving or dispersing the oligomer in the proper medium. Absorption enhancers can also be used to increase the flux of the agent across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the agent in a polymer matrix or gel, among other methods known in the art. Pharmaceutical compositions suitable for parenteral administration may comprise one or more oligomers of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject oligomers may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension of crystalline or amorphous material having poor water solubility, among other methods known in the art. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms may be made by forming microencapsulated matrices of the subject oligomers in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of oligomer to polymer, and the nature of the particular polymer employed, the rate of oligomer release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. When the oligomers of this disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. “Amyotrophic lateral sclerosis” or “ALS” are terms understood in the art and are used herein to denote a progressive neurodegenerative disease that affects upper motor neurons (motor neurons in the brain) and / or lower motor neurons (motor neurons in the spinal cord) and results in motor neuron death. As used herein, the term “ALS” includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS). “Angelman syndrome” (AS) is a neurodevelopmental disorder characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and / or tremulousness of the limbs, seizures, microcephaly and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, affinity for water, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of Angelman syndrome do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious. As used herein “Frontotemporal dementia” or “FTD”, is a neurodegenerative disease characterized by severe frontotemporal lobar degeneration. FTD is distinguished from Alzheimer's disease and Lewy body dementia based on several factors one of which being that it does not manifest with amyloid plaques, neurofibrillary tangles, or Lewy bodies. Symptoms of FTD typically appear around 45 to 65 years of age. Symptoms typically progress at a rapid, steady rate. Some patients with FTD also exhibit motor neuron disease (MND) e.g. AFS (i.e. FTD-AFS). Typically, symptoms are classified into three groups based on the functions of the frontal and temporal lobes: (1) Behavioral variant FTD (bvFTD) exhibits symptoms of lethargy and aspontaneity on the one hand, and disinhibition on the other. Apathetic patients may become socially withdrawn and stay in bed all day or no longer take care of themselves. Disinhibited patients can make inappropriate (sometimes sexual) comments or perform inappropriate acts (e.g. stealing or speeding). (2) Progressive nonfluent aphasia (PNFA), also referred to as nonfluent variant primary progressive aphasia (nfvPPA), presents with a breakdown in speech fluency due to articulation difficulty, phonological and / or syntactic errors but preservation of word comprehension. (3) Semantic dementia (SD), also referred to as semantic variant primary progressive aphasia (svPPA), can be found in some patients that remain fluent with normal phonology and syntax, but increasing difficulty with naming and word comprehension. It has been researched that some may even go through depression and lose their inhibitions and exhibit antisocial behavior. As used herein “PEG10 protein” means a protein that is substantially identical to all or a part of SEQ ID NO.1, or its discrete gag or pol subunits or any protein having between 80-99% sequence homology with PEG10. In one embodiment, PEG10 mRNA means all or a fragment of NCBI reference transcript for Homo sapiens PEG10 (mRNA) NM_001040152.2, or all or a fragment of NCBI reference transcript for NCBI reference transcript (mRNA) NM_001040611.1) or mRNA sequence having 80-99% or more sequence homology with SEQ ID NOs.2-3. Notably, disclosure of a nucleotide sequence further encompasses and incorporates by reference the corresponding amino acid sequence thereof. Similarly, disclosure of an amino acid sequence further encompasses and incorporates by reference the corresponding nucleotide sequence thereof. The terms “antisense oligomer” and “antisense compound” and “antisense oligonucleotide” and “ASO” are used interchangeably and refer to a sequence of cyclic subunits, each bearing a base-pairing moiety, linked by intersubunit linkages that allow the base-pairing moieties to hybridize to a target sequence in a nucleic acid (typically an RNA) by Watson-Crick base pairing, to form a nucleic acid:oligomer heteroduplex within the target sequence. The cyclic subunits are based on ribose or another pentose sugar or, in a preferred embodiment, a morpholino group (see description of morpholino oligomers below). The oligomer may have exact or near sequence complementarity to the target sequence; variations in sequence near the termini of an oligomer are generally preferable to variations in the interior. Also contemplated are peptide nucleic acids (PNAs), locked nucleic acids (LNAs), and 2’-O-Methyl (2’-OMe) oligonucleotides, among other antisense agents known in the art. The terms “morpholino oligomer” or “thiomorpholino oligomer” or “TMO” refer to an oligonucleotide analog composed of morpholino subunit structures (including thiomorpholinos), where (i) the structures are linked together by phosphorothioate-containing linkages, one to three atoms long, preferably two atoms long, that may be uncharged or cationic, joining the morpholino nitrogen of one subunit to a 5’ exocyclic carbon of an adjacent subunit, and (ii) each morpholino ring bears a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide. Variations can be made to this linkage as long as they do not interfere with binding or activity. The 5’ oxygen may be substituted with amino or lower alkyl substituted amino. The pendant nitrogen attached to phosphorus may be unsubstituted, monosubstituted, or disubstituted with (optionally substituted) lower alkyl. The purine or pyrimidine base pairing moiety is typically adenine, cytosine, guanine, uracil, thymine or inosine. The synthesis, structures, and binding characteristics of morpholino oligomers are detailed in Application No. PCT / US2017 / 051839, which is incorporated herein by reference in its entirety. In some embodiments, the antisense oligonucleotides have the chemical composition of a naturally occurring nucleic acid molecule, i.e., the antisense oligonucleotides do not include a modified or substituted base, sugar, or inter-subunit linkage. In a preferred embodiment, the antisense oligonucleotides of the present invention are non-naturally occurring nucleic acid molecules, or “oligonucleotide analogues.” For example, non-naturally occurring nucleic acids can include one or more non-natural base, sugar, and / or inter-subunit linkage, e.g., a base, sugar, and / or linkage that has been modified or substituted with respect to that found in a naturally occurring nucleic acid molecule. Exemplary modifications are described below. In some embodiments, non- naturally occurring nucleic acids include more than one type of modification, e.g., sugar and base modifications, sugar and linkage modifications, base and linkage modifications, or base, sugar, and linkage modifications. For example, in some embodiments, the antisense oligonucleotides contain a non-natural (e.g., modified or substituted) base. In some embodiments, the antisense oligonucleotides contain a non-natural (e.g., modified or substituted) sugar. In some embodiments, the antisense oligonucleotides contain a non-natural (e.g., modified or substituted) inter-subunit linkage. In some embodiments, the antisense oligonucleotides contain more than one type of modification or substitution, e.g., a non-natural base and / or a non- natural sugar, and / or a non- natural inter-subunit linkage. Thus, included are non-naturally occurring antisense oligomers having (i) a modified backbone structure, e.g., a backbone other than the standard phosphodiester linkage found in naturally occurring oligo- and polynucleotides, and / or (ii) modified sugar moieties, e.g., morpholino moieties rather than ribose or deoxyribose moieties. Oligonucleotide analogues support bases capable of hydrogen bonding by Watson-Crick base pairing to standard polynucleotide bases, where the analogue backbone presents the bases in a manner to permit such hydrogen bonding in a sequence-specific fashion between the oligonucleotide analogue molecule and bases in a standard polynucleotide (e.g., single-stranded RNA or single-stranded DNA). Preferred analogues are those having a substantially uncharged, phosphorus containing backbone. One method for producing antisense oligomers is the methylation of the 2’ hydroxyribose position and the incorporation of a phosphorothioate backbone produces molecules that superficially resemble RNA but that are much more resistant to nuclease degradation, although persons skilled in the art of the invention will be aware of other forms of suitable backbones that may be useable in the objectives of the invention. To avoid degradation of pre-RNA during duplex formation with the antisense oligomers, the antisense oligomers used in the method may be adapted to minimise or prevent cleavage by endogenous RNase H. Antisense molecules that do not activate RNase H can be made in accordance with known techniques (see, e.g., U.S. Pat. No.5,149,797). Such antisense molecules, which may be deoxyribonucleotide or ribonucleotide sequences, simply contain any structural modification which sterically hinders or prevents binding of RNase H to a duplex molecule containing the oligonucleotide as one member thereof, which structural modification does not substantially hinder or disrupt duplex formation. Because the portions of the oligonucleotide involved in duplex formation are substantially different from those portions involved in RNase H binding thereto, numerous antisense molecules that do not activate RNase H are available. This property is highly preferred, as the treatment of the RNA with the unmethylated oligomers, either intracellular or in crude extracts that contain RNase H, leads to degradation of the pre- mRNA:antisense oligomer duplexes. Any form of modified antisense oligomers that is capable of by-passing or not inducing such degradation may be used in the present method. The nuclease resistance may be achieved by modifying the antisense oligomers of the invention so that it comprises partially unsaturated aliphatic hydrocarbon chain and one or more polar or charged groups including carboxylic acid groups, ester groups, and alcohol groups. An example of antisense oligomers which when duplexed with RNA are not cleaved by cellular RNase H is 2’-O-methyl derivatives. Such 2’-O-methyl-oligoribonucleotides are stable in a cellular environment and in animal tissues, and their duplexes with RNA have higher Tm values than their ribo- or deoxyribo- counterparts. Alternatively, the nuclease resistant antisense oligomers of the invention may have at least one of the last 3’-terminus nucleotides fluoridated. Still alternatively, the nuclease resistant antisense oligomers of the invention have phosphorothioate bonds linking between at least two of the last 3-terminus nucleotide bases, preferably having phosphorothioate bonds linking between the last four 3’-terminal nucleotide bases. The terms “5′” and “3′” is a convention used to describe features of a nucleic acid sequence related to either the position of genetic elements and / or the direction of events (5′ to 3′), such as e.g. transcription by RNA polymerase or translation by the ribosome which proceeds in 5′ to 3′ direction. Synonyms are upstream (5′) and downstream (3′). Conventionally, DNA sequences, gene maps, vector cards and RNA sequences are drawn with 5′ to 3′ from left to right or the 5′ to 3′ direction is indicated with arrows, wherein the arrowhead points in the 3′ direction. Accordingly, 5′ (upstream) indicates genetic elements positioned towards the left hand side, and 3′ (downstream) indicates genetic elements positioned towards the right hand side, when following this convention. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res., 19:5081 (1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91-98 (1994). A “locked nucleic acids” or “LNA” means a modified RNA nucleotides that are chemically modified by a bicyclic bridge between the 2' oxygen and 4' carbon of the sugar ring. This bridge locks the sugar ring into a 3'-endo conformation, which is the same conformation found in RNA, and increases the stability and affinity of the LNA. As used herein, "phosphorothioate internucleotide linkage" refers to a linkage between nucleosides where one of the non-bridging atoms is a sulfur atom. As used herein, a “2'-O-methoxyethyl” or “MOE” refers to a ribose sugar in a RNA molecule having a methoxyethyl group to the 2' position. As used herein, "2'-0-methoxyethyl sugar" or "2'-MOE sugar" means a sugar having a O- methoxyethyl modification at the 2' position. As used herein, "2'-0-methoxyethyl nucleoside" means a 2'-modified nucleoside having a 2'-0- methoxy ethyl sugar modification. As used herein, “2’-O-Methyl,” or “2’-OMe” refers to a modification where a methyl group is added to the 2' hydroxyl position of the ribose sugar in an RNA molecule. As used herein, “PS” refers to phosphorothioate modification which replaces a non- bridging oxygen with a sulfur atom in the phosphate backbone. In a preferred embodiment, the ASO of the disclosure comprises an RNA ASO containing at least one PS modification forming a phosphorothioate linkage. As used herein, “PS-MOE” refers to phosphorothioate (PS) modified 2'-O-methoxyethyl (MOE) RNA. In a preferred embodiment, the ASO of the disclosure comprises an RNA ASO containing at least one PS, and at least one MOE modification. As used herein, “PS-LNA” refers to Phosphorothioate-modified Locked Nucleic Acid (LNA). In a preferred embodiment, the ASO of the disclosure comprises an RNA ASO containing at least one PS, and at least one LNA modification. As used herein, “PS-OMe” refers to Phosphorothioate-modified 2’-O-Methyl RNA. In a preferred embodiment, the ASO of the disclosure comprises an RNA ASO containing at least one PS, and at least one 2’-OMe modification. As used herein, “gapmer” means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.” As used herein, “cap gapmer” refers to an antisense oligonucleotide (ASO) designed to interact with or prevent the formation of the 5' cap structure on mRNA molecules. In some embodiments of the current disclosure, the methods and compositions comprising TMO and TMO chimera oligomers, such as TMO / DNA and TMO / RNA chimeras and cap gapmers, and gapmers can form ASO that are complementary to a target sequence. Sequences are described as “complementary” to one another when hybridization occurs in an antiparallel configuration. A double-stranded polynucleotide can be “complementary” to another polynucleotide. A targeting sequence may have “near” or “substantial” complementarity to the target sequence and still function for the purpose of the present disclosure. Preferably, the oligonucleotide analogs of this disclosure have at most one mismatch with the target sequence out of 10 nucleotides, and preferably at most one mismatch out of 20. Alternatively, the antisense oligomers of this disclosure have at least 90% sequence homology, and preferably at least 95% sequence homology, with the exemplary targeting sequences as designated herein. Thus, the oligomers made by the methods of this disclosure are particularly useful as therapeutic antisense molecules when administered to treat a disease state amenable to antisense therapy. Modified or modulated RNA splicing may also be achieved with alternative oligonucleotide chemistry (see, e.g., U.S. Pat. No.5,149,797). For example, the antisense oligomer may be chosen from the list comprising: a thiomorpholino oligomer (TMO); phosphoramidate or phosphorodiamidate morpholino oligomer (PMO); PMO-X; PPMO; peptide nucleic acid (PNA); a locked nucleic acid (LNA) and derivatives including alpha-L-LNA, 2’-amino LNA, 4’-methyl LNA and 4’-O-methyl LNA; ethylene bridged nucleic acids (ENA) and their derivatives; phosphorothioate oligomer; tricyclo-DNA oligomer (tcDNA); tricyclophosphorothioate oligomer; 2’O-Methyl-modified oligomer (2’-OMe); 2’-O-methoxy ethyl (2’-MOE); 2’-fluoro, 2’- fluroarabino (FANA); unlocked nucleic acid (UNA); hexitol nucleic acid (HNA); cyclohexenyl nucleic acid (CeNA); 2’-amino (2’-NH2); 2’-O-ethyleneamine or any combination of the foregoing as mixmers or as gapmers. By “isolated” is meant material that is substantially or essentially free from components that normally accompany it in its native state. For example, an “isolated polynucleotide” or “isolated oligonucleotide,” as used herein, may refer to a polynucleotide that has been purified or removed from the sequences that flank it in a naturally-occurring state, e.g., a DNA fragment that is removed from the sequences that are adjacent to the fragment in the genome. The term “isolating” as it relates to cells refers to the purification of cells (e.g., fibroblasts, lymphoblasts) from a source subject (e.g., a subject with a polynucleotide repeat disease). In the context of mRNA or protein, “isolating” refers to the recovery of mRNA or protein from a source, e.g., cells. An antisense oligomer can be said to be “directed to” or “targeted against” a target sequence with which it hybridizes. In certain embodiments, the target sequence includes a region including the pseudoknot structure of the PEG10 mRNA and preferably loop 1 of the pseudoknot structure. An oligomer is more generally said to be “targeted against” a biologically relevant target, such as a protein, virus, or bacteria, when it is targeted against the nucleic acid of the target in the manner described above. The term “modulate” or “modulates” includes to “increase” or “decrease” one or more quantifiable parameters, optionally by a defined and / or statistically significant amount. The terms “increase” or “increasing,” “enhance” or “enhancing,” or “stimulate” or “stimulating” refer generally to the ability of one or antisense oligomers or compositions to produce or cause a greater physiological response (i.e., downstream effects) in a cell or a subject relative to the response caused by either no antisense oligomer or a control compound. For example, modulation of the ribosomal frameshifting of the PEG10 mRNA during translation, results in a decrease in the formation of a long form gag-pol protein an increase in the short form gag protein. As used herein, “inhibits,” “inhibition” or “decease” refer generally to the ability of one or antisense oligomers or compositions to produce or cause a reduced physiological response (i.e., downstream effects) in a cell or a subject relative to the response caused by either no antisense oligomer or a control compound. The term “reduce” or “inhibit” may relate generally to the ability of one or more antisense compounds of the invention to “decrease” a relevant physiological or cellular response, such as a symptom of a disease or condition described herein, as measured according to routine techniques in the diagnostic art, or a reduction in ribosomal frameshifting of the PEG10 mRNA resulting in a reduction or inhibition of the gag-pol protein. Relevant physiological or cellular responses (in vivo or in vitro) will be apparent to persons skilled in the art and may include reductions in the symptoms or pathology of a PEG10 related condition. A “decrease” in a response may be statistically significant as compared to the response produced by no antisense compound or a control composition, and may include a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease, including all integers in between. By “treating” a disease, disorder, or condition is meant delaying an initial or subsequent occurrence of a disease, disorder, or condition; increasing the disease-free survival time between the disappearance of a condition and its reoccurrence; stabilizing or reducing one or more (e.g., two, three, four, or five) adverse symptom(s) associated with a condition; or inhibiting, slowing, or stabilizing the progression of a condition. The term “treating” also includes reducing (e.g., by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% the severity or duration of one or more (e.g., one, two, three, four, or five) symptoms of a disease (i.e., ALS, FTD, or AS) in a patient. Desirably, at least 20%, 40%, 60%, 80%, 90%, or 95% of the treated subjects have a complete remission in which all evidence of the disease disappears. In another desirable embodiment, the length of time a patient survives after being diagnosed with a condition and treated using the methods of the invention is at least 20%, 40%, 60%, 80%, 100%, 200%, or even 500% greater than (i) the average amount of time an untreated patient survives or (ii) the average amount of time a patient treated with another therapy survives. As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. In an aspect, prevent or preventing refers to the ameliorating of one or more signs and symptoms associated with ALS or FTD. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. A “therapeutically effective amount” of a compound of a pharmaceutical composition thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. A “therapeutically effective amount” may also mean “prophylactically effective amount” of a compound of the present invention is an amount sufficient to prevent a disease or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. Administration of a treatment may be effected by any method that enables delivery of the compositions to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the composition and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present invention. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well- known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein. The term “subject” refers to any animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human (e.g., a man, a woman, or a child). The human may be of either sex, or may be at any stage of development. In certain embodiments, the subject has been diagnosed with ALS. In other embodiments, the subject is at risk of developing the neurodegenerative condition or disease, such as ALS, FTD, AS or other diseases or conditions related to the differential translation of PEG10 due to ribosomal frameshifting. In certain embodiments, the subject is an experimental animal (e.g., mouse (murine), rat, rabbit, dog, pig, or primate). The experimental animal may be genetically engineered. As used herein, the phrase “in need thereof” means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal may be in need thereof. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent. As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. For example, “contacting” a compound disclosed herein with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the compounds or pharmaceutical compositions disclosed herein. The terms “cell penetrating peptide” and “CPP” are used interchangeably and refer to cationic cell penetrating peptides, also called “transport peptides,” “carrier peptides,” or “peptide transduction domains.” The peptides, as shown herein, have the capability of inducing cell penetration within 100% of cells of a given cell culture population and allow macromolecular translocation within multiple tissues in vivo upon systemic administration. A preferred CPP embodiment is an arginine-rich peptide as described further below. As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. The abbreviation, “i.e.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “i.e.” is synonymous with the term “for example By “about” is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. The disclosure now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain aspects of the embodiments of the present disclosure. The examples are not intended to limit the disclosure, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed disclosure. EXAMPLES Example 1: Effect of Different Chemistries on PEG10 Pseudoknot Targeting and Protein Modulation. The effect of various chemistries was tested to evaluate their potential for modulating the production ratio of two alternative proteins, gag and gag-pol, by targeting the PEG10 pseudoknot structure. The most potent candidate identified from fully TMO-modified sequences (H3; SEQ ID NO.6) was synthesized using several standard chemistries to directly compare their impact on this approach. The selected chemistries (Fig.6a) represent a range of increasing duplex stability with complementary RNA and were tested on an established cell line to assess their influence on Gag and gag-pol protein production ratios. Cells were treated under identical conditions, using the same procedures optimized in prior screening studies performed by Applicants which would be known and understood by those of ordinary skill in the art. Western blot analysis (Fig. 6b) revealed that the TMO-modified H3 sequence produced the strongest effect (Fig.6c), despite expectations that more stable chemistries would induce greater changes based on RNA-binding strength. To verify the stability of these sequences, a thermal melting study was conducted on all constructs and chemistries. As expected, traditional chemistries demonstrated increasing duplex stability with complementary RNA (Fig. 7). However, the TMO-modified sequence showed thermal stability comparable to RNA:RNA duplexes, suggesting that the observed biological effect of TMO is not primarily driven by thermodynamic binding strength. These findings prompted a localization study to determine whether the TMO-induced effect occurs in the cytoplasm, prior to translation, or in the nucleus. Given the known rapid nuclear accumulation of TMO-modified sequences, experiments were designed using fluorescein (FAM) and cyanine-5 (Cy-5)–labeled oligonucleotides (Fig.8a). The localization of single-stranded TMO-modified H3 (FAM-labeled) and the PS-RNA sense strand (Cy-5–labeled) was examined using confocal microscopy. As shown in Fig. 8b–c, the TMO- modified sequence localized primarily to the nucleus (visualized with DAPI), while the PS-RNA sequence accumulated in the cytoplasm, likely near the endoplasmic reticulum. To assess whether the nuclear localization of TMO could be altered by introducing it as a double-stranded duplex with a complementary sense strand, both strands were labeled with distinct fluorophores and transfected into cells. Confocal imaging using DAPI, FAM (Fig.8d), and Cy-5 (Fig.8e) channels confirmed that duplex formation changed the localization of the TMO strand from the nucleus to the cytoplasm. Merged imaging (Fig. 8f) confirmed colocalization, suggesting that duplexing TMO prevents its nuclear accumulation. To further validate the mechanism, we tested two constructs: (1) a fully TMO-modified, RNase H1–inactive single-stranded sequence and (2) a “cap-gap” chimera (TMO-modified in the cap regions and PS-DNA in the central gap), which is RNase H1–active. Both constructs were evaluated in single- and double-stranded forms (Fig.9a). Western blot analysis (Fig. 9b) and quantification (Fig. 9c) showed that the double-stranded versions abolished the protein modulation effect observed with the single-stranded TMO constructs. Interestingly, the RNase H1–active cap-gap construct resulted in downregulation of total gag and gag-pol protein levels, as expected, but also caused a shift in their ratio, favoring degradation of the gag protein variant. In contrast, the fully TMO-modified sequence led to a significant alteration in the gag:gag-pol ratio, with selective downregulation of gag-pol, as originally observed. These results suggest a distinct mechanism of action for TMO sequences: rather than melting a preformed pseudoknot, they may inhibit its formation in the nucleus, potentially during or immediately after transcription. This supports the existence of a fully locked pseudoknot structure that can be weakened by alternative binding sites within the higher-order organization of mRNA. The originally proposed pseudoknot structure (Fig. 10a), confirmed by AlphaFold predictions (Fig. 10b), could be destabilized by such alternative interactions. This would allow TMO sequences not only to prevent pseudoknot formation but also to influence the gag:gag-pol protein ratio by binding to a secondary structure intermediate where the pseudoknot is partially weakened (Fig.10c). This model is further supported by results from the RNase H1– active TMO sequence, which reduced the total levels of both gag and gag-pol, presumably by preventing pseudoknot formation. However, it also caused a pronounced reduction in gag levels while maintaining a substantial portion of gag-pol production. This suggests that while the intermediate, weakened structure may be susceptible to ASO-mediated interference, the fully formed and most stable pseudoknot conformation remains largely resistant to disruption by standard ASOs. The enhanced activity of TMO-modified sequences, compared to other chemistries with greater thermal stability, arises from their unique properties, especially their rapid nuclear localization and structural flexibility. These features likely promote hybridization with the target mRNA as it is being transcribed, interfering with pseudoknot formation rather than destabilizing a pre-formed structure. This is further supported by the loss of activity when TMO sequences are delivered as duplexes, preventing nuclear access. Finally, RNase H1 experiments revealed that while some degradation of the PEG10 transcript can be achieved using active chimeras, they do not significantly disrupt the pseudoknot once it is formed. In light of these findings, Applicants propose a model where pseudoknot dynamics shift between two conformations: one that favors gag-pol translation (intact pseudoknot) and another more accessible to ASO binding, favoring gag translation and degradation. This dynamic equilibrium may explain why targeting the early stages of pseudoknot formation with TMO-modified ASOs is particularly effective. Example 2: materials and Methods. Thermal stability study: Thermal denaturation experiments were performed using a Cary 100 Bio UV-VIS spectrophotometer, equipped with a 6x6 thermostatted multicell holder and a Peltier temperature controller. Oligonucleotides (ONs) and their complementary strands were mixed in equimolar ratios (1.0 µM per strand) in a buffer containing 100 mM NaCl, 50 mM NaH2PO4, and 1 mM EDTA at pH 7.2. The samples were transferred to 1 mL cuvettes and subjected to a heating cycle starting from 20°C and increasing to 100°C at a rate of 1°C per minute. After reaching 100°C, the samples were held at this temperature for 5 minutes before cooling down to 4°C at the same rate. Thermal denaturation measurements were taken after cooling. The denaturation curves were recorded at 260 nm, with a ramp rate of 0.5°C per minute. Data analysis and processing were carried out using Cary WinUV software. The melting temperature (Tm) values were determined by locating the peak in the first-derivative plots of absorbance versus temperature, with a precision of ±1°C. Confocal microscopy: To study cellular uptake and localization of oligos, HEK293 cells were subjected to lipofection in above mentioned process in a 24 well plate.72h post lipofection, the cells were washed gently with 500ul of DPBS twice. Next, 500ul of Trypsin EDTA(0.25% Trypsin-EDTA, phenol red, Gibco) were added to each well of the 24 well plate and the plate was placed in an incubator for 2-3 min. Once the cells were dislodged, 500ul of DMEM media was added to each well to neutralize the solution. Then cells were collected and spun down at 1000 g for 10 min. After that, the supernatant was removed and 500ul of fresh DMEM media was added. Next, cells were plated with ~5000 cells / well seeding density in a 24 well SensoPlate (SensoPlate™ 24 well, PS, F-bottom, glass bottom, black, with lid, sterile, single packed, Greiner Bio-One, Catalog # 82050-898) and incubated overnight for the cells to be attached on to the plate surface. The SensoPlates were used for this study as they are considered ideal for applications requiring low autofluorescence with exceptional optical clarity. Next day, cells were fixed using 2%PFA solution by adding 400ul in each well for 10 min at 37oC. Then the PFA solution was removed and the cells were washed 3 times with 1X PBS. Next, for permeabilization, 400ul of 0.1% Triton X-100 (Invitrogen) in 1X PBS was added in each well and the cells were incubated at room temperature for 15 min. Again, cells were washed with 1X PBS three times and cell nuclei were stained with DAPI (Invitrogen). For DAPI staining, a 5 mg / mL DAPI stock solution was diluted to 300 nM in PBS. Approximately 400 µL of the diluted DAPI staining solution was added to each well and the cells were kept incubated for 15 minutes with the lid on at RT. Then the cells were again washed with 1X PBS thrice. Next, cells were imaged in confocal microscopy (Nikon AXR) using 405 / 488 and 561 laser lines.

Claims

CLAIMS What is claimed is:

1. An antisense oligomer targeted to a nucleic acid molecule encoding a human paternally expressed gene 10 (PEG10), wherein the antisense oligomer has a modified backbone structure, and wherein the antisense oligomer inhibits ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein.

2. The antisense oligomer of any of claims 1, wherein the antisense oligomer targets a pseudoknot structure of the PEG10 mRNA.

3. The antisense oligomer of any of claim 1-2, wherein the antisense oligomer targets loop 1 of the pseudoknot structure of the PEG10 mRNA.

4. The antisense oligomer of any of claims 1 to 3, wherein the PEG10 mRNA comprises a nucleotide sequence according to SEQ ID NO. 3, or a sequence having at least 80% or more sequence identity with SEQ ID NO.

3.

5. The antisense oligomer of any of claims 1 to 4 , wherein the antisense oligomer has a nucleobase sequence selected from SEQ ID NO.’s: 6-7, or a combination of the same..

6. The antisense oligomer of any of claims 1 to 5, wherein the antisense oligomer contains one or more nucleotide positions subject to an alternative chemistry or modification selected from: (i) modified sugar moieties; (ii) resistance to RNase H; and / or (iii) oligomeric mimetic chemistry; and / or wherein the antisense oligomer is modified by: (i) a chemical conjugate coupled to a moiety by a linker, and wherein said chemical conjugate is selected from Vitamin E, Cholesterol, and / or N-Acetylgalactosamine (GalNAc); (ii) tagging with a cell penetrating peptide; and / or (iii) encapsulated in a liposome nanoparticle structure.

7. The antisense oligomer of any of claims 1 to 6, wherein, if a uracil is present in the antisense oligomer, the uracil (U) of the antisense oligomer is replaced by a thymine (T).

8. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises a thiomorpholino oligomer (TMO).

9. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises a phosphorodiamidate morpholino oligomer (PMO).

10. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises a 2’-O-Methyl (2’-OMe) antisense oligomer.

11. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises at least one phosphorothioate (PS) modification forming an antisense oligomer having at least one phosphorothioate internucleotide linkage.

12. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises at least one chemical modification forming a locked nucleic acid (LNA) antisense oligomer.

13. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer is a PS-LNA antisense oligomer.

14. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer is a phosphorothioate modified 2'-O-methoxyethyl (PS-MOE) antisense oligomer.

15. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer is a PS-OMe antisense oligomer.

16. The antisense oligomer of any of claims 1 to 7, wherein said antisense oligomer comprises a gapmer.

17. The antisense oligomer of claim 1, wherein said antisense oligomer comprises SEQ ID NO.6.

18. A pharmaceutical composition for the treatment of a treat, prevent, or ameliorate the effects of a disease associated the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation, the composition comprising an isolated antisense oligomer according to any one of claims 1 to 17, and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the disease associated the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation is a neurodegenerative disease.

20. The pharmaceutical composition of claim 19, wherein the neurodegenerative disease is selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS).

21. A method of treating, preventing, or ameliorating the effects of a disease associated with associated the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation, comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the pharmaceutical composition of claim 18.

22. The method of claim 21, wherein the disease associated the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation is a neurodegenerative disease.

23. The method of any of any claims 16 to 17, wherein the neurodegenerative disease is selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS).

24. A lipid nano-particle encapsulating one or more isolated antisense oligomers according to any one of claims 1 to 17.

25. An isolated antisense oligomer according to any one of claims 1 to 17.

26. The use of isolated antisense oligomers according to claim 25, for the manufacture of a medicament to treat, prevent or ameliorate the effects of a disease associated with the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation.

27. The use of purified and isolated antisense oligomers according to claim 25, to treat, prevent or ameliorate the effects of a disease associated with the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation.

28. The use of any of claims 26 or 27, wherein the disease is a neurodegenerative disease.

29. The use of claim 28, wherein the neurodegenerative disease is selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS).

30. A kit to treat, prevent or ameliorate the effects of a disease associated with the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation, the kit comprising at least an antisense oligomer or a pharmaceutical composition containing an antisense oligomer according to any one of claims 1-17, packaged in a suitable container, together with instructions for its use.

31. The kit of claim 30, wherein the disease is a neurodegenerative disease.

32. The kit of claim 31, wherein the neurodegenerative disease is selected from: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Angelman’s Syndrome (AS).

33. A method for inhibiting ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein, comprising the step of providing one or more of the antisense oligomers according to any one of claims 1 to 17, and allowing the oligomer(s) to bind to a target nucleic acid site.

34. The method of claim 33, wherein the step of inhibiting occurs in vivo, ex vivo, or in vitro.

35. An antisense oligomer targeted to a nucleic acid molecule encoding a mouse paternally expressed gene 10 (PEG10), wherein the antisense oligomer has a modified backbone structure, and wherein the antisense oligomer inhibits ribosomal frameshifting of the PEG10 mRNA during translation, thereby inhibiting the formation of a long form gag-pol protein.

36. The antisense oligomer of any of claims 35, wherein the antisense oligomer targets a pseudoknot structure of the PEG10 mRNA.

37. The antisense oligomer of claim 35 to 36, wherein the antisense oligomer targets loop 1 of the pseudoknot structure of the PEG10 mRNA.

38. The antisense oligomer of any of claims 35 to 37, wherein the antisense oligomer has a nucleobase sequence selected from: SEQ ID NO.:

9.

39. The antisense oligomer of any of claims 35 to 38, wherein the PEG10 mRNA comprises a nucleotide sequence according to SEQ ID NO. 2, or a sequence having at least 80% or more sequence identity with SEQ ID NO.

2.

40. The antisense oligomer of any of claims 35 to 38, wherein the antisense oligomer contains one or more nucleotide positions subject to an alternative chemistry or modification selected from: (i) modified sugar moieties; (ii) resistance to RNase H; and / or (iii) oligomeric mimetic chemistry; and / or wherein the antisense oligomer is modified by: (i) a chemical conjugate coupled to a moiety by a linker, and wherein said chemical conjugate is selected from Vitamin E, Cholesterol, and / or N-Acetylgalactosamine (GalNAc); (ii) tagging with a cell penetrating peptide; and / or (iii) encapsulated in a liposome nanoparticle structure.

41. The antisense oligomer of any of claims 35 to 40, wherein, if a uracil is present in the antisense oligomer, the uracil (U) of the antisense oligomer is replaced by a thymine (T).

42. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer comprises a thiomorpholino oligomer (TMO).

43. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer comprises a phosphorodiamidate morpholino oligomer (PMO)..

44. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer comprises a 2’-O-Methyl (2’-OMe) antisense oligomer.

45. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer comprises at least one phosphorothioate (PS) modification forming an antisense oligomer having at least one phosphorothioate internucleotide linkage.

46. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer comprises at least one chemical modification forming a locked nucleic acid (LNA) antisense oligomer.

47. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer is a PS- LNA antisense oligomer.

48. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer is a phosphorothioate modified 2'-O-methoxyethyl (PS-MOE) antisense oligomer.

49. The antisense oligomer of any of claims 35 to 41, wherein said antisense oligomer is a PS- OMe antisense oligomer.

50. A kit to treat, prevent or ameliorate the effects of a disease associated with the production of a gag-pol protein(s) resulting from ribosomal frameshifting of the PEG10 mRNA during translation in a mouse disease model, the kit comprising at least an antisense oligomer according to any one of claims 35-49, or a pharmaceutical composition containing at least an antisense oligomer according to any one of claims 35-49, packaged in a suitable container, together with instructions for its use.

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