Treatments for lymphedema

Abstract

The invention relates to oligonucleotide agents capable of suppressing the expression of Mannose Receptor C-Type 2 (MRC2) and their use for treating lymphedema.

Description

[0001]TREATMENTS FOR LYMPHEDEMA FIELD The present invention lies in the medical field, particularly in the field of treatments for lymphedema. BACKGROUND Lymphedema is a chronic and debilitating condition characterised by impaired lymphatic drainage, tissue swelling, and fibrosis, remaining an incurable disorder of the lymphatic vascular system. It can manifest either as primary lymphedema, which is mainly due to genetic causes, or secondary lymphedema (SL). SL can result from or be associated with filariasis, cancer, or cancer treatment such as lymphadenectomy. To date, lymphedema treatments encompass manual massage, compression therapy, and surgical interventions such as vascularised lymph node transfer. Preclinical assays in mice have been centred around administration of pro-lymphangiogenic (VEGF-C), anti- fibrotic (anti-TGFbeta), or anti-inflammatory factors. Further lymphedema treatments are needed. Mannose Receptor C-Type 2 (MRC2), also known as Urokinase-Type Plasminogen Activator Receptor-Associated Protein (uPARAP), Endocytic Receptor 180 (ENDO180), CD280 Antigen, CLEC13E, and KIAA0709, mediates the internalisation and lysosomal degradation of collagen ligands and shows involvement in both fibrotic and lymphangiogenic processes (Gucciardo et al. uPARAP / Endo180: a multifaceted protein of mesenchymal cells. Cell. Mol. Life Sci. CMLS.2022, vol. 79, 255). Durré et al. (uPARAP / Endo180 receptor is a gatekeeper of VEGFR-2 / VEGFR-3 heterodimerisation during pathological lymphangiogenesis. Nat. Commun. 2018, vol. 9, 5178) demonstrated the role of uPARAP in restricting VEGF-C-driven VEGFR-2 / VEGFR-3 heterodimerisation, leading to enhanced VEGFR-3 / JNK / Rac1 signalling, impaired directional migration of lymphatic endothelial cell (LEC), and increased lymphangiogenesis. SUMMARY The present invention is at least in part based on the inventors’ demonstration that administration of oligonucleotide agents capable of suppressing the expression of MRC2 / uPARAP reduced lymphedema formation in a mouse model of secondary lymphedema. This amelioration of lymphedema appeared associated with atypical lymphatic vasculature with increased tortuosity and hyperbranching. Accordingly, an aspect of the invention provides an oligonucleotide agent capable of suppressing the expression of Mannose Receptor C-Type 2 (MRC2) / uPARAP for use in treating lymphedema. A related aspect provides a method for treating lymphedema in a subject in need thereof, comprising administering to the subject an effective amount of an oligonucleotide agent capable of suppressing MRC2 / uPARAP. A further aspect provides a pharmaceutical composition comprising an oligonucleotide agent capable of suppressing the expression of MRC2 / uPARAP. These and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. The subject-matter of the appended claims is hereby specifically incorporated in this specification. BRIEF DESCRIPTION OF DRAWINGS The following description of the figures of specific embodiments of the invention is merely exemplary in nature and is not intended to limit the present teachings, their application or uses. Fig. 1 illustrates the efficacy of anti-uPARAP gapmers in vitro and in vivo, in an animal model of secondary lymphedema. Primary mouse fibroblasts were transfected with gapmers targeting uPARAP (G1, G2, G3, G4 and G5) or a negative control gapmer (CTRL). A. RT-qPCR analysis of uPARAP and GAPDH mRNA from fibroblasts cultured for 48, 72 and 96 hours post-transfection. Data are means ± SD from 3 independent experiments. Statistical test: One sample t test. B. Western blot revealing uPARAP and GAPDH protein levels, in fibroblasts at 48, 72 and 96 hours post- transfection. C. Timeline of secondary lymphedema (SL) induction in WT mice treated with a gapmer targeting uPARAP (n=8), a negative control gapmer (n=8), or PBS (n=8). The graph corresponds to the follow-up of the relative volume of the limb. Results are expressed as percentage of control limb volume (100%, dotted line). Data are means ± SEM. Statistical test: two-way ANOVA with Holm-Sidak post hoc test for multiple comparisons. D. Z-stack projections of deeper Lyve-1-positive lymphatic vessels in lymphedema skin. Scale bars: 250 µm. E.3D-quantification of deeper Lyve-1 positive vessels in whole-mount SL skin samples of CTRL and G4-treated mice. The two graphs correspond to 3D-branching density (left) and 3D-tortuosity (right). Data are means ± SEM. Statistical test: one-way ANOVA with Holm-Sidak post hoc test for multiple comparisons. ns: non-significant; p* < 0.05; p** < 0.01; p*** < 0.001; p**** < 0.0001. Fig.2 illustrates uPARAP silencing through RNA interference in human LECs. Human LECs were transfected with a pool of 4 siRNA against uPARAP (KD) or a pool of 4 control siRNA (CTRL). Mock correspond to untransfected cells. Transfection efficiency was determined at protein level through Western blot (A, B) and RNA level through RT-qPCR (C). A-B. Western blotting of uPARAP with GAPDH as loading control protein (A) and its quantification (B). C. uPARAP RNA level was quantified by RT-qPCR. B-C. Data are means ± SEM of 3 independent experiments. Statistical tests: One sample t test. p** < 0.01. Fig.3 illustrates that uPARAP silencing enhances overlapping conformation of cell-cell junctions in human LECs. Human LECs transfected with a pool of 4 siRNA against uPARAP (KD) or a pool of 4 control siRNA (CTRL) were treated with VEGF-C for 24h (A) or 2h (B, C) A-B. VE-cadherin immunolabelings. Arrows show linear junctions and asterisks indicate overlapping junctions (referring to wave-like lamellipodia or wave-like and overlapping protrusions or O.P.). C. Quantification of 7 different cell-cell junctions (as depicted in annotated images) (B) determined in 5 independent microscope fields by condition and by experiment (C). Data are means ± SEM from 3 independent experiments (C). Scale bars: 20 µm. Fig. 4 illustrates that human LEC permeability is reduced under uPARAP silencing. Relative permeability of FITC-dextran (40 kDa) assessed after 60 min of VEGF-C stimulation, in uPARAP knock-down cells (KD) compared to WT human LECs. Data are means ± SEM from 10 independent experiments. Statistical test: unpaired t test. p** < 0.01. Fig.5 illustrates comparative efficacy of Gapmer designs targeting uPARAP in human cells. Primary human lymphatic endothelial cells (hLECs) were transfected with gapmers targeting uPARAP, G4 and 4 human Gapmers, or a negative control gapmer (CTRL). Human gapmers shared the same nucleotide sequence but differed in the number and positioning of locked nucleic acids (LNAs), with configurations of 3–3, 2–2, 2–3, and 3–2 at the 5′ and 3′ ends, respectively. A. RT-qPCR analysis of uPARAP and GAPDH mRNA from hLECs cultured for 48-, 72- and 96-hours post-transfection. Data are means ± SEM from 3 independent experiments. B. Western blot revealing uPARAP and GAPDH protein levels, in hLECs at 48-, 72- and 96-hours post-transfection. Statistical test: one-way ANOVA with Holm-Sidak post hoc test for multiple comparisons. p**** < 0.0001. Fig.6 illustrates that Human Gapmers attenuates SL in vivo. Timeline of SL induction in WT mice treated with a gapmer (G4) targeting uPARAP (n=8), a human gapmer (LNA 2-2) (n=8), a human gapmer (LNA 2-3) (n=8) and a negative control gapmer (CTRL; n=8). The graph corresponds to the follow-up of the relative volume of the limb (percentage of control limb volume; dotted line=100%). Data are means ± SEM. Statistical test: two-way repeated measures ANOVA with Holm-Sidak post hoc test for multiple comparisons. ns: non-significant; p* < 0.05; p** < 0.01. DESCRIPTION OF EMBODIMENTS As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise. The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including”, “includes”, “containing”, or “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “constituted of”, “consists in”, “consisting of”, and “consists of”, and also the terms “consisting essentially of”, “consisting essentially in” and “consists essentially of”, which enjoy well-established meanings in patent terminology. The recitation of numerical ranges by endpoints includes all intervening values between the lower and upper endpoints, as well as the recited endpoints. Intervening values may be integers or, where applicable, fractions, i.e., more broadly any real numbers such as any rational numbers. This applies to numerical ranges irrespective of whether they are introduced by the expression “from… to…” or the expression “between… and…” or another expression. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, each sub-range between any stated value in a stated range and any other stated value in that stated range is also specifically disclosed. Each sub-range between any stated value in a stated range and either the lower endpoint or the upper endpoint of the stated range is also specifically disclosed. The stated value may be an isolated value or an endpoint of a range subsumed by or overlapping with the stated range. For example, for a stated range with lower endpoint L1 and upper endpoint U1 (i.e., stated range L1-U1) and a stated sub- range nested within the stated range with lower endpoint L2 and upper endpoint U2 (i.e., stated sub- range L2-U2), also specifically disclosed are the subranges L1-L2, L1-U2, L2-U1, and U2-U1. The terms “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass variations of and from the specified value, such as variations of + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” or “approximately” refers is itself also specifically, and preferably, disclosed. Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order, unless specified. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. Whereas the terms “one or more” or “at least one”, such as one or more members or at least one member of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any ≥3, ≥4, ≥5, ≥6 or ≥7 etc. of said members, and up to all said members. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7 or more. As used herein, the term “and / or” when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and / or C, the list can comprise A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B, and C in combination. The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims. Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference. Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the invention. When specific terms are defined in connection with a particular aspect of the invention or a particular embodiment of the invention, such connotation or meaning is meant to apply throughout this specification, i.e., also in the context of other aspects or embodiments of the invention, unless otherwise defined. In the following passages, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment so defined may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. Reference throughout this specification to “one embodiment”, “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination. Similarly, it should be appreciated that in the description of illustrative embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. In the present description of the invention, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration only of specific embodiments in which the invention may be practiced. Parenthesized or emboldened reference numerals affixed to respective elements merely exemplify the elements by way of example, with which it is not intended to limit the respective elements. Unless otherwise indicated, all figures and drawings in this document are not to scale and are chosen for the purpose of illustrating different embodiments of the invention. In particular the dimensions of the various components are depicted in illustrative terms only, and no relationship between the dimensions of the various components should be inferred from the drawings, unless so indicated. An aspect of the invention provides an oligonucleotide agent capable of downregulating / suppressing the expression of MRC2 for use in treating lymphedema. The phrase “for use in treating lymphedema” may be used interchangeably with alternative phrases such as “for treating lymphedema”, “for treatment of lymphedema”, or “for use in a method of treating lymphedema”. Such phrases may optionally include an explicit reference to a treated subject, e.g., “for use in treating lymphedema in a subject”. A related aspect provides a method for treating lymphedema in a subject in need thereof, comprising administering to the subject an effective amount of an oligonucleotide agent capable of suppressing the expression of MRC2. A related aspect provides the use of an oligonucleotide agent capable of suppressing the expression of MRC2 for the manufacture of a medicament for the treatment of lymphedema. A related aspect provides the use of an oligonucleotide agent capable of suppressing the expression of MRC2 for the treatment of lymphedema. Lymphedema is a medical condition characterised by impaired lymphatic drainage leading to the accumulation of lymphatic fluid in tissues and tissue swelling. Lymphedema encompasses primary lymphedema which typically occurs due to congenital abnormalities in the lymphatic system. Primary lymphedema is often associated with genetic mutations that affect the development and function of the lymphatic vessels. Examples of primary lymphedema include, without limitation, congenital lymphedema, which manifests before the age of 2 years, including inter alia Milroy’s Disease, an autosomal dominant familial form associated with mutations in the FLT4 gene encoding VEGFR-3; lymphedema praecox which appears between ages 2 and 35 years, usually in women at onset of menses or pregnancy; Meige Disease, an autosomal dominating familial form of lymphedema praecox, which has been linked to mutations in the transcription factor gene FOXC2; and lymphedema tarda, which occurs after the age of 35 and of which there are familial and sporadic forms with less well understood genetic basis. Hence, in certain embodiments, the lymphedema is primary lymphedema. Lymphedema more commonly occurs as a secondary condition, i.e., secondary lymphedema, following damage to the lymphatic system. Such damage can result from various medical interventions and health conditions, including lymph node dissection, radiation therapy, surgical procedures, musculoskeletal injuries (e.g., fractures, tendon releases, joint replacements), neurological disorders causing muscle paresis, vascular surgeries, skin injuries, deep vein thrombosis, and chemotherapy treatments such as involving tamoxifen. Infectious diseases like filariasis and cellulitis, as well as non-infectious conditions such as lipedema, may also precipitate lymphedema. Secondary lymphedema is frequently associated with cancer treatments, such as chemotherapy, radiation therapy, or surgery. As used herein, the term “cancer” refers to a malignant neoplasm characterised by deregulated or unregulated cell growth. The term includes primary malignant cells or tumours (e.g., those whose cells have not migrated to sites in the subject’s body other than the site of the original malignancy or tumor) and secondary malignant cells or tumours (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor). The term “metastatic” or “metastasis” generally refers to the spread of a cancer from one organ or tissue to another non-adjacent organ or tissue. Cancers the treatment of which frequently leads to lymphedema include, without limitation, breast cancer – breast cancer surgeries, especially those involving axillary lymph node dissection, and radiation therapy, are highly associated with lymphedema of the arm on the side of the surgery; gynaecological cancers (cervical, ovarian, uterine) – pelvic lymph node dissection and radiation therapy can damage pelvic lymph nodes and channels, leading to lower extremity lymphedema; melanoma – lymph node dissection near the affected skin areas (such as groin or axillary regions), particularly if combined with radiation therapy, can lead to lymphedema; prostate and testicular cancer – prostatectomy and lymph node dissection, along with radiation, can lead to lymphedema typically in the genital area and / or legs; head and neck cancers – surgery and radiation therapy to the neck can damage lymph nodes and lymphatic channels, leading to lymphedema of the face, neck, and upper airway; and lymphoma – treatment for lymphoma often involves extensive radiation therapy and lymph node dissection, which can disrupt normal lymphatic drainage. Hence, in certain embodiments the lymphedema is secondary lymphedema, such as secondary lymphedema resulting from or associated with any of the aforementioned conditions, circumstances, and / or treatments. In certain embodiments, the secondary lymphedema is filariasis lymphedema. In certain embodiments, the secondary lymphedema is cancer-related lymphedema or cancer-treatment- related lymphedema. In certain embodiments, the cancer is breast cancer, a gynaecological cancer such as cervical, ovarian, or uterine cancer, melanoma, prostate cancer, testicular cancer, head and neck cancer, or lymphoma. In certain embodiments, the cancer treatment comprises chemotherapy, radiation therapy, surgery, or any combination thereof. Lymphedema is also a symptom in certain genetic syndromes that include other abnormalities, such as Turner Syndrome, Noonan Syndrome, Klippel-Trénaunay Syndrome (KTS), Yellow Nail Syndrome, or Hennekam syndrome. Hence, in certain embodiments, the lymphedema is syndromic lymphedema, such as lymphedema associated with one of the above genetic syndromes. In therapeutic contexts, compositions currently used in the art to treat or prevent lymphedema aim to alleviate swelling by facilitating tissue and lymphatic regeneration and reducing inflammation. It shall be understood that the presently disclosed treatments can be combined with any one or more of such established lymphedema treatments. Reference to “therapy” or “treatment” broadly encompasses both curative and preventative treatments, and the terms may particularly refer to the alleviation or measurable lessening of one or more symptoms or measurable markers of a pathological condition such as a disease or disorder. The terms encompass primary treatments as well as neo-adjuvant treatments, adjuvant treatments and adjunctive therapies. Measurable lessening includes any statistically significant decline in a measurable marker or symptom. Generally, the terms encompass both curative treatments and treatments directed to reduce symptoms and / or slow progression of the disease. The terms encompass both the therapeutic treatment of an already developed pathological condition, as well as prophylactic or preventative measures, wherein the aim is to prevent or lessen the chances of incidence of a pathological condition. In certain embodiments, the terms may relate to therapeutic treatments. In certain other embodiments, the terms may relate to preventative treatments. Treatment of a chronic pathological condition during the period of remission may also be deemed to constitute a therapeutic treatment. The term may encompass ex vivo or in vivo treatments as appropriate in the context of the present invention. The term “therapeutically effective amount” refers to an amount which can elicit a biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and in particular can prevent or alleviate one or more of the local or systemic symptoms or features of a disease or condition being treated. Appropriate therapeutically effective amounts may be determined by a qualified physician with due regard to the nature and severity of the disease condition, and the age, size and condition of the subject. The terms “subject”, “individual” or “patient” are used interchangeably throughout this specification, and typically and preferably denote humans, but may also encompass reference to non-human animals, preferably warm-blooded animals, even more preferably non-human mammals, in particular equine species. The term “equine” s used herein encompasses horses (Equus ferus), domesticated horses (Equus ferus caballus), donkeys (Equus africanus asinus), zebras (e.g., Equus zebra, Equus quagga, Equus grevyi), and hybrids thereof such as mules and hinnies. In particular embodiments, the subject is a horse, such as domesticated horse. Particularly preferred are human subjects including both genders and all age categories thereof. In other embodiments, the subject is an experimental animal or animal substitute as a disease model. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as foetuses, whether male or female, are intended to be covered. The term subject is further intended to include transgenic non-human species. In preferred embodiments, the subject is human. The term “subject in need of treatment” or similar as used herein refers to subjects diagnosed with or having a disease as recited herein and / or those in whom said disease is to be prevented. Mannose Receptor C-Type 2 (MRC2) is also known as Urokinase-Type Plasminogen Activator Receptor-Associated Protein (uPARAP), Endocytic Receptor 180 (ENDO180), CD280 Antigen, C- Type Lectin Domain Family 13 Member E (CLEC13E), and KIAA0709. Human MRC2 is annotated under U.S. government’s National Center for Biotechnology Information (NCBI) Genbank (http: / / www.ncbi.nlm.nih.gov / ) Gene ID no.9902. A human wild-type MRC2 amino acid sequence may be as annotated under Genbank accession no: NP_006030.2 or Swissprot / Uniprot (http: / / www.uniprot.org / ) accession no: Q9UBG0 (sequence version 2), the NP_006030.2 sequence reproduced here below from N to C terminus (SEQ ID NO : 72): MGPGRPAPAPWPRHLLRCVLLLGCLHLGRPGAPGDAALPEPNVFLIFSHGLQGCLEAQGG QVRVTPACNTSLPAQRWKWVSRNRLFNLGTMQCLGTGWPGTNTTASLGMYECDREALN LRWHCRTLGDQLSLLLGARTSNISKPGTLERGDQTRSGQWRIYGSEEDLCALPYHEVYTIQ GNSHGKPCTIPFKYDNQWFHGCTSTGREDGHLWCATTQDYGKDERWGFCPIKSNDCETF WDKDQLTDSCYQFNFQSTLSWREAWASCEQQGADLLSITEIHEQTYINGLLTGYSSTLWIG LNDLDTSGGWQWSDNSPLKYLNWESDQPDNPSEENCGVIRTESSGGWQNRDCSIALPYVC KKKPNATAEPTPPDRWANVKVECEPSWQPFQGHCYRLQAEKRSWQESKKACLRGGGDL VSIHSMAELEFITKQIKQEVEELWIGLNDLKLQMNFEWSDGSLVSFTHWHPFEPNNFRDSL EDCVTIWGPEGRWNDSPCNQSLPSICKKAGQLSQGAAEEDHGCRKGWTWHSPSCYWLGE DQVTYSEARRLCTDHGSQLVTITNRFEQAFVSSLIYNWEGEYFWTALQDLNSTGSFFWLSG DEVMYTHWNRDQPGYSRGGCVALATGSAMGLWEVKNCTSFRARYICRQSLGTPVTPELP GPDPTPSLTGSCPQGWASDTKLRYCYKVFSSERLQDKKSWVQAQGACQELGAQLLSLAS YEEEHFVANMLNKIFGESEPEIHEQHWFWIGLNRRDPRGGQSWRWSDGVGFSYHNFDRSR HDDDDIRGCAVLDLASLQWVAMQCDTQLDWICKIPRGTDVREPDDSPQGRREWLRFQEA EYKFFEHHSTWAQAQRICTWFQAELTSVHSQAELDFLSHNLQKFSRAQEQHWWIGLHTSE SDGRFRWTDGSIINFISWAPGKPRPVGKDKKCVYMTASREDWGDQRCLTALPYICKRSNV TKETQPPDLPTTALGGCPSDWIQFLNKCFQVQGQEPQSRVKWSEAQFSCEQQEAQLVTITN PLEQAFITASLPNVTFDLWIGLHASQRDFQWVEQEPLMYANWAPGEPSGPSPAPSGNKPTS CAVVLHSPSAHFTGRWDDRSCTEETHGFICQKGTDPSLSPSPAALPPAPGTELSYLNGTFRL LQKPLRWHDALLLCESRNASLAYVPDPYTQAFLTQAARGLRTPLWIGLAGEEGSRRYSWV SEEPLNYVGWQDGEPQQPGGCTYVDVDGAWRTTSCDTKLQGAVCGVSSGPPPPRRISYH GSCPQGLADSAWIPFREHCYSFHMELLLGHKEARQRCQRAGGAVLSILDEMENVFVWEH LQSYEGQSRGAWLGMNFNPKGGTLVWQDNTAVNYSNWGPPGLGPSMLSHNSCYWIQSN SGLWRPGACTNITMGVVCKLPRAEQSSFSPSALPENPAALVVVLMAVLLLLALLTAALILY RRRQSIERGAFEGARYSRSSSSPTEATEKNILVSDMEMNEQQE According to the annotation, MRC2 is a single-pass type I membrane protein with amino acids 31- 1414 corresponding to the extracellular domain, amino acids 1415-1435 to the transmembrane domain and amino acids 1436-1479 to the cytoplasmic domain. According to the annotation, amino acids 1-30 correspond to the signal peptide. Any transcription product or transcript, in particular a transcript endogenously produced by a cell, that comprises a coding sequence encodes the MRC2 protein can be targeted by oligonucleotide agents described herein. The agents may target either the coding or non-coding sequences of such transcript. In certain embodiments the transcript is the MRC2 messenger RNA (mRNA). Human MRC2 complementary DNA (cDNA), the sequence of which corresponds to that of MRC2 mRNA except that T nucleobases in the former are U nucleobases in the latter, may be as annotated under NCBI Genbank accession no: NM_006039.5, the sequence of which is reproduced here below from 5’ to 3’ end (SEQ ID NO : 73): ATCACTTCGTCCCGACCCGGAGGAGGACGCGAGCCCCTTGCGGGCGGTCATCACAGCC CAGCCTCGGGGCTGCCACAGCGCGTTGCGCCTGTGCGCCCTCGGTCCCCGCGTCCACT GAGCGCCGCGCTCGGGGATGGGGCCCGGCCGGCCGGCCCCCGCGCCCTGGCCTCGTCA CCTGCTGCGCTGCGTCCTGCTCCTCGGGTGCCTGCACCTCGGCCGTCCCGGCGCCCCTG GGGACGCCGCCCTCCCGGAACCCAACGTCTTCCTCATCTTCAGCCATGGACTGCAGGG CTGCCTGGAGGCCCAGGGCGGGCAGGTCAGAGTCACCCCGGCTTGCAATACCAGCCTC CCTGCCCAGCGCTGGAAGTGGGTCTCCCGAAACCGGCTATTCAACCTGGGTACCATGC AGTGCCTGGGCACAGGCTGGCCAGGCACCAACACCACGGCCTCCCTGGGCATGTATGA GTGTGACCGGGAAGCACTGAATCTTCGCTGGCATTGTCGTACACTGGGTGACCAGCTG TCCTTGCTCCTGGGGGCCCGCACCAGCAACATATCCAAGCCTGGCACCCTTGAGCGTG GTGACCAGACCCGCAGTGGCCAGTGGCGCATCTACGGCAGCGAGGAGGACCTATGTG CTCTGCCCTACCACGAGGTCTACACCATCCAGGGAAACTCCCACGGAAAGCCGTGCAC CATCCCCTTCAAATATGACAACCAGTGGTTCCACGGCTGCACCAGCACGGGCCGCGAG GATGGTCACCTGTGGTGTGCCACCACCCAGGACTACGGCAAAGACGAGCGCTGGGGCT TCTGCCCCATCAAGAGTAACGACTGCGAGACCTTCTGGGACAAGGACCAGCTGACTGA CAGCTGCTACCAGTTTAACTTCCAGTCCACGCTGTCGTGGAGGGAGGCCTGGGCCAGC TGCGAGCAGCAGGGTGCGGATCTGCTGAGCATCACGGAGATCCACGAGCAGACCTAC ATCAACGGCCTCCTCACTGGGTACAGCTCCACCCTGTGGATCGGCTTGAATGACTTGG ACACGAGCGGAGGCTGGCAGTGGTCGGACAACTCGCCCCTCAAGTACCTCAACTGGG AGAGTGACCAGCCGGACAACCCCAGTGAGGAGAACTGTGGAGTGATCCGCACTGAGT CCTCGGGCGGCTGGCAGAACCGTGACTGCAGCATCGCGCTGCCCTATGTGTGCAAGAA GAAGCCCAACGCCACGGCCGAGCCCACCCCTCCAGACAGGTGGGCCAATGTGAAGGT GGAGTGCGAGCCGAGCTGGCAGCCCTTCCAGGGCCACTGCTACCGCCTGCAGGCCGAG AAGCGCAGCTGGCAGGAGTCCAAGAAGGCATGTCTACGGGGCGGTGGCGACCTGGTC AGCATCCACAGCATGGCGGAGCTGGAATTCATCACCAAGCAGATCAAGCAAGAGGTG GAGGAGCTGTGGATCGGCCTCAACGATTTGAAACTGCAGATGAATTTTGAGTGGTCTG ACGGGAGCCTTGTGAGCTTCACCCACTGGCACCCCTTTGAGCCCAACAACTTCCGGGA CAGTCTGGAGGACTGTGTCACCATCTGGGGCCCGGAAGGCCGCTGGAACGACAGTCCC TGTAACCAGTCCTTGCCATCCATCTGCAAGAAGGCAGGCCAGCTGAGCCAGGGGGCCG CCGAGGAGGACCATGGCTGCCGGAAGGGTTGGACGTGGCACAGCCCATCCTGCTACTG GCTGGGAGAAGACCAAGTGACCTACAGTGAGGCCCGGCGCCTGTGCACTGACCATGG CTCTCAGCTGGTCACCATCACCAACAGGTTCGAGCAGGCCTTCGTCAGCAGCCTCATCT ACAACTGGGAGGGCGAGTACTTCTGGACGGCCCTGCAGGACCTCAACAGCACCGGCTC CTTCTTCTGGCTCAGTGGGGATGAAGTCATGTACACCCACTGGAACCGGGACCAGCCC GGGTACAGCCGTGGGGGCTGCGTGGCGCTGGCCACTGGCAGCGCCATGGGGCTGTGG GAGGTGAAGAACTGTACCTCGTTCCGGGCCCGCTACATCTGCCGGCAGAGCCTGGGCA CTCCAGTGACGCCGGAGCTGCCGGGGCCAGATCCCACGCCCAGCCTCACTGGCTCCTG TCCCCAGGGCTGGGCCTCGGACACCAAACTCCGGTATTGCTATAAGGTGTTCAGCTCA GAGCGGCTGCAGGACAAGAAGAGCTGGGTCCAGGCCCAGGGGGCCTGCCAGGAGCTG GGGGCCCAGCTGCTGAGCCTGGCCAGCTACGAGGAGGAGCACTTTGTGGCCAACATGC TCAACAAGATCTTCGGTGAATCAGAACCCGAGATCCACGAGCAGCACTGGTTCTGGAT CGGCCTGAACCGTCGGGATCCCAGAGGGGGTCAGAGTTGGCGCTGGAGCGACGGCGT AGGGTTCTCTTACCACAATTTCGACCGGAGCCGGCACGACGACGACGACATCCGAGGC TGTGCGGTGCTGGACCTGGCCTCCCTGCAGTGGGTGGCCATGCAGTGCGACACACAGC TGGACTGGATCTGCAAGATCCCCAGAGGTACGGACGTGCGGGAGCCCGACGACAGCC CTCAAGGCCGACGGGAATGGCTGCGCTTCCAGGAGGCCGAGTACAAGTTCTTTGAGCA CCACTCCACGTGGGCGCAGGCGCAGCGCATCTGCACGTGGTTCCAGGCCGAGCTGACC TCGGTGCACAGCCAGGCGGAGCTAGACTTCCTGAGCCACAACTTGCAGAAGTTCTCCC GGGCCCAGGAGCAGCACTGGTGGATCGGCCTGCACACCTCTGAGAGCGATGGGCGCTT CAGATGGACAGATGGTTCCATTATAAACTTCATCTCCTGGGCACCAGGCAAACCTCGG CCTGTCGGCAAGGACAAGAAGTGCGTGTACATGACAGCCAGCCGAGAGGACTGGGGG GACCAGAGGTGCCTGACAGCCTTGCCCTACATCTGCAAGCGCAGCAACGTCACCAAAG AAACGCAGCCCCCAGACCTGCCAACTACAGCCCTGGGGGGCTGCCCCTCTGACTGGAT CCAGTTCCTCAACAAGTGTTTTCAGGTCCAGGGCCAGGAACCCCAGAGCCGGGTGAAG TGGTCAGAGGCACAGTTCTCCTGTGAACAGCAAGAGGCCCAGCTGGTCACCATCACAA ACCCCTTAGAGCAAGCATTCATCACAGCCAGCCTGCCCAATGTGACCTTTGACCTTTGG ATTGGCCTCCATGCCTCGCAGAGGGACTTCCAGTGGGTGGAGCAGGAGCCTTTGATGT ATGCCAACTGGGCACCTGGGGAGCCCTCTGGCCCTAGCCCTGCTCCCAGTGGCAACAA ACCGACCAGCTGTGCAGTGGTCCTGCACAGCCCCTCAGCCCACTTCACTGGCCGCTGG GACGATCGGAGCTGCACGGAGGAGACCCATGGCTTCATCTGCCAGAAGGGCACGGAC CCCTCCCTGAGCCCGTCCCCAGCAGCGCTGCCCCCCGCCCCGGGCACTGAGCTCTCCTA CCTCAACGGCACCTTCCGGCTGCTTCAGAAGCCGCTGCGCTGGCACGATGCCCTCCTG CTGTGTGAGAGCCGCAATGCCAGCCTGGCCTACGTGCCCGACCCCTACACCCAGGCCT TCCTCACGCAGGCTGCCCGAGGGCTGCGCACGCCGCTCTGGATTGGGCTGGCTGGCGA GGAGGGCTCTCGGCGGTACTCCTGGGTCTCAGAGGAGCCGCTGAACTACGTGGGCTGG CAGGACGGGGAGCCGCAGCAGCCGGGGGGCTGTACCTACGTAGATGTGGACGGGGCC TGGCGCACCACCAGCTGTGACACCAAGCTGCAGGGGGCTGTGTGTGGGGTTAGCAGTG GGCCCCCTCCTCCCCGAAGAATAAGCTACCATGGCAGCTGTCCCCAGGGACTGGCAGA CTCCGCGTGGATTCCCTTCCGGGAGCACTGCTATTCTTTCCACATGGAGCTGCTGCTGG GCCACAAGGAGGCGCGACAGCGCTGCCAGAGAGCGGGTGGGGCCGTCCTGTCTATCC TGGATGAGATGGAGAATGTGTTTGTCTGGGAGCACCTGCAGAGCTATGAGGGCCAGA GTCGGGGCGCCTGGCTGGGCATGAACTTCAACCCCAAAGGAGGCACTCTGGTCTGGCA GGACAACACAGCTGTGAACTACTCCAACTGGGGGCCCCCGGGCTTGGGCCCCAGCATG CTGAGCCACAACAGCTGCTACTGGATTCAGAGCAACAGCGGGCTATGGCGCCCCGGCG CTTGCACCAACATCACCATGGGTGTCGTCTGCAAGCTTCCTCGTGCTGAGCAGAGCAG CTTCTCCCCATCAGCGCTTCCAGAGAACCCAGCGGCCCTGGTGGTGGTGCTGATGGCG GTGCTGCTGCTCCTGGCCTTGCTGACCGCAGCCCTCATCCTTTACCGGAGGCGCCAGAG CATCGAGCGCGGGGCCTTTGAGGGTGCCCGCTACAGCCGCAGCAGCTCCAGCCCCACC GAGGCCACTGAGAAGAACATCCTGGTGTCAGACATGGAAATGAATGAGCAACAAGAA TAGAGCCAGGCGCGTGGGCAGGGCCAGGGCGGGAGGAGCTGGGGAGCTGGGGCCCTG GGTCAGTCTGGCCCCCCACCAGCTGCCTGTCCAGTTGGCCTATGGAAGGGTGCCCTTG GGAGTCGCTGTTGGGAGCCGGAGCTGGGCAGAGCCTGGGCTGGTGGGGTGCCACCCTC CCACAAGGGCTGGGCTGAGACCCAGCTGAGTGCAGCGTGGCGTTTCCCTTTCTGGGGG GGCCTGAGGTCTTGTCACCTGGTCCTGTGCCCCCACAGGAACCAGAGGTAGGATGGGA GGGGGAACGAGAGCCTCTTTCTCCCCAGAGCCCCCGGCCCAGGCCTGTTGATCCGCGC CCCAGGACCCCCTTCTTTGCAGAGCCCGAGGAGCCTCCCCTGTCCCCTCGGGCAGATCT GTTGTGTCTCTCTTCCCACCTGGCAGCCTCAGCTCTGTGCCCCTCACCCTGCTCCCTCTC GCCCCTTCTCTCCCACCCCTTCCTTCTGAGCCGGGCCCTGGGGATTGGGGAGCCCTCTT GTTCCTGATGAGGGTCAGCTGAGGGGGCTGAGCATCCATCACTCCTGTGCCTGCTGGG GTGGCTGTGGGGCGTGGCAGGAGGGGCCTAGGTGGGTTGGGCCTGAGAACCAGGGCA CGGGTGTGGTGTCTGCTGGGCTGGAGATAAGACTGGGGAGAGACACCCCAACCTCCCA GGGTGGGAGCTGGGCCGGGCTGGGATGTCATCTCCTGCCGGGCGGGGGAGGGCTCTG CCCCTGGAAGAGTCCCCTGTGGGGACCAAAATAAGTTCCCTAACATCTCCAGCTCCTG GCTCTGGTTTGGAGCAAGGGGAAGGGTTGCCAGAGTCCTGGGGGCCCCAGAGGAGCA GGAGTCTGGGAGGGCCCAGAGTTCACCCTCTAGTGGATCCAGGAGGAGCAGCACCCG AGCCCTGGAGTGGCCCAGTACCCTTCCAAGAGGCCACAGTCCCAGCCAGGACAAAGT ATGCGGCCCATCCTGGTGCGACAGCGTGGGACAATGTGAACATGGACTCGAAGACAT GGCCCTTTCTCTGTAGTTGATTTTTTAAATGTGCCATTATTGTTTTTAAAAAAAAAGGA AAAAAGAAAAGCAAACAAATAAAACACCTTTAAGAGGCTTGAAAGAGAA According to the annotation, the coding sequence for the MRC2 protein is located between the start codon ATG at position 134-136 and the TAG stop codon at position 4571-4573 of the above sequence cDNA sequence. In certain embodiments, the MRC2 protein or transcript is a human MRC2 protein or transcript. The qualifier “human” may particularly refer to MRC2 protein or transcript as found in or present in humans, regardless of whether the MRC2 protein forms a part of or has been at least partly isolated from human subjects, organs, cells, or tissues, or obtained by technical means, e.g., by recombinant expression, cell-free transcription or translation, or non-biological peptide or nucleic acid synthesis. In certain embodiments, the endogenous human MRC2 protein or transcript is intended. A skilled person understands that the amino acid or nucleic acid sequence of a given native protein or transcript, such as a MRC2 protein or transcript, may display variation, for example as a result of differential splicing and that any such variants or isoforms of the protein or transcript are subsumed by the reference to or designation of the protein. By means of an example and without limitation, certain MRC2 mRNA variants are annotated under NCBI Genbank accession no: XM_047437208.1 and XM_011525543.2, and certain MRC2 protein variants are annotated under NCBI Genbank accession no: XP_047293164.1 and XP_011523845.1. Horse MRC2 is annotated under NCBI Genbank Gene ID no.100064998. A horse wild-type MRC2 amino acid sequence and complementary DNA (cDNA) sequence may be as annotated under Genbank accession no: XP_023508036.1 and XM_023652268.2 (isoform X1), XP_023508037.1 and XM_023652269.2 (isoform X2), XP_023508038.1 and XM_023652270.2 (isoform X3), XP_070083191.1 and XM_070227090.1 (isoform X4), XP_023508039.1 and XM_023652271.2 (isoform X5), XP_023508040.1 and XM_023652272.2 (isoform X6), XP_070083192.1 and XM_070227091.1 (isoform X7), XP_070083193.1 and XM_070227092.1 (isoform X8), and XP_070083195.1 and XM_070227094.1 (isoform X9). For further guidance and illustration but without limitation, the sequence of XP_023508036.1 is reproduced here below from N to C terminus (SEQ ID NO : 74): MGMGPGRPAPAPWPRHLLGCVLLLGGLHLGRPGAPGDPNAAALPEPNVFLIFSHGLQGCL EAQGGQVRVSPGCNASLPAQRWKWVSRNRLFNLGTMQCLGTGWPGTNTTASLGMYECD REALNLRWHCRTLGDQLSLLLGGRASNTSKAGTPERGDQTRSGQWRIYGSDEDLCARPY YEVYTIQGNSHGKPCTIPFKYDNQWFHGCTSTGREDGHLWCATTQDYGKDERWGFCPIKS NDCETFWDKDQLTDSCYQFNFQSTLSWREAWASCEQQGADLLSITEIHEQTYINGLLTGYS STLWIGLNDLDTSGGWQWSDNSPLKYLNWESDQPDNPSEENCGVIRTESSGGWQNRDCSI ALPYVCKKKPNATAEPPPPDVWANVKVECEPSWQPFQGHCYRLQAEKRSWQESKKACLR VGGDLLSIHSMAELEFITKQIKQEVEELWIGLNDLKLQMNFEWSDGSLVSFTHWHPFEPNN FRDSLEDCVTIWGPEGRWNDSPCNQSLPSICKKAGQLSQGAAEEDHGCRKGWTWHSPSC YWLGEDQVTYSEARRLCTDHGSQLVTITNRFEQAFVSSLIYNWDGEYFWTALQDLNSTGS FRWLSGDEVMYTHWNRDQPGYSRGGCVALATGSAMGLWEVKNCTVFRARYICRQSLGT PVTPELPGPDPTPSLTGSCPQGWASDPKLRHCYKVFSSDRLQDKKSWVQAQGACQELGAQ LLSLASYEEEHFVANMLNKIFGESEPESHEQHWFWIGLNRRDPGGRQSWRWSDGLGFSYH NFDRSRHDDDDIRGCAVLDLASLQWVAMQCDTQLDWICKIPRGADVREPDVSPQGRREW LRFQEAEYKFFEHHSTWAQAQRICTWFQAELASVHSQAELDFLGHNLQKFSRGQEQHWW IGLHTAESDGRFRWTDGSIINFISWAPGKPRPIGKDKKCVYVTASREDWGDQRCLTGLPYI CKRSNSTRKTQPPDLPPTALGGCPSGWNQFLNKCFRIQGQDPQDRVKWSEAQFSCEQQEA QLVTIANPLEQAFITASLPNVTFDLWIGLHASQKDFQWVEQEPLLYTNWAPGEPSGPSPAPS GNIPTSCTVVLHSPSAHFTGRWDDRSCTEETHGFICQKGTDPSLSPSPAALPPAPGTELSYL NGTFRLLQKPLRWHDALLLCESRNASLAHVPDPYTQAFLTQAARGLRTPLWIGLASEEGS RRYSWVSEEPLSYVSWQDGEPQQPGGCAYVDVDGTWRTTSCDTKLQGAVCGGNSGPPPP RRISYHGSCPQDLADSAWIPFREHCYSFHMELLLGHKEALQRCQRAGGAVLSILDEMENV FVWEHLQSSEGQSRGAWLGMNFNPKGGTLVWQDNTAVNYSNWGPPGLGPSMLSHNSCY WIQSSSGLWRPGACTNITMGVVCKLPRGPSLFPAAEESTFSPSAALPENPAALVVVLMAVL LLLALLTAALILYRRRQSVERGAFEGARYSRSSSSPGEATEKNILVSDMEMNEQQE For further guidance and illustration but without limitation, the sequence of XM_023652268.2 is reproduced here below from 5’ to 3’ end (SEQ ID NO: 75): AGAAAGAGGCGGGATAGAGGGGGCGCCAGCGGCCCAGGTCTGGCCGCCTGGGTCAGC CGTGCGCCCCCGCCCCCGCCCCCGCCGAGTGAGGCCTTGCAGCCCACGTCCCGCCACG CCGTGAAGTTTGCGGAAAGTTCCCCACCAGCGCCAGCCGGGGAGTTGTGACGCAGTGT CTGGGGCTCCAGTCCCGGACAGAGAAGAGAGGGAAGGCGAGGCGGGGAGAGAGGGA AACGGAGAGCGAGGGCAAGAGCGCACGCGGGGTCGTCCTCTACCCGACGGATCCTCC CTCCCACCTCCCCCTTCTCCATTCCCGGCCCCAGCCCCGCGCCCGCACGCGCCTCTTCC CCTCCCACGCTGCCCGCTTCCCTTCCCCTCTGCCCCTCAAACCCTCCTCCTGGGTTCTGC GCTCCTCCCTCCGCCCTCCCTCCGCCCGGCCTGCCTCCTTCCCTCCTCCTCCCCTCCTCT CGCCCGGAGGCATCACTTCGTCCCGACCCGGAGGAAGACGCGAGCCCCTCGCGGGCG GTCATCACAGCCCAGCGCCGTGTCTGCCAACGCGCGCCGCGCTCGTGCGCCCTCGGTC CCCGCGTCCCCAGAGCGCCGCGCCATGGGCATGGGGCCAGGCCGGCCGGCCCCCGCG CCCTGGCCTCGTCACCTGCTGGGCTGCGTCCTGCTCCTCGGGGGTCTGCACCTCGGCCG CCCGGGCGCCCCTGGGGACCCCAACGCCGCCGCCCTCCCGGAGCCCAACGTCTTCCTC ATCTTCAGCCATGGACTGCAGGGCTGCCTGGAGGCCCAGGGTGGGCAAGTCAGAGTCT CCCCAGGCTGCAACGCCAGTCTTCCTGCCCAGCGCTGGAAATGGGTCTCCCGAAACCG GCTCTTCAACCTGGGTACCATGCAGTGCCTGGGCACAGGCTGGCCGGGCACCAACACC ACAGCCTCCCTGGGCATGTACGAATGTGACCGGGAGGCACTGAATCTTCGCTGGCACT GTCGCACACTGGGTGACCAGCTGTCCCTGCTCCTGGGGGGCCGTGCCAGCAACACTTC CAAGGCTGGCACCCCTGAGCGTGGTGACCAGACCCGCAGTGGCCAGTGGCGCATCTAT GGCAGTGACGAGGATCTATGTGCTCGGCCCTACTATGAGGTCTACACCATCCAGGGGA ACTCCCATGGGAAGCCGTGCACCATCCCTTTCAAGTATGACAACCAGTGGTTCCATGG CTGCACCAGCACGGGCCGCGAGGACGGGCATCTGTGGTGCGCCACCACCCAGGACTAT GGCAAGGACGAGCGCTGGGGCTTCTGCCCCATCAAGAGTAATGACTGTGAGACCTTCT GGGACAAGGACCAGCTGACCGACAGCTGCTACCAGTTTAACTTCCAGTCCACGCTGTC CTGGAGGGAGGCATGGGCCAGTTGCGAGCAGCAGGGGGCAGATCTGCTGAGCATCAC TGAGATCCACGAGCAGACCTACATCAATGGGCTCCTCACTGGCTACAGCTCCACACTA TGGATTGGCCTTAATGACCTGGACACCAGTGGAGGCTGGCAGTGGTCGGACAACTCGC CCCTCAAGTACCTCAACTGGGAGAGTGATCAGCCGGACAACCCGAGCGAGGAGAACT GCGGAGTGATCCGCACGGAGTCCTCGGGCGGCTGGCAGAACCGCGACTGCAGCATCG CGCTGCCCTACGTGTGCAAGAAGAAGCCCAACGCCACGGCCGAGCCCCCTCCTCCTGA CGTATGGGCCAACGTGAAGGTGGAGTGCGAGCCCAGCTGGCAGCCCTTCCAGGGCCA CTGCTACCGCCTGCAGGCAGAGAAGCGCAGCTGGCAGGAGTCCAAGAAGGCATGTCT GCGGGTCGGGGGCGACCTGCTCAGCATCCACAGCATGGCCGAGCTGGAGTTCATCACC AAGCAGATCAAGCAAGAGGTGGAGGAGCTGTGGATCGGCCTCAACGATTTGAAACTA CAGATGAATTTTGAGTGGTCAGATGGGAGCCTTGTGAGCTTCACCCACTGGCACCCCT TTGAGCCCAACAACTTCCGGGACAGCCTGGAGGACTGTGTCACCATCTGGGGGCCGGA AGGTCGCTGGAATGACAGTCCCTGTAACCAATCTTTGCCATCCATCTGCAAGAAGGCA GGCCAGCTGAGCCAGGGAGCCGCCGAAGAGGACCATGGCTGCCGGAAGGGTTGGACA TGGCACAGCCCATCCTGCTACTGGCTGGGCGAGGACCAAGTGACCTACAGTGAGGCCC GGCGCCTGTGCACTGACCACGGCTCTCAGCTGGTCACCATCACCAACAGGTTCGAGCA GGCCTTTGTCAGCAGCCTCATCTATAACTGGGATGGCGAGTACTTCTGGACTGCCCTGC AGGACCTCAACAGCACCGGCTCCTTCCGTTGGCTCAGTGGGGATGAGGTCATGTACAC CCACTGGAACCGGGACCAGCCCGGGTACAGCCGTGGGGGCTGCGTGGCCCTGGCCAC AGGCAGCGCCATGGGGCTGTGGGAGGTGAAGAACTGCACCGTGTTCCGGGCTCGCTAC ATCTGCCGGCAGAGCCTGGGCACGCCAGTGACGCCTGAACTGCCCGGGCCAGATCCCA CGCCCAGCCTCACCGGCTCCTGTCCCCAGGGCTGGGCCTCAGACCCCAAACTCCGGCA CTGCTATAAGGTGTTCAGCTCGGACCGGCTGCAGGACAAGAAGAGCTGGGTCCAGGCC CAGGGGGCCTGCCAGGAGTTGGGGGCCCAGCTACTGAGCCTGGCCAGCTATGAGGAG GAACACTTTGTGGCCAACATGCTTAACAAGATCTTCGGTGAATCAGAGCCTGAGAGCC ACGAGCAGCACTGGTTCTGGATCGGCCTGAACCGTCGAGACCCGGGAGGGAGGCAGA GCTGGCGCTGGAGCGACGGCCTGGGGTTCTCTTACCACAATTTCGACCGGAGCCGGCA TGACGACGACGACATTCGGGGCTGCGCAGTGCTCGACCTGGCCTCCCTGCAGTGGGTG GCCATGCAATGCGATACGCAGCTGGACTGGATCTGCAAGATCCCTAGAGGTGCGGACG TGCGGGAACCTGATGTCAGCCCGCAAGGCCGGCGGGAATGGCTGCGTTTCCAGGAGG CCGAGTACAAGTTCTTCGAGCACCACTCCACGTGGGCGCAGGCACAGCGCATCTGCAC GTGGTTCCAGGCCGAGCTGGCCTCCGTGCACAGCCAGGCCGAGCTGGACTTCCTGGGG CACAACCTGCAGAAGTTCTCCCGGGGTCAGGAGCAGCACTGGTGGATTGGCCTGCACA CCGCAGAGAGCGACGGGCGCTTCAGGTGGACAGATGGTTCCATTATAAACTTCATCTC CTGGGCACCTGGCAAACCTCGGCCCATCGGCAAGGATAAGAAGTGCGTGTACGTGAC GGCCAGTAGAGAGGACTGGGGGGACCAGAGGTGCCTGACAGGATTGCCCTACATCTG CAAGCGCAGCAACAGCACCAGAAAGACACAGCCCCCAGACCTGCCTCCCACAGCCCT GGGGGGCTGCCCCTCTGGTTGGAACCAGTTCCTCAACAAGTGTTTCCGAATCCAGGGC CAGGACCCCCAGGACCGGGTGAAGTGGTCAGAGGCACAGTTCTCCTGTGAACAGCAA GAGGCCCAACTGGTCACCATTGCAAACCCCTTAGAGCAAGCATTCATCACAGCCAGCC TGCCCAATGTGACCTTTGACCTTTGGATTGGCCTCCATGCCTCGCAGAAGGACTTCCAG TGGGTGGAGCAGGAGCCTCTGCTGTATACCAACTGGGCCCCTGGGGAGCCCTCTGGCC CTAGCCCTGCTCCCAGCGGCAACATCCCGACCAGCTGCACGGTGGTCCTGCACAGCCC CTCAGCTCACTTCACTGGCCGCTGGGATGACCGGAGCTGCACGGAGGAGACACATGGC TTCATCTGCCAGAAGGGCACAGACCCTTCCCTGAGCCCATCCCCAGCAGCGTTGCCCC CTGCCCCGGGCACTGAGCTCTCCTACCTCAACGGCACCTTCCGGCTGCTGCAGAAGCC GCTGCGCTGGCATGATGCCCTCCTGCTGTGTGAGAGTCGCAACGCCAGCCTGGCCCAC GTGCCTGACCCCTACACCCAGGCCTTCCTCACACAGGCCGCCCGAGGGCTGCGCACGC CACTCTGGATTGGGCTGGCCAGTGAGGAGGGCTCCCGGCGGTACTCCTGGGTCTCAGA AGAGCCACTGAGCTACGTGAGCTGGCAGGACGGGGAGCCTCAGCAGCCAGGGGGCTG CGCCTATGTGGATGTGGATGGGACCTGGCGTACTACCAGTTGCGACACCAAGTTGCAG GGGGCTGTGTGTGGAGGTAACAGTGGGCCCCCTCCTCCCAGAAGAATAAGTTACCATG GCAGCTGTCCCCAGGACCTGGCCGACTCGGCTTGGATTCCCTTCCGGGAGCACTGTTA CTCCTTCCACATGGAGCTGCTGCTGGGCCATAAGGAGGCGCTGCAGCGCTGCCAGAGA GCGGGCGGGGCAGTCCTGTCCATTCTGGATGAGATGGAAAACGTGTTTGTCTGGGAGC ACCTGCAGAGCTCCGAGGGCCAGAGTCGGGGTGCCTGGCTGGGCATGAACTTCAACCC CAAAGGAGGCACCCTGGTCTGGCAGGACAACACAGCTGTGAACTACTCCAACTGGGG GCCCCCTGGCCTGGGCCCCAGCATGCTGAGCCACAACAGCTGCTACTGGATCCAGAGC AGCAGCGGGCTGTGGCGCCCCGGCGCCTGCACCAACATCACCATGGGCGTTGTCTGCA AGCTCCCTCGAGGTCCCTCCCTCTTCCCCGCAGCTGAGGAGAGCACCTTCTCCCCATCA GCAGCGCTCCCAGAGAACCCAGCGGCCCTGGTGGTGGTGCTGATGGCCGTGCTGCTGC TCCTGGCCCTGCTGACTGCGGCCCTGATCCTCTACCGGCGGCGACAGAGCGTTGAGCG TGGGGCCTTTGAGGGTGCCCGCTACAGCCGGAGCTCCTCCAGCCCTGGCGAGGCCACG GAGAAGAACATCCTGGTGTCTGACATGGAAATGAATGAGCAGCAGGAGTAGAGCGAA GGGAGTGGGCAGGGCTGGGGAGGAGGAGCTAGGGAGGCTGGGCCCTGGGGTAACCG GGCCCCCCACCAGCTACCAGTCCAGATGGCCTGTGAGGGGTGCCCTTGGGAGCCGCTG TTGGAAGCTGGGGCTGGGCAGGGCCTGGGCTGGTGGGGCCCCTCCCTCGCCTGAGGGC TGGGCTGAGGCCTGGCTGAGTGCAGCGTGGCGTTTCCCTTTTTGGGGGCCAAGGTCTT GTCACCTGGGCCTGTGCCCCCACGGCAACCAGAGGCAGGATGGGAGCCCCCTTCTGCA TCTCTCTCCTCAGGCCCCCCTGCCCAGGCCTGCTGACCCGTGCCCGGGGACCCCTTCTC ATTGCAGAGCCTGAGGAGCGCCCCCCTGAGTCCTCAGCCAGCCTCTGCCGCTTCTCTGC TCCCCACCTGGCAGCCTCAGCTCTGAGCCCCTCACTCTGGCCCCTGTCCACGCTCCTCA CCCAGCTCTTCCTTCTGAGTCAGGGCCCTGGGATCTGGGGAGCCCTCTTGCTCTTGGTG GGGGTCGGCTGAGGGGGCTGAGCATCTGTCACTCCTGTGCCTGCTGGAGTGGCCATGG GGCGTGGCAGGAGGGGCCTGGGTGGGGCCTGAGAATCAGGGCACCACTATGGTGTCA GCTGAGCTGAAGACAGGACTGGGGAGAGACACCCAGACCTCCTGGGGGTGACCAGGC TGGACTAGGGTGTCATCTCCTGCCGGTCGGGGGGAGGGCTCTGTCCCTAAAGAGTCCC CTGTGGGGACCAAAATAAGTTCCCTAATATTTTCAGCTCCTGGGTCTGGTTTGGAGAG AGTGGAGGGGGTTGCCAGAGTCCTGGGGGCCTCAGAGAAGCGGGAGCCTAGGGATGG CCCCAGTGCCCGCCCTCTGATGGGTCCCAGAGGAACAGCGCCCGAGCTCCTGGAGCTG CCCAGTGATGGGAGGCTGACCCCGTGCCTTTCCCAGAGGTCGGAATCCCGCCTGAGGA GTGACCGGCCAGTCCTGGTGCCGCCGCGCGGGACAATGTGAACACAGACTCAAAGAC ATGGTCCTTTCTTTGTAGTTCTTAATTTTTTTAATGTGTCAATATTGTTAAAAAAAAAAA AAAGGAAAAAGAAAAGCAAACAAATAAAACACCTTTAAGAGGCCCGA A skilled person understands that the amino acid or nucleic acid sequence of a given native protein or transcript, such as a MRC2 protein or transcript, may differ between or within different individuals of the same species due to normal genetic diversity (allelic variation, polymorphism) within that species and / or due to differences in post-transcriptional or post-translational modifications. Any such variants or isoforms of the native protein or transcript are subsumed by the reference to or designation of the protein. The human MRC2 reference mRNA as annotated under NM_006039.5 is composed of 30 exons, which in the genomic sequence of the human MRC2 gene as annotated under NCBI Genbank accession no: NC_000017.11 correspond to the following positions: 1-251, 36879-37280, 38425- 38598, 38786-38950, 39088-39201, 39721-39864, 43980-44168, 44329-44483, 46394-46501, 48121-48236, 48714-48862, 49600-49817, 50835-50977, 52131-52233, 52501-52639, 52749- 52784, 53131-53291, 53393-53460, 54168-54268, 54566-54708, 60620-60734, 60832-60995, 61183-61291, 61853-62091, 62225-62393, 62487-62636, 62973-63092, 63280-63459, 64443- 64469, 64562-65928. The start codon is in exon 1 and the stop codon in exon 30. The present oligonucleotide agents may be configured to target any portion of a MRC2 transcript, such as MRC2 mRNA. For example, the present oligonucleotide agents may be designed against a sequence comprised by any portion of a MRC2 transcript, such as MRC2 mRNA. For instance, an oligonucleotide agent may target / be designed against a sequence of nucleotides, preferably consecutive nucleotides, comprised by the 5’ untranslated region (UTR); against a sequence of nucleotides, preferably consecutive nucleotides, spanning or connecting the 5’ UTR and the coding region; against a sequence of nucleotides, preferably consecutive nucleotides, comprised by the coding region; against a sequence of nucleotides, preferably consecutive nucleotides, spanning or connecting the coding region and the 3’ UTR; or against a sequence of nucleotides, preferably consecutive nucleotides, comprised by the 3’ UTR. In certain embodiments, an oligonucleotide agent may target / be designed against a sequence of nucleotides, preferably consecutive nucleotides, comprised by any one MRC2 exon; or against a sequence of nucleotides, preferably consecutive nucleotides, spanning or connecting any two or more MRC2 exons. In certain embodiments, an oligonucleotide agent may target / be designed against a sequence of nucleotides, preferably consecutive nucleotides, within any one of MRC2 exons 2, 6, 12, 21 or 22, or spanning or connecting exons 21 and 22. In certain embodiments, an oligonucleotide agent may target / be designed against a sequence of nucleotides, preferably consecutive nucleotides, within any one of MRC2 exons 11, 15, 17, 18, 21, 22, 28, or 29 or spanning or connecting exons 17 and 18, exons 21 and 22, or exons 28 and 29, preferably spanning or connecting exons 21 and 22. Combinations or compositions comprising two or more oligonucleotide agents as disclosed herein each targeting / designed against the same or different sequence within an MRC2 transcript are within the scope of the invention. The oligonucleotide agents disclosed herein are capable of suppressing the expression of MRC2. The term “expression” of a polypeptide by a cell generally refers to the production of said polypeptide by the cell. As commonly known, the expression of polypeptides by cells involves several successive molecular mechanisms, more particularly but without limitation, the transcription of a gene encoding said polypeptide into RNA, the polyadenylation and where applicable splicing and / or other post- transcriptional modifications of the RNA into mRNA, the localisation of the mRNA into cell cytoplasm, where applicable other post-transcriptional modifications of the mRNA, the translation of the mRNA into a polypeptide chain, where applicable post-translational modifications of the polypeptide, and folding of the polypeptide chain into the mature conformation of the polypeptide. For compartmentalised polypeptides, such as secreted polypeptides and transmembrane polypeptides, the production process further involves trafficking of the polypeptides, i.e., the cellular mechanism by which polypeptides are transported to the appropriate sub-cellular compartment or organelle, membrane, e.g. the plasma membrane, or outside the cell. Without wishing to be bound by any theory, the oligonucleotide agents envisaged herein may interfere with MRC2 expression at the level of mRNA and may in particular induce cleavage and degradation of the targeted mRNA, for example by RNAse H in case of antisense oligonucleotides or by the Argonaute 2 (Ago2) enzyme part of RNA-induced silencing complex (RISC) in case of RNA interference agents, or may prevent the translation of the mRNA to which they are bound by ribosomes, or may interfere with splicing of the respective pre-mRNA into mature mRNA resulting in exon skipping or intron retention in the produced mRNA, whereby the produced mRNA may, for example, become less stable or may encode a non-functional mutant protein, e.g., a truncated protein or a protein lacking crucial domains responsible for the protein’s activity. That said, any mechanisms of action are intended to be encompassed herein insofar the agents can downregulate the expression of MRC2 by a cell once introduced into the cell. The term “suppress” as used herein is intended to be synonymous with terms such as “inhibit”, “decrease”, “reduce”, “diminish”, “interfere”, “disrupt”, or “disturb”, and denotes a qualitative or quantitative decrease in that which is being suppressed. Any meaningful extent of suppression of the expression of MRC2 is envisaged. Hence, the terms may in appropriate contexts, such as in experimental or therapeutic contexts, denote a statistically significant decrease relative to a reference. The skilled person is able to select such a reference. An example of a suitable reference may be the MRC2 expression when exposed to a ‘negative control’ molecule, such as a molecule of similar composition but known to have no effects on MRC2. For example, such decrease may fall outside of error margins for the reference (as expressed, for example, by standard deviation or standard error, or by a predetermined multiple thereof, e.g., ±1xSD or ±2xSD, or ±1xSE or ±2xSE). By means of an illustration, the expression of MRC2 may be considered reduced when it is decreased by at least 10%, such as by at least 20% or by at least 30%, preferably by at least 40%, such as by at least 50% or by at least 60%, more preferably by at least 70%, such as by at least 80% or by at least 90% or more, as compared to the reference, up to and including a 100% decrease (i.e., absent activity as compared to the reference). The extent of such suppression can be conveniently determined by measuring the quantity of the MRC2 mRNA or MRC2 protein expressed by the cells, or both, by known techniques such as quantitative reverse transcription PCR (qRT-PCR) or immunoassays such as Western blotting or ELISA, as also illustrated in the examples. The term “oligonucleotide agent” broadly encompasses any molecule, substance or composition that comprises one or more oligonucleotides. As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may each independently be modified or unmodified. Oligonucleotides as intended herein may be preferably between about 8 and about 100 linked nucleosides in length, optionally between about 8 and about 60, between about 10 and about 50, between about 15 and about 40, such as between 8 and 16, between 10 and 20, between 20 and 30, between 30 and 40, or between 40 and 50 linked nucleosides in length. The term “nucleotide length” as used herein means the total number of nucleotides or modified nucleotides in a given sequence. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside linkage modifications. Oligonucleotides encompass both modified and unmodified oligonucleotides. As used herein, “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are, each independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. “Linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e., no additional nucleosides are presented between those that are linked). As used herein, “2'- deoxynucleoside” means a nucleoside comprising a 2’-H(H) furanosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA), and a nucleobase. In certain embodiments, a 2’- deoxynucleoside may comprise a modified nucleobase and a 2’-H(H) furanosyl sugar moiety or may comprise an RNA nucleobase (uracil) and a 2’-H(H) furanosyl sugar moiety. As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein, an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase or modified nucleobase. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification. Non-limiting examples of nucleobases include other naturally-occurring bases, such as xanthine, inosine, or hypoxanthine, as well as chemically or biochemically modified, non-natural or derivatised bases. Exemplary modified nucleobases include without limitation 5-substituted pyrimidines, 6- azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5- propynyluracil and 5-propynylcytosine. In particular, 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and may be preferred base substitutions in for example antisense agents, even more particularly when combined with 2’-O-methoxyethyl sugar modifications. Further non-limiting examples of modified nucleobases include isocytosine, pseudoisocytosine, 5-bromouracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2- chloro-6-aminopurine. Oligonucleotide agents may be herein denoted as comprising uracil (U) bases. It shall be appreciated that U may be optionally substituted by thymine (T) in (at least some) such agents. For example, as 2’-O-methyl phosphorothioate antisense oligonucleotides are more ‘RNA- like’, U may be used in such molecules. With other antisense chemistries, such as peptide nucleic acids or morpholino backbones, T bases may be preferably used. As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. The (’) symbol is used to describe the numbering of a sugar in a nucleoside or nucleotide (the nucleobase positions are numbered without this symbol). When describing the sugar only, the symbol is not used. As used herein, “unmodified sugar moiety” means a 2-OH(H) furanosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”). As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate. In certain embodiments, a modified furanosyl sugar moiety is a 2-substituted sugar moiety. Such modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars. “Bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety. “Non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring. Further non-limiting examples of sugar moieties and modified sugar moieties that may form part of nucleosides include arabinose, 2-deoxyarabinose, threose or hexose sugar groups, 2’-O-alkylated (e.g., 2’-O-methylated or 2’-O-ethylated) sugars such as ribose, 2’-O-alkyloxyalkylated (e.g., 2’-O-methoxyethylated) sugars such as ribose, and 2’-O,4’- C-alkylene-linked (e.g., 2’-O,4’-C-methylene-linked or 2’-O,4’-C-ethylene-linked) sugars such as ribose, 2’-fluoro-ribose, 2’-fluoro-arabinose, etc, such as a ribose comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA). As used herein, the term “internucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. By means of an example and without limitation, “phosphorothioate linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulphur atom. The 5’ terminal nucleotide of an oligonucleotide does not comprise a 5’ internucleoside linkage group, although it can comprise a 5’ terminal group. Hence, nucleosides can linked by numerous known internucleoside linkages, including without limitation phosphodiester linkages common in naturally-occurring nucleic acids, and further modified phosphate- or phosphonate-based linkages such as phosphorothioate, alkyl phosphorothioate such as methyl phosphorothioate, phosphorodithioate, alkylphosphonate such as methylphosphonate, alkylphosphonothioate, phosphotriester such as alkylphosphotriester, phosphoramidate, phosphoropiperazidate, phosphoromorpholidate, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate; and further siloxane, carbonate, sulfamate, carboalkoxy, acetamidate, carbamate such as 3’-N-carbamate, morpholino, borano, thioether, 3’-thioacetal, and sulfone internucleoside linkages. Preferably, internucleoside linkages may be phosphate-based linkages including modified phosphate-based linkages, such as more preferably phosphodiester, phosphorothioate or phosphorodithioate linkages or combinations thereof, most preferably phosphorothioate linkages. “Alkyl” as used herein particularly encompasses lower hydrocarbon moieties, e.g., C1-C4 linear or branched, saturated or unsaturated hydrocarbon, such as methyl, ethyl, ethenyl, propyl, 1-propenyl, 2-propenyl, or isopropyl. Hence, in certain embodiments, oligonucleotides as intended herein may comprise one or more or all non-naturally occurring nucleobases and / or one or more or all non-naturally occurring sugar moieties and / or one or more or all non-naturally occurring internucleoside linkages, the inclusion of which may improve properties such as, for example, enhanced cellular uptake, increased stability in the presence of nucleases and increased hybridization affinity, increased tolerance for mismatches, etc. The term “nucleic acid” as used herein typically refers to a polymer, preferably a linear polymer, of any length composed essentially of nucleoside units. Nucleic acids as intended herein may include naturally occurring nucleosides, modified nucleosides or mixtures thereof. The term encompasses DNA, RNA and DNA / RNA hybrid molecules, specifically including hnRNA, pre-mRNA, mRNA, cDNA, genomic DNA, amplification products, oligonucleotides, and synthetic (e.g., chemically synthesised) DNA, RNA or DNA / RNA hybrids. A nucleic acid can be naturally occurring, e.g., present in or isolated from nature, can be recombinant, i.e., produced by recombinant DNA technology, and / or can be, partly or entirely, chemically or biochemically synthesised. A nucleic acid can be double-stranded, partly double stranded, or single-stranded. Where single-stranded, the nucleic acid can be the sense strand or the antisense strand. In addition, nucleic acid can be circular or linear. The terms “oligonucleotide” and “nucleic acid” also encompass any other nucleobase containing polymers such as without limitation peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups (PHONA), morpholino phosphorodiamidate-backbone nucleic acids (PMO), cyclohexene nucleic acids (CeNA), tricyclo-DNA (tcDNA), and nucleic acids having backbone sections with alkyl linkers or amino linkers. Such oligonucleotides or nucleic acids are comprised of modified nucleoside units as broadly conceived herein, such as for example nucleoside units comprising a (modified) nucleobase, a modified sugar (which may include a sugar surrogate), and / or a modified internucleoside linkage. Hence, in certain embodiments, the oligonucleotide, such as an antisense oligonucleotide (ASO) or an RNA interference (RNAi) compound, comprises one or more modifications selected from the group consisting of a modified internucleoside linkage, a modified nucleoside base, a modified sugar moiety, and combinations thereof. In certain embodiments, the oligonucleotide, such as ASO or RNAi agent, displays any one or any combination of two or more or all of the following features i) to v): i) the oligonucleotide, such as ASO or RNAi agent, comprises one or more modified internucleoside linkages selected from the group consisting of phosphorothioate, phosphorothioate Rp isomer, phosphorothioate Sp isomer, phosphorodithioate, methylphosphonate, methoxypropylphosphonate, and combinations thereof, preferably phosphorothioate; ii) the oligonucleotide, such as ASO or RNAi agent, comprises peptide nucleic acid (PNA); iii) the oligonucleotide, such as ASO or RNAi agent, comprises one or more selected from the group consisting of 2’-O-methyl modified ribose (2’-OMe), 2’-O-methoxyethyl modified ribose (2’-MOE), 2’-deoxy-2’-fluoro modified ribose (2’-F), 2’-arabino-fluoro modified ribose (2’-Ara-F), 2’-O- benzyl modified ribose, 2’-O-methyl-4-pyridine modified ribose (2’-O-CH2Py(4)), a constrained ethyl ribose (cEt) (a bicyclic furanosyl sugar moiety comprising a bridge connecting the 4’-carbon and the 2’-carbon, wherein the bridge has the formula: 4’-CH(CH3)-O-2’), a ribose comprising a 2’- O,4’-C-methylene bridge (Locked Nucleic Acid, LNA), and combinations thereof, preferably a ribose comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA); iv) the oligonucleotide, such as ASO or RNAi agent, comprises one or more selected from the group consisting of tricyclo-DNA, phosphorodiamidate morpholino oligomer (PMO), unlocked nucleic acid (UNA), glycol nucleic acid (GNA), and combinations thereof; v) the oligonucleotide, such as ASO or RNAi agent, comprises one or more selected from the group consisting of 5’-methylcytidine, N6’-methyladenosine, 5’-fluoro-2’-deoxyuridine, pseudouridine, 2’-thiouridine, and combinations thereof. In certain embodiments, a modified oligonucleotide has a fully modified sugar motif wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif wherein each nucleoside of the region comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified oligonucleotide comprises the same 2’-modification. It is not necessary for all positions in a given oligonucleotide to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single agent or even at a single nucleoside within an oligonucleotide. Further included are oligonucleotides that are chimeric. “Chimeric” or “chimeras” oligonucleotides which contain two or more chemically distinct regions, each made up of at least one nucleotide. In certain embodiments, the oligonucleotide agent comprises an antisense oligonucleotide (ASO). The term “antisense oligonucleotide” generally refers to an oligonucleotide configured to specifically anneal with / hybridise to a given sequence in a target nucleic acid, such as for example in a target RNA, such as mRNA, and typically comprises, consist essentially of or consist of a nucleic acid sequence that is complementary or substantially complementary to said target nucleic acid sequence. Antisense oligonucleotides suitable for use herein may typically be capable of annealing with / hybridising to the respective target nucleic acid sequences at high stringency conditions, and capable of hybridising specifically to the target under physiological conditions. Preferably, an antisense oligonucleotide is (substantially) single-stranded, for example, at least 80%, at least 90%, or 100% of the ASO’s length is single stranded. The terms “complementary” or “complementarity” as used herein with reference to nucleic acids, refer to the normal binding of single-stranded nucleic acids under permissive salt (ionic strength) and temperature conditions by base pairing, preferably Watson-Crick base pairing. By means of example, complementary Watson-Crick base pairing occurs between the bases A and T, A and U, G and C, or G and 5-methylcytosine (mC). For example, the sequence 5’A-G-U 3’ is complementary to sequence 5’ A-C-U 3’. An antisense oligonucleotide need not be 100% complementary to its target sequence to bind or hybridise specifically with the latter. An antisense agent may be said to be specifically hybridisable when binding of the agent to a target nucleic acid molecule interferes with the normal function of the target nucleic acid such as to attain an intended outcome (e.g., loss of utility), and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense agent 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. Thus, “specifically hybridisable” and “complementary” may indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between an antisense agent and a nucleic acid target. Preferably, to ensure specificity of antisense oligonucleotides towards the desired target over unrelated molecules, the sequence of said antisense oligonucleotides may be at least about 90% complementary, or in increasing order of preference at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% complementary to the respective target sequence. Expressed differently, the sequence of said antisense oligonucleotides may display at least about 90% identity, or in increasing order of preference at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to the complement of the target sequence. Hence, complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. By means of an example and without limitation, the sequence of an antisense oligonucleotide may display in increasing order of preference at most 5, at most 4, at most 3, at most 2, at most 1, or no mismatches with the complement of the target sequence. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide. The terms “identity”, “sequence identity” or “identical” in the context of nucleotide sequences may be used interchangeably herein, and refer to the extent that nucleic acid sequences are identical on a nucleotide-by-nucleotide basis. The percentage of sequence identity may be calculated by comparing two optimally aligned sequences, determining the number of positions at which the identical nucleic acid base occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions, and multiplying the result by 100 to yield the percentage of sequence identity. Sequence identity between nucleic acids may be conveniently determined using suitable algorithms for performing sequence alignments and determination of sequence identity as know per se. Exemplary but non-limiting algorithms include those based on the Basic Local Alignment Search Tool (BLAST) originally described by Altschul et al. 1990 (J Mol Biol 215: 403-10), such as the “Blast 2 sequences” tool described by Tatusova and Madden 1999 (FEMS Microbiol Lett 174: 247-250), or the “blastn suite-2sequences” sequence alignment algorithm described by Zheng Zhang et al. 2000 (J Comput Biol 2000, vol.7(1-2), 203-14), now incorporated into the BLAST program suite available at ncbi.nlm.nih.gov. The skilled person can implement such algorithms and set the requisite parameters. By means of an example and without limitation, parameters for the BLASTN program may be as follows: cost to open a gap = 0, cost to extend a gap = 2.5, reward for a match = 1, penalty for a mismatch = -2, Expect value = 0.05, word size = 28, Low Complexity Filter = Yes. In certain embodiments, the ASO is capable of specifically hybridising to MRC2 mRNA. In certain embodiments, the ASO displays at least 90% sequence complementarity to MRC2 mRNA, or in increasing order of preference at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% complementarity to MRC2 mRNA. In certain embodiments, the length of the ASO is between 12 and 60 nucleotides or modified nucleotides. In certain embodiments, exemplary ASO lengths are between 10 and 20, between 15 and 20, between 15 and 25, between 20 and 25, between 20 and 30, between 25 and 30, between 25 and 35, between 30 and 40, between 40 and 50, or between 50 and 60 nucleotides or modified nucleotides. In embodiments, the ASO hybridises to a portion of the target nucleic acid of matching length. In certain embodiments, oligonucleotides comprise one or more type of modified sugar and / or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modifications discussed herein. In certain embodiments the ASO is a gapmer. 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.” Hence, in certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which comprises two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5’-wing, the gap, and the 3’-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3’-most nucleoside of the 5’-wing and the 5’-most nucleoside of the 3’-wing) differ from the sugar moiety of the neighbouring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing / gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5’-wing differs from the sugar motif of the 3’-wing (asymmetric gapmer). In certain preferred embodiments, the 5’-wing and the 3’-wing comprise locked nucleic acids, in particular locked ribonucleic acids. In certain embodiments, the wings of a gapmer comprise each independently 1-10 nucleosides. In certain embodiments, the wings of a gapmer comprise each independently 2-10 nucleosides. In certain embodiments, the wings of a gapmer comprise each independently 3-10 nucleosides. In certain embodiments, the wings of a gapmer comprise each independently 1-5 nucleosides. In certain embodiments, the wings of a gapmer comprise each independently 2-5 nucleosides. In certain embodiments, the wings of a gapmer comprise each independently 3-5 nucleosides. In certain embodiments, the gap of a gapmer comprises 7-30 nucleosides, or in increasing order of preference 7-25, 7-20, 7-15, or 7-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 8-30 nucleosides, or in increasing order of preference 8-25, 8-20, 8-15, or 8-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 9-30 nucleosides, or in increasing order of preference 9-25, 9-20, 9-15, or 9-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 10-30 nucleosides, or in increasing order of preference 10-25, 10-20, 10-15, or 10-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 8, 9, 10, 11, or 12 nucleosides. In certain embodiments, the gapmer is a deoxy gapmer. In such embodiments, the nucleosides on the gap side of each wing / gap junction are unmodified 2’-deoxynucleosides and the nucleosides on the wing sides of each wing / gap junction are modified nucleosides. In certain such embodiments, each nucleoside of the gap is an unmodified 2’-deoxynucleoside. In certain such embodiments, each nucleoside of each wing is a modified nucleoside. In certain embodiments, the nucleosides of a gapmer are all modified nucleosides. In certain embodiments, the structure of the gapmer is as follows: Ax-By-Czwherein A and C are each independently ribonucleotides or modified ribonucleotides, such as optionally 2’-OMe ribonucleotides, 2’-MOE ribonucleotides, 2’-F ribonucleotides, cEt ribonucleotides, or LNA ribonucleotides, or a combination thereof, preferably LNA ribonucleotides; B are deoxyribonucleotides or modified deoxyribonucleotides, preferably unmodified deoxyribonucleotides; x and z each independently are 1-10; and y is 7-30. Preferred gap (Ax) and wing (By, Cz) lengths are each independently as listed in the preceding sections. In certain embodiments, the gapmer comprises unmodified internucleoside linkages. In preferred embodiments, the gapmer comprises one or preferably more modified internucleoside linkages. In more preferred embodiments, all internucleoside linkages of the gapmer are modified. Particularly preferably, the gapmer comprises one, preferably more than one, and more preferably all phosphorothioate internucleoside linkages. By means of an example, at least 50% or in increasing order of preference, at least 60%, at least 70%, at least 80%, at least 90% or 100% of internucleoside linkages in the gapmer are phosphorothioate linkages. In certain embodiments, the gapmer comprises at least one modified nucleobase, such as 5- methylcytosine. In certain embodiments, a gapmer may comprise a gap segment consisting of linked deoxynucleosides; a 5’ wing segment consisting of linked nucleosides; and a 3’ wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, a gapmer may comprise a gap segment consisting of linked deoxynucleosides; a 5’ wing segment consisting of linked nucleosides; and a 3’ wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing segment and wherein any one or any combination of two or all features i*)-iii*) applies: i*) each nucleoside of each wing segment comprises each independently a cEt nucleoside or a 2’-O- methoxyethyl nucleoside; ii*) each internucleoside linkage is a phosphorothioate linkage; iii*) each cytosine is a 5-methylcytosine. In certain embodiments, the oligonucleotide, such as ASO, in particular a gapmer, displays the combination of: i) the oligonucleotide, such as ASO, in particular a gapmer, comprises one or more phosphorothioate internucleoside linkages, preferably wherein all internucleoside linkages are phosphorothioate internucleoside linkages; ii) the oligonucleotide, such as ASO, in particular a gapmer, comprises one or more ribose comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA), preferably one or more 5’ and one or more 3’ ribose comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA), more preferably comprising independent from each other two or three 5’ and 3’ riboses comprising a 2’- O,4’-C-methylene bridge (Locked Nucleic Acid, LNA). In a preferred embodiment, the oligonucleotide comprises one or more modified riboses at its 5’ terminal region and one or more modified riboses at its 3’ terminal region, each modified ribose comprising a 2’-O,4’-C-methylene bridge (LNA modification). In a more preferred embodiment, the oligonucleotide comprises multiple riboses modified with a 2’- O,4’-C-methylene bridge independently located at each of the terminal regions. Specifically, the oligonucleotide preferably comprises two or three LNA-modified riboses independently located within the 5’ terminal region and two or three LNA-modified riboses independently located within the 3’ terminal region. It is to be understood that the number of modified riboses in the 5’ region need not match the number in the 3’ region. In the context of gapmer-type oligonucleotides, which typically comprise a central DNA "gap" region flanked by modified terminal regions, the terms "5’ terminal region" and "3’ terminal region" refer to the respective end segments flanking the central DNA gap. However, the defined modifications may also apply to other types of oligonucleotides and are not strictly limited to gapmers. In certain embodiments, the oligonucleotide is a gapmer, and displays the combination of: i) the oligonucleotide comprises phosphorothioate internucleoside linkages, wherein all internucleoside linkages are phosphorothioate internucleoside linkages; ii) the oligonucleotide comprises two or three 5’ terminal ribose each comprising a 2’-O,4’-C- methylene bridge (Locked Nucleic Acid, LNA), and comprises two or three 3’ terminal ribose each comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence selected from 5’ CCGAGTAGGAGAGGTG 3’ (SEQ ID NO: 26), 5’ CATAGGTCTTCTTCAC 3’ (SEQ ID NO: 27), 5’ ATAGCAGTGTCGGAGT 3’ (SEQ ID NO: 28), 5’ TAAATGCTTGCTCTAA 3’ (SEQ ID NO: 29), or 5’ TCTTCTTGCAAACATA 3’ (SEQ ID NO: 30); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleobase sequence selected from 5’ CCGAGTAGGAGAGGTG 3’ (SEQ ID NO: 26), 5’ CATAGGTCTTCTTCAC 3’ (SEQ ID NO: 27), 5’ ATAGCAGTGTCGGAGT 3’ (SEQ ID NO: 28), 5’ TAAATGCTTGCTCTAA 3’ (SEQ ID NO: 29), or 5’ TCTTCTTGCAAACATA 3’ (SEQ ID NO: 30). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleobase sequence 5’ AATGCTTGCTCTAAGG 3’ (SEQ ID NO: 1); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleobase sequence 5’ AATGCTTGCTCTAAGG 3’ (SEQ ID NO: 1). Such gapmers are particularly effective against human MRC2 mRNA. In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleotide sequence of any of SEQ ID NOs: 6-9; or the gapmer may comprise, consist essentially of, or consist of a nucleotide sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleotide sequence of any of SEQ ID NOs: 6-9. Such gapmers are particularly effective against human MRC2 mRNA. In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleobase sequence 5’ TTCTCTGGAAGCGCTGATG 3’ (SEQ ID NO: 2); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleobase sequence 5’ TTCTCTGGAAGCGCTGATG 3’ (SEQ ID NO: 2). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleotide sequence of any of SEQ ID NOs: 10-13 or 48; or the gapmer may comprise, consist essentially of, or consist of a nucleotide sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleotide sequence of any of SEQ ID NOs: 10-13 or 48. Such gapmers are particularly effective against human MRC2 mRNA. In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleobase sequence 5’ TCCATCTGAAGCGCCCATC 3’ (SEQ ID NO: 3); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleobase sequence 5’ TCCATCTGAAGCGCCCATC 3’ (SEQ ID NO: 3). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleotide sequence of any of SEQ ID NOs: 14-17 or 49; or the gapmer may comprise, consist essentially of, or consist of a nucleotide sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleotide sequence of any of SEQ ID NOs: 14-17 or 49. Such gapmers are particularly effective against human MRC2 mRNA. In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleobase sequence 5’ TCACCGAAGATCTTGTTGA 3’ (SEQ ID NO: 4); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleobase sequence 5’ TCACCGAAGATCTTGTTGA 3’ (SEQ ID NO: 4). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleotide sequence of any of SEQ ID NOs: 18-21 or 50; or the gapmer may comprise, consist essentially of, or consist of a nucleotide sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleotide sequence of any of SEQ ID NOs: 18-21 or 50. Such gapmers are particularly effective against human MRC2 mRNA. In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleobase sequence 5’ TATAGCAATACCGGAGTTT 3’ (SEQ ID NO: 5); or the gapmer may comprise, consist essentially of, or consist of a nucleobase sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleobase sequence 5’ TATAGCAATACCGGAGTTT 3’ (SEQ ID NO: 5). In certain embodiments, the gapmer may comprise, consist essentially of, or consist of the nucleotide sequence of any of SEQ ID NOs: 22-25 or 51; or the gapmer may comprise, consist essentially of, or consist of a nucleotide sequence at least 90% identical, or in increasing order of preference at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the nucleotide sequence of any of SEQ ID NOs: 22-25 or 51. Such gapmers are particularly effective against human MRC2 mRNA. In certain further embodiments, the oligonucleotide agent comprises an RNA interference (RNAi) compound. “RNAi compound” means an oligonucleotide compound that acts, at least in part, through RISC or Ago2, but not through RNase H, to suppress the expression of a target nucleic acid and / or protein encoded by the target nucleic acid. In certain embodiments, RNAi compounds may include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and / or sequester a target nucleic acid (thus, include microRNA / microRNA-mimic compounds). As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double- stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term “RNAi” is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics. In certain embodiments, the RNAi compound may be small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ssRNA, or any combination thereof. An RNAi agent typically comprises, consists essentially of or consists of a double-stranded portion or region (notwithstanding the optional and potentially preferred presence of single-stranded overhangs) of annealed complementary strands, one of which has a sequence corresponding to a target nucleotide sequence, such as to at least a portion of an mRNA, of the target gene to be down- regulated. The other strand of the RNAi agent is complementary to said target nucleotide sequence. Whereas the sequence of an RNAi agent need not be completely identical to a target sequence to be down-regulated, the number of mismatches between a target sequence and a nucleotide sequence of the RNAi agent is preferably no more than 1 in 5 bases, or 1 in 10 bases, or 1 in 20 bases, or 1 in 50 bases. Preferably, to ensure specificity of RNAi agents towards the desired MRC2 targets over unrelated molecules, the sequence of said RNAi agents may be at least about 90% identical, preferably at least about 95% identical, such as, e.g., about 96%, about 97%, about 98%, about 99% and up to 100% identical to the respective target MRC2 sequence. An RNAi agent may be formed by separate sense and antisense strands or, alternatively, by a common strand providing for fold-back stem-loop or hairpin design where the two annealed strands of an RNAi agent are covalently linked. An siRNA molecule may be typically produced, e.g., synthesised, as a double stranded molecule of separate, substantially complementary strands, wherein each strand is about 18 to about 35 bases long, preferably about 19 to about 30 bases, more preferably about 20 to about 25 bases and even more preferably about 21 to about 23 bases. shRNA is in the form of a hairpin structure. shRNA can be synthesized exogenously or can be formed by transcribing from RNA polymerase III promoters in vivo. Preferably, shRNAs can be engineered in host cells or organisms to ensure continuous and stable suppression of a desired gene. It is known that siRNA can be produced by processing a hairpin RNA in cells. RNAi agents as intended herein may include any modifications as set out herein for nucleic acids and oligonucleotides, in order to improve their therapeutic properties. In embodiments, at least one strand of an RNAi molecules may have a 3’ overhang from about 1 to about 6 bases in length, e.g., from 2 to 4 bases, more preferably from 1 to 3 bases. For example, one strand may have a 3’ overhang and the other strand may be either blunt-ended or may also have a 3’overhang. The length of the overhangs may be the same or different for each strand. The 3’ overhangs can be stabilised against degradation. For example, the RNA may be stabilised by including purine nucleotides, such as A or G nucleotides. Alternatively, substitution of pyrimidine nucleotides by modified analogues, e.g., substitution of U 3’ overhangs by 2’-deoxythymidine is tolerated and does not affect the efficiency of RNAi. An exemplary siRNA may be characterised by any one or any combination of two or more or all of the following criteria i#)-v#): i#) having a double-stranded nucleic acid length of between 16 to 30 bases and preferably of between 18 to 23 bases, and preferably of 19 nucleotides; ii#) having GC content between about 30 and about 50 % iii#) having a TT(T) sequence at 3’ end; iv#) showing no secondary structure when adopting the duplex form; v#) having a Tm (melting temperature) of lower than 20°C. Production of oligonucleotide agents intended herein, such as antisense oligonucleotides and RNAi compounds, can be carried out by any processes known in the art, such as inter alia partly or entirely by chemical synthesis, e.g., routinely known solid phase synthesis; an exemplary and non-limiting method for synthesising oligonucleotides on a modified solid support is described in US 4,458,066; in another example, diethyl-phosphoramidites are used as starting materials and may be synthesised as described by Beaucage et al. 1981 (Tetrahedron Letters 22: 1859-1862)), or partly or entirely by biochemical (enzymatic) synthesis, e.g., by in vitro transcription from a nucleic acid construct (template) using a suitable polymerase such as a T7 or SP6 RNA polymerase, or by recombinant nucleic acid techniques, e.g., expression from a vector in a host cell or host organism. Modified nucleotides can be introduced by in vitro chemical or biochemical synthesis. In an embodiment, the oligonucleotide agents of the invention are synthesised in vitro and do not include compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of the oligonucleotide agents. In certain embodiments, the oligonucleotide agents taught here may be purified. By means of example and not limitation, purified nucleic acids (including NA-based or NA-comprising agents) may preferably constitute by weight ≥ about 10%, more preferably ≥ about 50%, such as ≥ about 60%, yet more preferably ≥ about 70%, such as ≥ about 80%, and still more preferably ≥ about 90%, such as ≥ about 95%, ≥ about 96%, ≥ about 97%, ≥ about 98%, ≥ about 99% or even 100%, of the nucleic acid content of the discrete environment (a discrete environment denotes a single medium, such as for example a single solution, gel, precipitate, lyophilisate, etc.). For example, purity of a nucleic acid may be determined by measuring absorbance A260 / A280. Also, an isolated nucleic acid may be purified to homogeneity as determined by agarose- or polyacrylamide-gel electrophoresis and ethidium bromide or similar staining. Purified substances may be obtained by known methods including, for example, laboratory or recombinant synthesis, chromatography, preparative electrophoresis, centrifugation, precipitation, affinity purification, etc. Oligonucleotide agents as taught herein may be further conjugated (e.g., covalently or non- covalently, directly or via a suitable linker) to 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 cholesterol moiety, cholic acid, a thioether, e.g., beryl-S- tritylthiol or hexyl-S-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. Any agent as taught herein may be administered to subjects in any suitable or operable form or format. For example, the reference to the agent as intended herein may encompass a given therapeutically useful agent as well as any pharmaceutically acceptable forms of such agent, such as any addition salts, hydrates or solvates of the agent. The term “pharmaceutically acceptable” as used herein inter alia in connection with salts, hydrates, solvates and excipients, is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the agent is able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form of a agent with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. A compound containing an acidic proton may also be converted into its non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, aluminum salts, zinc salts, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form. The term solvate comprises the hydrates and solvent addition forms which the agent is able to form, as well as the salts thereof. Examples of such forms are, e.g., hydrates, alcoholates and the like. For example, the agent may be a part of a composition. The term “composition” generally refers to a thing composed of two or more components, and more specifically particularly denotes a mixture or a blend of two or more materials, such as elements, molecules, substances, biological molecules, or microbiological materials, as well as reaction products and decomposition products formed from the materials of the composition. By means of an example, a composition may comprise any agent as taught herein in combination with one or more other substances. For example, a composition may be obtained by combining, such as admixing, the agent as taught herein with said one or more other substances. In certain embodiments, the present compositions may be configured as pharmaceutical compositions. Pharmaceutical compositions typically comprise one or more pharmacologically active ingredients (chemically and / or biologically active materials having one or more pharmacological effects) and one or more pharmaceutically acceptable carriers. Compositions as typically used herein may be liquid, semisolid or solid, and may include solutions or dispersions. The oligonucleotide agents as taught herein are useful for therapy. The agents as taught herein can be conveniently formulated into pharmaceutical compositions. Therefore, any reference to the use of the agent in therapy (or any variation of such language) also subsumes the use of pharmaceutical compositions comprising the agent or a combination of such agents in therapy. A further aspect of the invention thus provides a pharmaceutical composition comprising an oligonucleotide agent capable of suppressing the expression of MRC2, optionally wherein the agent is in accordance with any of the embodiments described heretofore. The terms “pharmaceutical composition” and “pharmaceutical formulation” may be used interchangeably. The pharmaceutical compositions as taught herein may comprise in addition to the one or more actives, one or more pharmaceutically or acceptable carriers. Suitable pharmaceutical excipients depend on the dosage form and identities of the active ingredients and can be selected by the skilled person (e.g., by reference to the Handbook of Pharmaceutical Excipients 7thEdition 2012, eds. Rowe et al.). As used herein, the terms “carrier” or “excipient” are used interchangeably and broadly include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), solubilisers (such as, e.g., Tween® 80, Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (such as, e.g., EDTA or glutathione), amino acids (such as, e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavourings, aromatisers, thickeners, agents for achieving a depot effect, coatings, antifungal agents, preservatives (such as, e.g., ThimerosalTM, benzyl alcohol), antioxidants (such as, e.g., ascorbic acid, sodium metabisulfite), tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (such as, e.g., lactose, mannitol) and the like. The use of such media and agents for the formulation of pharmaceutical and cosmetic compositions is well known in the art. Acceptable diluents, carriers and excipients typically do not adversely affect a recipient's homeostasis (e.g., electrolyte balance). The use of such media and agents for pharmaceutical active substances is well known in the art. Such materials should be non- toxic and should not interfere with the activity of the actives. Acceptable carriers may include biocompatible, inert or bioabsorbable salts, buffering agents, oligo- or polysaccharides, polymers, viscosity-improving agents, preservatives and the like. One exemplary carrier is physiologic saline (0.15 M NaCl, pH 7.0 to 7.4). Another exemplary carrier is 50 mM sodium phosphate, 100 mM sodium chloride. The precise nature of the carrier or other material will depend on the route of administration. For example, the pharmaceutical composition may be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has suitable pH, isotonicity and stability. The pharmaceutical formulations may comprise pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, preservatives, complexing agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium phosphate, sodium hydroxide, hydrogen chloride, benzyl alcohol, parabens, EDTA, sodium oleate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. Preferably, the pH value of the pharmaceutical formulation is in the physiological pH range, such as particularly the pH of the formulation is between about 5 and about 9.5, more preferably between about 6 and about 8.5, even more preferably between about 7 and about 7.5. Illustrative, non-limiting carriers for use in formulating the pharmaceutical compositions include, for example, oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for intravenous (IV) use, liposomes or surfactant-containing vesicles, microspheres, microbeads and microsomes, powders, tablets, capsules, suppositories, aqueous suspensions, aerosols, and other carriers apparent to one of ordinary skill in the art. Liposomes are artificial membrane vesicles which are useful as delivery vehicles in vitro and in vivo. These formulations may have net cationic, anionic or neutral charge characteristics and are useful characteristics with in vitro, in vivo and ex vivo delivery methods. It has been shown that large unilamellar vesicles (LUV), which range in size from 0.2-4.0 PHI.m can encapsulate a substantial percentage of an aqueous buffer containing large macromolecules. The composition of the liposome is usually a combination of phospholipids, particularly high-phase-transition-temperature phospholipids, usually in combination with steroids, especially cholesterol. Other phospholipids or other lipids may also be used. The physical characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations. Pharmaceutical compositions as intended herein may be formulated for essentially any route of administration, such as without limitation, oral administration (such as, e.g., oral ingestion or inhalation), intranasal administration (such as, e.g., intranasal inhalation or intranasal mucosal application), parenteral administration (such as, e.g., subcutaneous, intravenous (I.V.), intramuscular, intraperitoneal or intrasternal injection or infusion), transdermal or transmucosal (such as, e.g., oral, sublingual, intranasal) administration, topical administration, rectal, vaginal or intra-tracheal instillation, and the like. In this way, the therapeutic effects attainable by the methods and compositions can be, for example, systemic, local, tissue-specific, etc., depending of the specific needs of a given application. For example, for oral administration, pharmaceutical compositions may be formulated in the form of pills, tablets, lacquered tablets, coated (e.g., sugar-coated) tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions. In an example, without limitation, preparation of oral dosage forms may be is suitably accomplished by uniformly and intimately blending together a suitable amount of the agent as disclosed herein in the form of a powder, optionally also including finely divided one or more solid carrier, and formulating the blend in a pill, tablet or a capsule. Exemplary but non-limiting solid carriers include calcium phosphate, magnesium stearate, talc, sugars (such as, e.g., glucose, mannose, lactose or sucrose), sugar alcohols (such as, e.g., mannitol), dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Compressed tablets containing the pharmaceutical composition can be prepared by uniformly and intimately mixing the agent as disclosed herein with a solid carrier such as described above to provide a mixture having the necessary compression properties, and then compacting the mixture in a suitable machine to the shape and size desired. Moulded tablets maybe made by moulding in a suitable machine, a mixture of powdered compound moistened with an inert liquid diluent. Suitable carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. For example, for oral or nasal aerosol or inhalation administration, pharmaceutical compositions may be formulated with illustrative carriers, such as, e.g., as in solution with saline, polyethylene glycol or glycols, DPPC, methylcellulose, or in mixture with powdered dispersing agents, further employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilising or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the agents as taught herein or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. Illustratively, delivery may be by use of a single-use delivery device, a mist nebuliser, a breath-activated powder inhaler, an aerosol metered-dose inhaler (MDI) or any other of the numerous nebuliser delivery devices available in the art. Additionally, mist tents or direct administration through endotracheal tubes may also be used. Examples of carriers for administration via mucosal surfaces depend upon the particular route, e.g., oral, sublingual, intranasal, etc. When administered orally, illustrative examples include pharmaceutical grades of mannitol, starch, lactose, magnesium stearate, sodium saccharide, cellulose, magnesium carbonate and the like, with mannitol being preferred. When administered intranasally, illustrative examples include polyethylene glycol, phospholipids, glycols and glycolipids, sucrose, and / or methylcellulose, powder suspensions with or without bulking agents such as lactose and preservatives such as benzalkonium chloride, EDTA. In a particularly illustrative embodiment, the phospholipid 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) is used as an isotonic aqueous carrier at about 0.01-0.2% for intranasal administration of the compound of the subject invention at a concentration of about 0.1 to 3.0 mg / ml. For example, for parenteral administration, pharmaceutical compositions may be advantageously formulated as solutions, suspensions or emulsions with suitable solvents, diluents, solubilisers or emulsifiers, etc. Suitable solvents are, without limitation, water, physiological saline solution, PBS, Ringer’s solution, dextrose solution, or Hank’s solution, or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose, invert sugar, sucrose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. The agents and pharmaceutically acceptable salts thereof of the invention can also be lyophilised and the lyophilisates obtained used, for example, for the production of injection or infusion preparations. For example, one illustrative example of a carrier for intravenous use includes a mixture of 10% USP ethanol, 40% USP propylene glycol or polyethylene glycol 600 and the balance USP Water for Injection (WFI). Other illustrative carriers for intravenous use include 10% USP ethanol and USP WFI; 0.01-0.1% triethanolamine in USP WFI; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI; and 1-10% squalene or parenteral vegetable oil-in-water emulsion. Illustrative examples of carriers for subcutaneous or intramuscular use include phosphate buffered saline (PBS) solution, 5% dextrose in WFI and 0.01-0.1% triethanolamine in 5% dextrose or 0.9% sodium chloride in USP WFI, or a 1 to 2 or 1 to 4 mixture of 10% USP ethanol, 40% propylene glycol and the balance an acceptable isotonic solution such as 5% dextrose or 0.9% sodium chloride; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI and 1 to 10% squalene or parenteral vegetable oil-in-water emulsions. Where aqueous formulations are preferred, such may comprise one or more surfactants. For example, the composition can be in the form of a micellar dispersion comprising at least one suitable surfactant, e.g., a phospholipid surfactant. Illustrative examples of phospholipids include diacyl phosphatidyl glycerols, such as dimyristoyl phosphatidyl glycerol (DPMG), dipalmitoyl phosphatidyl glycerol (DPPG), and distearoyl phosphatidyl glycerol (DSPG), diacyl phosphatidyl cholines, such as dimyristoyl phosphatidylcholine (DPMC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (DSPC); diacyl phosphatidic acids, such as dimyristoyl phosphatidic acid (DPMA), dipahnitoyl phosphatidic acid (DPPA), and distearoyl phosphatidic acid (DSPA); and diacyl phosphatidyl ethanolamines such as dimyristoyl phosphatidyl ethanolamine (DPME), dipalmitoyl phosphatidyl ethanolamine (DPPE) and distearoyl phosphatidyl ethanolamine (DSPE). Typically, a surfactant:active substance molar ratio in an aqueous formulation will be from about 10:1 to about 1:10, more typically from about 5:1 to about 1:5, however any effective amount of surfactant may be used in an aqueous formulation to best suit the specific objectives of interest. When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and / or dissolve in the rectal cavity to release the drug. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. One skilled in this art will recognise that the above description is illustrative rather than exhaustive. Indeed, many additional formulations techniques and pharmaceutically-acceptable excipients and carrier solutions are well-known to those skilled in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens. Further, there are several well-known methods of introducing nucleic acids (e.g., antisense oligonucleotides and RNAi agents) into animal cells, any of which may be used herein. At the simplest, the nucleic acid can be directly injected into the target cell / target tissue. Other methods include fusion of the recipient cell with bacterial protoplasts containing the nucleic acid, the use of compositions like calcium chloride, rubidium chloride, lithium chloride, calcium phosphate, DEAE dextran, cationic lipids or liposomes or methods like receptor-mediated endocytosis, biolistic particle bombardment (“gene gun” method), infection with viral vectors, for example such as taught herein (these are known as such and include vectors derived from for example, but without limitation, retroviruses, vaccinia viruses, poxviruses, adenoviruses, and adeno-associated viruses (AAV); such viral vectors may me be engineered by recombinant techniques as known per se to introduce thereto nucleic acid sequence(s) encoding any one of the antisense oligonucleotides or RNAi agents disclosed herein), electroporation, and the like. Other techniques or methods which are suitable for delivering nucleic acid molecules to target cells include the continuous delivery of an NA molecule from poly (lactic-Co-Glycolic Acid) polymeric microspheres or the direct injection of protected (stabilized) NA molecule(s) into micropumps delivering the product. Another possibility is the use of implantable drug-releasing biodegradable microspheres. Also envisaged is encapsulation of NA in various types of liposomes (immunoliposomes, PEGylated (immuno) liposomes), cationic lipids and polymers such as polyethyleneimine (PEI), nanoparticles or dendrimers, poly (lactic-Co- Glycolic Acid) polymeric microspheres, implantable drug-releasing biodegradable microspheres, exosomes, etc.; and co-injection of NA with protective agent like the nuclease inhibitor aurintricarboxylic acid. It shall be clear that also a combination of different above-mentioned delivery modes or methods may be used. It may be desirable to deliver a nucleic acid molecule in a colloidal dispersion system. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, beads, and lipid- based systems including oil-in- water emulsions, micelles, mixed micelles, and liposomes or liposome formulations. Liposomes are artificial membrane vesicles which are useful as delivery vehicles in vitro and in vivo. These formulations may have net cationic, anionic or neutral charge characteristics and are useful characteristics with in vitro, in vivo and ex vivo delivery methods. It has been shown that large unilamellar vesicles (LUV), which range in size from 0.2-4.0 PHI.m can encapsulate a substantial percentage of an aqueous buffer containing large macromolecules. RNA, and DNA can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form (Fraley et al.1981 (Trends Biochem ScL 6: 77). In order for a liposome to be an efficient gene transfer vehicle, the following characteristics should be present: (1) encapsulation of the nucleic acid molecule of interest at high efficiency while not compromising their biological activity; (2) preferential and substantial binding to a target cell in comparison to non-target cells; (3) delivery of the aqueous contents of the vesicle to the target cell cytoplasm at high efficiency; and (4) accurate and effective expression of genetic information (Mannino et al.1988 (Biotechniques 6: 682). The composition of the liposome is usually a combination of phospholipids, particularly high-phase- transition-temperature phospholipids, usually in combination with steroids, especially cholesterol. Other phospholipids or other lipids may also be used. The physical characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations. In particularly preferred embodiments, the oligonucleotide agent is to be administered subcutaneously. In further particularly preferred embodiments, the oligonucleotide agent is to be administered intradermally. In further particularly preferred embodiments, the oligonucleotide agent is to be administered systemically, such as intravenously (IV). In further particularly preferred embodiments, the oligonucleotide agent is to be administered to the lymphatic system. In further particularly preferred embodiments, the oligonucleotide agent is to be administered to one or more lymph nodes. In further particularly preferred embodiments, the oligonucleotide agent is to be administered by any combination of such administration routes. In certain preferred embodiments, the oligonucleotide agent is to be administered by a bolus injection or an infusion. The pharmaceutical formulations as disclosed herein, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques may generally include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. By means of an example, the pharmaceutical formulations as disclosed herein may be provided as an injectable solution or dispersion, in a container, syringe or an injection device or applicator holding a single or multiple administration doses. In particular embodiments, the agents as taught herein can be administered using a sustained delivery system, such as a (partly) implanted sustained delivery system. Skilled person will understand that such a sustained delivery system may comprise a reservoir for holding the agent as taught herein, a pump and infusion means (e.g., a tubing system). The dosage or amount of the agents as taught herein, optionally in combination with one or more other active compounds to be administered, depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, the unit dose and regimen depend on the nature and the severity of the disorder to be treated, and also on factors such as the species of the subject, the sex, age, body weight, general health, diet, mode and time of administration, immune status, and individual responsiveness of the human or animal to be treated, efficacy, metabolic stability and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to the agent of the invention. In order to optimize therapeutic efficacy, the agent as taught herein can be first administered at different dosing regimens. Typically, levels of the agent in a tissue can be monitored using appropriate screening assays as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. The frequency of dosing is within the skills and clinical judgement of medical practitioners (e.g., doctors, veterinarians or nurses). Typically, the administration regime is established by clinical trials which may establish optimal administration parameters. However, the practitioner may vary such administration regimes according to the one or more of the aforementioned factors, e.g., subject’s age, health, weight, sex and medical status. The frequency of dosing can be varied depending on whether the treatment is prophylactic or therapeutic. Toxicity and therapeutic efficacy of the agents as described herein or pharmaceutical compositions comprising the same can be determined by known pharmaceutical procedures in, for example, cell cultures or experimental animals. These procedures can be used, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions that exhibit high therapeutic indices are preferred. While pharmaceutical compositions that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to normal cells (e.g., non-target cells) and, thereby, reduce side effects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in appropriate subjects. The dosage of such pharmaceutical compositions lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For a pharmaceutical composition used as described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the pharmaceutical composition which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. Without limitation, depending on the type and severity of the disease, a typical dosage (e.g., a typical daily dosage or a typical intermittent dosage, e.g., a typical dosage for every two days, every three days, every four days, every five days, every six days, every week, every 1.5 weeks, every two weeks, every three weeks, every month, or other) of the agents as taught herein may range from about 10 µg / kg to about 500 mg / kg body weight of the subject, per dose, depending on the factors mentioned above, e.g., may range from 10 µg / kg to 100 µg / kg, or from 100 µg / kg to 500 µg / kg, or from 500 µg / kg to 1 mg / kg, or from 1 mg / kg to 5 mg / kg, or from 5 mg / kg to 10 mg / kg, or from 10 mg / kg to 50 mg / kg, or from 50 mg / kg to 100 mg / kg, or from 100 mg / kg to 500 mg / kg body weight of the subject, per dose, depending on the factors mentioned above. In certain embodiments, any oligonucleotide agent as taught herein may be administered as the sole pharmaceutical agent (active pharmaceutical ingredient) or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. By means of an example, two or more agents as taught herein may be co-administered. By means of another example, one or more agents as taught herein may be co-administered with a pharmaceutical agent that is not a molecule as envisaged herein. For example, the molecules as taught herein may be combined with, such as administered simultaneously or sequentially, in either order, with known anti-lymphedema therapy or therapies. In certain embodiments, the oligonucleotide agent is to be administered simultaneously or sequentially, in either order, with one or more pro-lymphangiogenic factors. Pro-lymphangiogenic factors include substances that promote the growth and formation of lymphatic vessels, i.e. lymphangiogenesis. Several growth factors and cytokines have been identified as key promoters of lymphangiogenesis, including without limitation Vascular Endothelial Growth Factor-C (VEGF-C), Vascular Endothelial Growth Factor-D (VEGF-D), Angiopoietin-2 (Ang-2), Fibroblast Growth Factors (FGF), Platelet-Derived Growth Factor-BB (PDGF-BB), Insulin-like Growth Factor (IGF), Hepatocyte Growth Factor (HGF), adrenomedullin, and Sphingosine-1-phosphate (S1P). In certain embodiments, the oligonucleotide agent is to be administered simultaneously or sequentially, in either order, with VEGF-C or an inducer of VEGF-C. In certain embodiments, the oligonucleotide agent is to be administered simultaneously or sequentially, in either order, with an inhibitor of Rho-associated Coiled coil containing Kinase (ROCK). In certain embodiments, the oligonucleotide agent is to be administered simultaneously or sequentially, in either order, with VEGF-C or an inducer of VEGF-C or with an inhibitor of ROCK, or with any combination thereof. A non-limiting example of an inhibitor of ROCK is compound Y-27632 of the following formula: , or a stereoisomer, enantiomer, tautomer, solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof, such as for example a dichloride salt thereof. Hence, an aspect also provides a pharmaceutical composition comprising one or more oligonucleotide agents as taught herein and further one or more pro-lymphangiogenic factors as set forth above, for example a pharmaceutical composition comprising one or more oligonucleotide agents as taught herein and VEGF-C or an inducer of VEGF-C or an inhibitor of ROCK, or any combination thereof. While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as follows in the spirit and scope of the appended claims. The herein disclosed aspects and embodiments of the invention are further supported by the following non-limiting examples. EXAMPLES EXAMPLE 1: targeting of mouse uPARAP mRNA and in vivo efficacy of Gapmers targeting murine uPARAP mRNA. Experiments were performed using adult female mice (6-8 weeks-old). The animals were housed in light- and temperature-controlled environments and fed ad libitum. The hindlimb lymphedema induction model combined local irradiation and surgical intervention (Buntinx et al. Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema. Front. Pharmacol. Sect. Exp. Pharmacol. Drug Discov. 2022). Lymphedema was induced in the left limb, while the right limb was used as an internal control. For irradiation, mice were anesthetized using 2% isoflurane (Zoetis, Louvain-la-Neuve, Belgium) and placed on their ventral side inside the precision X-ray irradiator (X-Rad SMART PXi Precision X-RAY irradiator) (GE Healthcare, Chicago, USA). First, to accurately target the inguinal region, X-rays radiography (40 kV, 0.5 mA) of the mouse was performed. A 20 mm-square collimator was placed at the targeted region to irradiate it (anteroposterior) with a single dose of 30 Gy (225.0 kV, 13.00 mA). The mouse left limb was irradiated for 317 seconds on the ventral side and then 317 seconds on the dorsal side. One week after irradiation, surgery was performed on the mice, using isoflurane 2% anesthetic gas on a heating pad at 37°C and under a horizontal airflow hood. The hind left limb was shaved and disinfected with dermal isobetadine. One dose of Evans Blue dye (2%; 5 µL) was then injected between the footpads of the left hindlimb to visualize the lymphatic vessels and lymph nodes. A drastic lymphatic injury was achieved through surgery in three steps: i) circumferential incision of the skin at the inguinal level, ii) excision of the inguinal and popliteal lymph nodes and finally, iii) ligation of the collecting lymphatic vessels parallel to the ischial vein with three separate stitches of non-absorbable 7 / 0 polypropylene sutures (ETHICON) under a 10x binocular magnifier. At the end of the procedure, the skin was sutured with separate stitches of 5 / 0 non-absorbable silk suture (ETHICON). Bilateral limb volume was determined every 3 days with a caliper and using the following formula of a cone: 15 x π / 3 x (r2+ (Rxr) + R2). R represents the radius of the base of the limb and r the upper radius. To account for individual variability, limb volume was normalized for each animal by calculating the percentage change from the control limb (non-operated right limb), using the formula (V / Vc) x100, where V was the volume of the operated limb and Vc is the volume of the control limb. Mice were weighed daily, and the injected volumes were adjusted according to their weight. For the in vivo testing of gapmers, ready gapmers (CTRL and G4 from Qiagen) were dissolved in PBS and sub-cutaneously injected every four days after surgery into the footpad at a concentration of 5 mg / kg. The injected volumes were adjusted according to the weight of each mouse. 5 gapmer antisense oligonucleotides (herein, gapmer or GAO) were designed (G1 to G5) targeting mouse uPARAP mRNA and one GAO control (CTRL), each 16 nucleotides in length. The respective gapmer sequences and the location in mouse uPARAP mRNA to which they bind were as follows: Gapmer Sequence uPARAP mRNA binding location SEQ ID NO G1 5’ CCGAGTAGGAGAGGTG 3’ Upstream untranslated region 26 (UTR) G2 5’ CATAGGTCTTCTTCAC 3’ Exon 2 27 G3 5’ ATAGCAGTGTCGGAGT 3’ Exon 12 28 G4 5’ TAAATGCTTGCTCTAA 3’ Exons 21-22 29 G5 5’ TCTTCTTGCAAACATA 3’ Exon 6 30 CTRL 5’ GCTCCCTTCAATCCAA 3’ - 31 In each gapmer, several consecutive nucleosides at the 5’ end and several consecutive nucleosides at the 3’ end were locked nucleic acid (LNA) ribonucleosides, schematically illustrated by the following formula: , whereas the interposed consecutive nucleosides were deoxyribonucleosides, schematically illustrated by the following formula: In these formulas “B” stands for a nucleobase. All nucleosides were connected by phosphorothioate internucleoside linkages, schematically illustrated by the following formula: The efficacy of the gapmers was tested on mouse fibroblasts that endogenously express uPARAP (Fig. 1A, B). Primary mouse fibroblasts were cultured in DMEM (Thermo Fisher Scientific) supplemented with 1% HEPES, 1% MEM non-essential amino acids, 1% L-Glutamine, 1% sodium pyruvate, 1% penicillin-streptomycin, and 10% foetal bovine serum (FBS). When cells reached about 70% confluence, transfections with 20 nM of gapmer were performed using Lipofectamine RNAiMAX according to the manufacturer’s instructions (ThermoFisher Scientific). Cells were recovered after 48, 72, or 96 hours. Total mouse fibroblast RNA was isolated using the High Pure RNA isolation kit (Roche) following the manufacturer’s instructions. RNAs (500 ng) were reverse transcribed with the FastGene Scriptase II cDNA 5x ReadyMix (Nippon Genetics) and PCR performed using SYBR Green Master mix II (Applied Biosystems). The primers used amplified MRC2 (Forward: 5’ CAAGACTTGCCACCTTCAGCCT 3’ – SEQ ID NO: 40; Reverse: 5’ GGCTTCTTGCTGTTCACAGGAG 3’ – SEQ ID NO: 41) and GAPDH (Forward: 5’ GGTGGACCTCATGGCCTACA 3’ – SEQ ID NO: 42; Reverse: 5’ CTCTCTTGCTCAGTGTCCTTGCT 3’ – SEQ ID NO: 43). Cell transfection with G1, G2, G3 and G5 led to a reduction of uPARAP mRNA levels ranging from 22% to 66.4%. Interestingly, cell transfection with G4 achieved a higher and sustained reduction of uPARAP expression (72.4% + / - 14,9 at 48h, 89.4% + / - 5,8 at 72h and 84.4% + / - 3.5 at 96h) (Fig. 1A). A reduction of uPARAP protein was also detected by Western blot for all tested gapmers (G1-G5) with an almost complete inhibition with G4 (Fig. 1B). Cells were lysed with cell lysis buffer 1 X (Cell Signaling) containing a cocktail of protease inhibitors (cOmplete™, Sigma-Aldrich, Saint- Louis, USA) and phosphatase inhibitors (phosSTOP™, Roche). The protein concentration was determined using Bradford Dye Reagent (Bio-Rad Temse, Belgium). Samples were run on SDS- PAGE gels and transferred onto PVDF membranes (PerkinElmer, Mechelen, Belgium). Proteins were identified by overnight incubation at 4 °C with the indicated primary antibodies (uPARAP antibody 1 / 2500: mAb 2H9F12 clone, Madsen et al. Extracellular Collagenases and the Endocytic Receptor, Urokinase Plasminogen Activator Receptor-associated Protein / Endo180, Cooperate in Fibroblast-mediated Collagen Degradation. J. Biol. Chem. 2007, vol. 282, 27037–27045; mouse GAPDH antibody 1 / 5000 from Merck Millipore) in Tris buffer containing 0,1% Tween (TBS-T) and 5% bovine serum albumin. Afterwards, membranes were washed three times in TBS-T for 5 minutes, and then incubated for 1h at room temperature with horseradish peroxidase-coupled secondary antibodies (Cell Signaling, 1 / 2000). Proteins were revealed using Pierce™ ECL (ThermoFisher Scientific, Courtaboeuf, France) and detected with a ImageQuant™ LAS4000 imager (GE Healthcare). Quantification of protein levels was performed on Fiji 2.9.0 software. The most efficient gapmer (G4) was then subcutaneously injected into mice subjected to secondary lymphedema (SL) (Fig.1C). For the in vivo testing of gapmers, ready gapmers (CTRL and G4) were dissolved in PBS and subcutaneously injected every four days after surgery into the footpad at a concentration of 5 mg / kg. The injected volumes were adjusted according to the weight of each mouse. While the control gapmer (CTRL) did not affect limb swelling, G4 administration drastically reduced SL formation as assessed by reduced limb swelling (Fig.1C). An atypical ‘labyrinthine’ lymphatic vasculature with increased tortuosity and hyperbranching (Fig. 1D) was detected in G4-treated mice as compared to control mice (either mice untreated or mice treated with CTRL gapmer). As quantified in Fig. 1E, both tortuosity (left panel) and branching density (right panel) of lymphatic vessels are greatly increased in the SL mouse model when treated with the anti-uPARAP gapmer G4. The histological staining and immunohistochemistry and the 3D reconstruction of lymphatic vessels were performed as follows. On the day of sacrifice (3 weeks after surgery), fur was removed from the hind limb using topical depilatory cream. Limb skin tissues were collected, fixed in 37% formalin and embedded in paraffin. Samples were cut with a microtome (5 μm thickness) and 3 sections separated by 50 μm were placed on each slide. Slides were deparaffinized / rehydrated. For immunohistochemistry, antigen retrieval was performed for 11 min at 126° C in citrate buffer (pH=6) and non-specific antigen blocking was achieved using a protein block buffer. To visualize the lymphatic vessels, polyclonal goat anti-mouse lymphatic vessel receptor Lyve-1 antibody (1:200, R&D Systems) and the secondary antibody donkey anti-goat coupled with AlexaFluor 555 fluorochrome (1:200, Invitrogen) were incubated for 1 hour at room temperature. Section images were acquired using x20 magnification with the NanoZoomer 2.0-HT system or with SLIDEVIEW VS200 research slide scanner and polarized light Olympus system (0.23 μm / pixel, scanning resolution). Image processing and quantification were performed using the images analysis toolbox of MATLAB R2022b, according to the following steps: (i) original images were registered in the full-color red, green, blue (RGB) space; (ii) contrast was enhanced by calculating the excess of each color (for example by performing 2*R-G-B, for the red component); (iii) the resulting images were binarized using an automatic thresholding technique, and then systematically compared to the original ones and corrected manually if required. A mean spatial distribution curve was established and used to determine the following parameters: (a) the area under the curve referred to as the “integrated area”, which determined the global extent of the stained region, (b) the distance (from the epithelial basal layer) up to which 50 or 90% of staining was detected (50thor 90thpercentile= P50or P90respectively). Values were normalized by considering the number of vessels. The reconstruction of the lymphatic network in 3-dimension images was performed from the whole (uncut) skin sample. After sample fixation in 37% formalin, the skin was permeabilized in a solution of PBS / 5% Triton X-100 / 0.01% sodium azide for 24 hours. The primary Lyve-1 antibody (1:200) was incubated at room temperature, for 48 h and followed by secondary donkey anti-goat AlexaFluor 555 (1:200) incubation, at room temperature, for 48 h. After 3 washes, the sample was clarified in a Rapiclear 1.52 solution (Sunjinlab). Images were taken on a confocal microscope (Leica, SP5) at 10x magnification (z-stack every 3 µm). Image processing and measurement were performed using the image analysis toolbox of Matlab 2022b software. After 3D reconstruction, a processing algorithm to eliminate noise images and smooth the lymphatic vessels borders was implemented. It consisted in the successive application of a median filter, followed by an alternate open-close transformation and finally by a Gaussian filter. All those functions are parametric, however as original images were acquired systematically with the same microscopy settings, parameter functions were fixed once and applied automatically on all images. Finally, images were binarized using an automatic threshold (Otsu. A Threshold Selection Method from Gray-Level Histograms. IEEE Trans. Syst. Man Cybern. 1979, vol. 9: 62–66). By this last operation, all pixels belonging to vascular network take the value 1 and those of the background the value 0. In order to characterize the degree of complexity of the vessel network, two parameters were measured: a) branching density defined as the number of branching divided by the total length of the vascular network and b) the tortuosity defined as actual path length (geodesic length) between successive points all along the vessel network divided by the linear distance between the same points (Gommes et al. Practical methods for measuring the tortuosity of porous materials from binary or gray-tone tomographic reconstructions. AIChE J.2009, vol.55, 2000–2012). Tortuosity ranges from 1 (corresponding to a line) to higher values in function of the degree of the complexity of the vessel shape reflecting loops or twisted shaped portions. To perform those measurements, vessel skeleton was first determined. Skeletonized transformation reduced the vessels to their centreline while preserving their topology. From 3D skeleton, branching and skeleton length was determined and consequently the branching density. Geodesic and Euclidean distances were calculated by using an algorithm previously described (Legland, D.2023. Geodesic distances and geodesic diameters within 2D / 3D images). Based on in silico modelling, the inventors propose without wishing to be bound by any hypothesis that the ‘labyrinthine’ vasculature observed in SL mice treated with anti-uPARAP gapmers reduces fluid pressure in the dermal tissue and optimises lymphatic drainage. Together, these data provide evidence for the capacity of an anti-uPARAP gapmers to block SL development. They demonstrate that the delivery of anti-uPARAP oligonucleotide agents such as gapmers is a new therapeutic option for lymphedema, including secondary lymphedema. EXAMPLE 2: Mathematical model of Interstitial fluid pressure simulation in mouse. MATERIAL AND METHODS Model formulation Tissue and capillary portions of the dermis models were separately meshed with four noded elements with characteristic edge length of 15µm and curvature controlled with 0.5 maximum deviation factor. Tissue and capillary vessel portions were considered in hard contact at the interfaces with no tangential sliding. Fluid velocity (V) from the tissue portion through the vessel walls was considered dependent on fluid pressure (p) in the tissue following the relationship below. No flow from the vessel into the tissue was considered. Fluid flow on the external model boundaries was set to zero. ^^^^ = ^^^^^^^^^^^^Seepage coefficient ^^^^^^^^associated with the vessel wall was set to 30 µm2.s.kg-1based on calculations from Huxley & Meyer. Fifty percent increase in vessel wall permeability was modelled with ^^^^^^^^= 45 µm2.s.kg-1. We used poroelastic finite-element formulations that are commonly used to predict pore pressure and fluid velocities in biological tissue microporosity. In order to describe completely the macroscopic condition of the material, the variation in fluid content ζ and its counterpart pore pressure p must also be considered. Considering the changes are small and occurring by reversible processes in an isotropic material, the constitutive material equations relating the strain variables εijand the variation in fluid content, to the stresses σijand the fluid pressure can be expressed as follows: where i and j are tensor components, σijthe stress tensor, εijthe strain tensor, ν the drained Poisson’s ratio, G the drained shear modulus related to drained Young’s modulus E and ν, and α the Biot effective stress coefficient. Assuming the fluid and solid constituents in tissue matrix to be incompressible, 1 / M=0 and α=1. The field equations governing the poroelastic problem can be obtained from these constitutive equations using equilibrium considerations, compatibility equations for strain, and a continuity equation for the fluid phase which accounts for the mass conservation of a compressible fluid. This last equation relies on Forcheimer’s transport law: Where:^^^^ = ^^^^^^^^^^^^^^^^ is the volumetric flow rate of the fluid^^^^ is the fluid saturation (s=1 for a fully saturated medium and s=0 for a completely dry medium)^^^^ is the interstitial porosity (^^^^ =^^^^ the void ratio) ^^^^ is the velocity coefficient, describing the influence of flow velocity on the effective permeability ^^^^^^^^is the fluid velocity ^^^^^^^^(^^^^) is a coefficient describing the influence of fluid saturation on the effective permeability. Thedefault relationship ^^^^^^^^ = ^^^^3 was used.^^^^^^^^is the specific weight of the wetting liquid ^^^^ is the permeability of the fully saturated interstitial tissue ^^^^ is the position^^^^^^^^ is the density of the fluid (^^^^^^^^ = ^^^^^^^^ / ^^^^)^^^^ is the gravitational acceleration In this study, ^^^^ was set to zero, reducing Forcheimer’s law to the well-known Darcy’s law. The permeability was considered isotropic with magnitude ^^^^ taken as: ^^^^ = ^^^^^^^^^^^^With K the hydraulic permeability of the interstitium, with dimension of distance4 / time / force. It should be noted that, although the terms ‘flow conductivity’ or ‘hydraulic conductivity’ are sometimes employed to refer to K in studies related to biological tissues, this should not be confused with the conventional meaning employed in physics where hydraulic conductivity is reported in dimensions of distance / time. Parameter values assigned to the tissue portion of the dermis are Lp= 30 µm2.s.kg-1, E = 200 kPa, v = 0.47, K = 1x10-14m4.N-1.s-1, void ratio φ = 0.05 (commonly used for other tissues, and specific weight of wetting liquid w = 9.807 kN / m3(Water specific weight). The capillary vessel volume was assigned a linear elastic material with Young’s modulus and Poisson’s ratio equal to those of the drained tissue portion. Loading scenario An arbitrary loading scenario was tested to compare the absorption potential of the different models. The bottom and right edges were fixed in vertical and horizontal directions, respectively. The top and left edges were assigned a 0.02 % downwards and rightwards displacements, respectively, applied linearly over 10 seconds, using transient soil analysis in Abaqus. Pore pressure fields and average values were extracted upon reaching the maximum edge displacement (t=10 s) (Gucciardo et al, Targeting uPARAP Modifies Lymphatic Vessel Architecture and Attenuates Lymphedema. Circulation.2025, 151(19), 1412-1429). RESULTS An in silico analysis was conducted to determine the drainage capacity of the normal “hierarchical” lymphatic vasculature observed in CTRL or untreated mice, and to compare it to the “labyrinthine” vasculature observed in (global or conditional) uPARAP-deficient mice. 2D finite element models of dermis sections were implemented using poroelastic formulation to capture both solid and fluid phase behaviour of the dermis. A computational model was designed to calculate the fluid pressure in the dermal tissue (excluding capillaries) under 0.02% horizontal and vertical compression, applied linearly for 10 seconds. Noticeably, this model was run on geometries derived from representative images of the lymphatic vasculature detected in both genetic mice, under lymphedematous conditions. In global and conditional uPARAP- / -mice (uPARAP- / -and uPARAPΔLECmice) -all of which exhibiting the “labyrinthine” vascular pattern- the average fluid pressures were substantially lower, reaching a 53% decrease in tissue pressure compared to their corresponding controls. Together, these in silico data support the observation of improved absorbing capacity of the labyrinthine topology featured by twisted and looped vessels, as compared to a normal hierarchical vasculature. EXAMPLE 3: targeting of human uPARAP mRNA and in vivo efficacy of Gapmers targeting human uPARAP mRNA. MATERIALS AND METHODS: Cell Culture and Treatments Primary human lymphatic endothelial cells (HMVEC-dLy from Lonza, Bâle, Switzerland) were cultured in EGM2-MV medium (herein referred to as complete medium) (Lonza) up to 80% of confluence. LEC transfections with a pool of siRNAs targeting uPARAP (#1: 5' CAUCAGCGCUUCCAGAGAA 3’ – SEQ ID NO: 32, #2: 5’ GAUGGGCGCUUCAGAUGGA 3’ – SEQ ID NO: 33, #3: 5’ UCAACAAGAUCUUCGGUGA 3’ – SEQ ID NO: 34, #4: 5 ’AAACUCCGGUAUUGCUAUA 3’ – SEQ ID NO: 35), or with control siRNAs (#1: 5’ UGGUUUACAUGUCGACUAA 3’ – SEQ ID NO: 36, #2: 5’UGGUUUACAUGUCGACUAA 3’ – SEQ ID NO: 37, #3: 5’ UGGUUUACAUGUUGUGUGA3’ – SEQ ID NO: 38, #4: 5’ UGGUUUACAUGUUUUCUGA 3’ – SEQ ID NO: 39) were performed using Interferin® according to the manufacturer’s recommendations (Polyplus, Illkirch, France). Specific 19-nt sequences were used to generate 21-nt sense and 21-nt antisense strands of the type (19N)TT (N, any nucleotide). Pools of four siRNA duplexes were used (for targeting siRNAs and control siRNA). When indicated, cells were stimulated with recombinant human VEGF-C (400 ng / mL; Abcam). In some assays, gapmers were used as an alternative method for gene knockdown, delivered using Lipofectamine RNAiMAX (Thermo Fisher Scientific) following the manufacturer’s protocol. Immunofluorescence LECs were seeded on glass coverslips in complete medium. The next day, LECs were transfected with either a pool of 4 control siRNA (CTRL) or a pool of 4 siRNA against uPARAP (KD) for at least 24 hours. LECs were starved overnight in serum-free EBM-2 medium, prior to stimulation with lymphangiogenic factors. At different time points, LECs were fixed in chilled PBS- paraformaldehyde 4%, at room temperature, for 10 min and then permeabilized and blocked in (PBS, 1% BSA, 0,1% Triton) using gentle agitation for 1h at room temperature. Cells were then incubated overnight with indicated primary antibodies at 4°C, while being gently agitated. The next day, cells were washed three times with PBS and AlexaFluor® secondary antibodies (Invitrogen) were added for 1h, at room temperature, using gentle agitation. DAPI was used to stain nuclei and coverslips were mounted onto glass slides using appropriate mounting medium (Fluoromount-G mounting medium; SouthernBiotech, Evere, Belgium). Image acquisition was performed on LSM880 with Airyscan Plan-Apochromat 40x / 1.3 Oil or 63x / 1.3 Oil confocal microscope (Zeiss, Oberkochen, Germany), LSM980 with Airyscan 2 Plan-Apochromat 40x / 1.2 Water or 63x / 1.4 Oil confocal microscope (Zeiss) or on TCS SP5 confocal microscope at 40x or 63x magnifications (Leica, Weltzar, Germany). RT-qPCR Total human LEC RNA was isolated using the High Pure RNA isolation Kit (Roche, Basel, Switzerland) following the manufacturer’s instructions. RNAs (1µg) were retro-transcribed with the Transcriptor First Strand cDNA Synthesis Kit (Roche) and PCR performed using SYBR Green Master mix II (Applied Biosystems, Waltham, USA). Gene expression levels were normalized to GAPDH. The primers used amplified MRC2 (Fwd: GAGACCCATGGCTTCATCTG – SEQ ID NO: 44; Rev: GGAAGGTGCCGTTGAGGTA – SEQ ID NO: 45) and GAPDH (Fwd: TGCCGTCTAGAAAAACCTGCCAAA – SEQ ID NO: 46; Rev: CTCTCTTCCTCTTGTGCTCTTGCT – SEQ ID NO: 47). All reactions were carried out in triplicate using QuantStudio Real-Time PCR system (AppliedBiosystems) and expression levels calculated using comparative Ct method (2-ΔΔCT). Western blotting Cells were lysed with cell lysis buffer 1X (Cell Signaling) containing a cocktail of protease inhibitors (cOmplete™, Sigma-Aldrich, Saint-Louis, USA) and phosphatase inhibitors (phosSTOP™, Roche). The protein concentration was determined using Bradford Dye Reagent (Bio-Rad Temse, Belgium). In some assays, serum samples from mice were used (1ml diluted 20X in PBS). Samples were run on SDS-PAGE gels and transferred onto PVDF membranes (PerkinElmer, Mechelen, Belgium). Proteins were identified by overnight incubation at 4 °C with the indicated primary antibodies, in Tris buffer containing 0,1% Tween (TBS-T) and 5% bovine serum albumin. Afterwards, membranes were washed three times in TBS-T for 5 minutes, and then incubated for 1h at room temperature with indicated secondary antibodies. Proteins were revealed using Pierce™ ECL (ThermoFisher Scientific, Courtaboeuf, France) and detected with a ImageQuant™ LAS4000 imager (GE Healthcare). When analyzing phosphorylated and total forms of a protein, blots were stripped and reprobed. Blots were run in duplicate, on parallel, gels when proteins of the same molecular weight or multiple phosphorylated residues of the same protein were analyzed. Quantification of protein levels was perfomed on Fiji 2.9.0 software. Antibodies for in vitro experiments The following primary antibodies were used: mouse anti-human uPARAP (mAb 2H9F12 clone, very kindly provided by N. Behrendt, Denmark, WB: 1 / 2500), rabbit anti-mouse uPARAP Antibody (Invitrogen, WB: 1 / 1000), rabbit anti-VE-cadherin (Cell signaling, WB:1 / 1000, IF: 1 / 400), goat anti- VE-cadherin (R&D system, IF: 1 / 500), mouse anti-GAPDH (Merck Millipore, WB: 1 / 5000). For Western blottings, horseradish peroxidase-coupled secondary antibodies (Cell Signaling, for cell lysate, 1 / 2000). Permeability assay LECs were cultured to confluence, on 24-well transwell inserts containing pores of 0.4 µm (Boyden chambers). Two hours after VEGF-C treatment (as described above), FITC-conjugated dextran (40 kDa, 1 mg / mL) was added to the upper compartment. Later, the fluorescence intensity of the medium at the lower compartment was measured in triplicate by using a fluorescence microplate reader (excitation at 485 nm and emission at 538 nm). Animals WT mice were purchased from Charles River (France). The health status of the mice was assessed daily using a humane endpoint checklist. Secondary hindlimb lymphedema (SL) model The hindlimb lymphedema induction model combined local irradiation and surgical intervention (Buntinx et al. Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema. Front. Pharmacol. Sect. Exp. Pharmacol. Drug Discov. 2022). Lymphedema was induced in the left limb, while the right limb was used as an internal control. For irradiation, mice were anesthetized using 2% isoflurane (Zoetis, Louvain-la-Neuve, Belgium) and placed on their ventral side inside the precision X-ray irradiator (X-Rad SMART PXi Precision X-RAY irradiator) (GE Healthcare, Chicago, USA). First, to accurately target the inguinal region, X-rays radiography (40 kV, 0.5 mA) of the mouse was performed. A 20 mm-square collimator was placed at the targeted region to irradiate it (anteroposterior) with a single dose of 30 Gy (225.0 kV, 13.00 mA). The mouse left limb was irradiated for 317 seconds on the ventral side and then 317 seconds on the dorsal side. One week after irradiation, surgery was performed on the mice, using isoflurane 2% anesthetic gas on a heating pad at 37°C and under a horizontal airflow hood. The hind left limb was shaved and disinfected with dermal isobetadine. One dose of Evans Blue dye (2%; 5 µL) was then injected between the footpads of the left hindlimb to visualize the lymphatic vessels and lymph nodes. A drastic lymphatic injury was achieved through surgery in three steps: i) circumferential incision of the skin at the inguinal level, ii) excision of the inguinal and popliteal lymph nodes and finally, iii) ligation of the collecting lymphatic vessels parallel to the ischial vein with three separate stitches of non-absorbable 7 / 0 polypropylene sutures (ETHICON) under a 10x binocular magnifier. At the end of the procedure, the skin was sutured with separate stitches of 5 / 0 non-absorbable silk suture (ETHICON). Bilateral limb volume was determined every 3 days with a caliper and using the following formula of a cone: 15 x π / 3 x (r2+ (Rxr) + R2). R represents the radius of the base of the limb and r the upper radius. To account for individual variability, limb volume was normalized for each animal by calculating the percentage change from the control limb (non-operated right limb), using the formula (V / Vc) x100, where V was the volume of the operated limb and Vc is the volume of the control limb. Mice were weighed daily, and the injected volumes were adjusted according to their weight. For the in vivo testing of gapmers, ready gapmers (CTRL, G4 from Qiagen and Human Gapmers from Eurogentec) were dissolved in PBS and sub-cutaneously injected every four days after surgery into the footpad at a concentration of 5 mg / kg. The injected volumes were adjusted according to the weight of each mouse. Gapmer and siRNA sequences Gapmer Sequence SEQ ID NO uPARAP mRNA binding location G4 5’ TAAATGCTTGCTCTAA 3’ 29 Exons 21-22 CTRL 5’ GCTCCCTTCAATCCAA 3’ 31 - Human 5’ AATGCTTGCTCTAAGG 3’ 1 Exons 21-22 Gapmers Suggested 5’ TTCTCTGGAAGCGCTGATG 3’ 2 1-Exons 28-29 Human 5’ TCCATCTGAAGCGCCCATC 3’ 3 1-Exons 17-18 Gapmers 5’ TCACCGAAGATCTTGTTGA 3’ 4 3-Exon 15 5’ TATAGCAATACCGGAGTTT 3’ 5 4-Exon 11 siRNA Sequence Pool of 5' -CAUCAGCGCUUCCAGAGAA-3’ 32 1-Exons 28-29 uPARAP 5’-GAUGGGCGCUUCAGAUGGA-3’ 33 1-Exons 17-18 siRNAs 5’-UCAACAAGAUCUUCGGUGA-3’ 34 3-Exon 15 5’-AAACUCCGGUAUUGCUAUA-3’ 35 4-Exon 11 Pool of 5’-UGGUUUACAUGUCGACUAA-3’ 36 - CTRL 5’-UGGUUUACAUGUCGACUAA-3’ 37 siRNAs 5’-UGGUUUACAUGUUGUGUGA-3’ 38 5’-UGGUUUACAUGUUUUCUGA-3’ 39 RESULTS To illustrate targeting of human uPARAP transcript, human primary LECs were transfected in vitro with multiple uPARAP siRNA (KD-LEC). As shown in Fig.2A-C, the siRNA approach resulted in significant silencing of uPARAP expression at RNA and protein levels. At the steady-state, both CTRL and KD-LECs organized into a cobblestone cell monolayer (data not shown). However, VEGF-C stimulation for 24h induced the elongation and alignment of CTRL- LECs (Fig. 3A). In contrast, VEGF-C-stimulated KD-LECs started to overlap with cytoplasmic extensions, showing disruption in VE-cadherin-based cell-cell junctions, characterized by overlapping cytoplasmic extensions (Fig.3A), as observed in vivo (data not shown). The types of LEC-LEC junctions observed under these conditions after 2h of VEGF-C stimulation (Fig. 3B) were classified into seven categories based on their morphology in high-magnification under confocal microscopy: linear, reticular, finger, spike, zipper, wave-like and overlapping protrusions (Fig.3C). The so-called wave-like junction, characterized by VE-cadherin spots without “gaps”, may fit into the Junction-Associated Intermittent Lamellipodia (JAIL) definition, a mechanism whereby endothelial cells remodel junctions and renew cell-cell contacts by transiently decreasing membrane-bound VE-cadherin. uPARAP silencing increased the percentage of overlapping protrusions (22.3% in KD-LECs vs 4.7% in CTRL) or wave-like lamellipodia (28.7% in KD-LECs vs 17.5% in CTRL) (Fig.3B-C). Furthermore, the shift in cell-cell junction morphologies was correlated with an increased permeability as assessed in Boyden chamber assays (p<0.05) (Fig. 4). In conclusion, the downregulation of uPARAP in human cells disrupts cell–cell junctions between lymphatic endothelial cells (LEC–LEC), leading to increased permeability in vitro under VEGF-C stimulation. This enhanced permeability may facilitate the uptake of interstitial fluid by lymphatic vessels, thereby improving drainage and contributing to the reduction of lymphedema. To enable the development of a human-appropriate therapy, we designed gapmers compatible with both human and mouse targets, called human gapmers (derived from SEQ ID NO: 1). Although these gapmers shared the same core nucleotide sequence with phosphorothioate modifications in their phosphate backbone, they differed in the number and distribution of locked nucleic acids (LNAs) incorporated at their ends. Specifically, the LNAs were arranged in various configurations, 3-3, 2-2, 2-3, and 3-2, corresponding to the number of LNA residues positioned at the 5′ and 3′ termini, respectively: (LNA 2-2) : 5’-{A*A*}T*G*C*T*T*G*C*T*C*T*A*A*{G*G}-3’ – SEQ ID NO : 6 (LNA 2-3) : 5’-{A*A*}T*G*C*T*T*G*C*T*C*T*A*{A*G*G}-3’ – SEQ ID NO : 7 (LNA 3-3) : 5’-{A*A*T*}G*C*T*T*G*C*T*C*T*A*{A*G*G}-3’ – SEQ ID NO : 8 (LNA 3-2) : 5’-{A*A*T*}G*C*T*T*G*C*T*C*T*A*A*{G*G}-3’ – SEQ ID NO : 9 Phosphorothioates = * LNA = {} To facilitate understanding of the gapmer design, LNA ribonucleosides as present at the 5’ and 3’ termini (marked above with “{}”) are schematically illustrated by the following formula: , whereas the interposed consecutive deoxyribonucleosides are schematically illustrated by the following formula: In these formulas “B” stands for a nucleobase. All nucleosides were connected by phosphorothioate internucleoside linkages (marked above with schematically illustrated by the following formula: . We observed that all of them reduced the expression of uPARAP at mRNA but also at protein levels (Fig.5A and B). Two candidates (LNA 2-2 and LNA 2-3) were tested in in vivo analysis. Quantitative assessment of limb volume percentages demonstrated that the human-adapted gapmers significantly reduced limb volume, exhibiting efficacy comparable to that of the murine G4 version. Nevertheless, based on this parameter alone, no clear superiority could be established between the two human-adapted gapmers (Fig.6). Additional human gapmers derived from SEQ ID NOs: 2-5 are: (LNA 2-2) : 5’-{T*T*}C*T*C*T*G*G*A*A*G*C*G*C*T*G*A*{T*G}-3’ – SEQ ID NO : 10 (LNA 2-3) : 5’-{T*T*}C*T*C*T*G*G*A*A*G*C*G*C*T*G*{A*T*G}-3’ – SEQ ID NO : 11 (LNA 3-3) : 5’-{T*T*C*}T*C*T*G*G*A*A*G*C*G*C*T*G*{A*T*G}-3’ – SEQ ID NO : 12 (LNA 3-2) : 5’-{T*T*C*}T*C*T*G*G*A*A*G*C*G*C*T*G*A*{T*G}-3’ – SEQ ID NO : 13 (LNA 2-2) : 5’-{T*C*}C*A*T*C*T*G*A*A*G*C*G*C*C*C*A*{T*C}-3’ – SEQ ID NO : 14 (LNA 2-3) : 5’-{T*C*}C*A*T*C*T*G*A*A*G*C*G*C*C*C*{A*T*C}-3’ – SEQ ID NO : 15 (LNA 3-3) : 5’-{T*C*C*}A*T*C*T*G*A*A*G*C*G*C*C*C*{A*T*C}-3’ – SEQ ID NO :16 (LNA 3-2) : 5’-{T*C*C*}A*T*C*T*G*A*A*G*C*G*C*C*C*A*{T*C}-3’ – SEQ ID NO :17 (LNA 2-2) : 5’-{T*C*}A*C*C*G*A*A*G*A*T*C*T*T*G*T*T*{G*A}-3’ – SEQ ID NO : 18 (LNA 2-3) : 5’-{T*C*}A*C*C*G*A*A*G*A*T*C*T*T*G*T*{T*G*A}-3’ – SEQ ID NO : 19 (LNA 3-3) : 5’-{T*C*A*}C*C*G*A*A*G*A*T*C*T*T*G*T*{T*G*A}-3’ – SEQ ID NO : 20 (LNA 3-2) : 5’-{T*C*A*}C*C*G*A*A*G*A*T*C*T*T*G*T*T*{G*A}-3’ – SEQ ID NO : 21 (LNA 2-2) : 5’-{T*A*}T*A*G*C*A*A*T*A*C*C*G*G*A*G*T*{T*T}-3’ – SEQ ID NO : 22 (LNA 2-3) : 5’-{T*A*}T*A*G*C*A*A*T*A*C*C*G*G*A*G*{T*T*T}-3’ – SEQ ID NO : 23 (LNA 3-3) : 5’-{T*A*T*}A*G*C*A*A*T*A*C*C*G*G*A*G*{T*T*T}-3’ – SEQ ID NO : 24 (LNA 3-2) : 5’-{T*A*T*}A*G*C*A*A*T*A*C*C*G*G*A*G*T*{T*T}-3’ – SEQ ID NO : 25 Phosphorothioates = * LNA = {} Other alternative human gapmers derived from SEQ ID NOs: 2-5 are: 5’-(T*T*C*T*)C*T*G*G*A*A*G*C*G*C*(T*G*A*T*G)-3’ – SEQ ID NO : 48 5’-(T*C*C*A*)T*C*T*G*A*A*G*C*G*C*(C*C*A*T*C)-3’ – SEQ ID NO : 49 5’-(T*C*A*C*)C*G*A*A*G*A*T*C*T*T*(G*T*T*G*A)-3’ – SEQ ID NO : 50 5’-(T*A*T*A*)G*C*A*A*T*A*C*C*G*G*(A*G*T*T*T)-3’ – SEQ ID NO : 51 Phosphorothioates = * 2'-O-Methoxyethyl modifications = () Additional mouse gapmers derived from SEQ ID NOs: 2-5 are (LNA 2-2) : 5’-{C*C*}G*A*G*T*A*G*G*A*G*A*G*G*{T*G}-3’ – SEQ ID NO : 52 (LNA 2-3) : 5’-{C*C*}G*A*G*T*A*G*G*A*G*A*G*{G*T*G}-3’ – SEQ ID NO : 53 (LNA 3-3) : 5’-{C*C*G*}A*G*T*A*G*G*A*G*A*G*{G*T*G}-3’ – SEQ ID NO : 54 (LNA 3-2) : 5’-{C*C*G*}A*G*T*A*G*G*A*G*A*G*G*{T*G}-3’ – SEQ ID NO : 55 (LNA 2-2) : 5’-{C*A*}T*A*G*G*T*C*T*T*C*T*T*C*{A*C}-3’ – SEQ ID NO : 56 (LNA 2-3) : 5’-{C*A*}T*A*G*G*T*C*T*T*C*T*T*{C*A*C}-3’ – SEQ ID NO : 57 (LNA 3-3) : 5’-{C*A*T*}A*G*G*T*C*T*T*C*T*T*{C*A*C*}-3’ – SEQ ID NO : 58 (LNA 3-2) : 5’-{C*A*T*}A*G*G*T*C*T*T*C*T*T*C*{A*C*}-3’ – SEQ ID NO : 59 (LNA 2-2) : 5’-{A*T*}A*G*C*A*G*T*G*T*C*G*G*A*{G*T}-3’ – SEQ ID NO : 60 (LNA 2-3) : 5’-{A*T*}A*G*C*A*G*T*G*T*C*G*G*{A*G*T}-3’ – SEQ ID NO : 61 (LNA 3-3) : 5’-{A*T*A*}G*C*A*G*T*G*T*C*G*G*{A*G*T}-3’ – SEQ ID NO : 62 (LNA 3-2) : 5’-{A*T*A*}G*C*A*G*T*G*T*C*G*G*A*{G*T}-3’ – SEQ ID NO : 63 (LNA 2-2) : 5’-{T*A*}A*A*T*G*C*T*T*G*C*T*C*T*{A*A}-3’ – SEQ ID NO : 64 (LNA 2-3) : 5’-{T*A*}A*A*T*G*C*T*T*G*C*T*C*{T*A*A}-3’ – SEQ ID NO : 65 (LNA 3-3) : 5’-{T*A*A*}A*T*G*C*T*T*G*C*T*C*{T*A*A}-3’ – SEQ ID NO : 66 (LNA 3-2) : 5’-{T*A*A*}A*T*G*C*T*T*G*C*T*C*T*{A*A}-3’ – SEQ ID NO : 67 (LNA 2-2) : 5’-{T*C*}T*T*C*T*T*G*C*A*A*A*C*A*{T*A}-3’ – SEQ ID NO : 68 (LNA 2-3) : 5’-{T*C*}T*T*C*T*T*G*C*A*A*A*C*{A*T*A}-3’ – SEQ ID NO : 69 (LNA 3-3) : 5’-{T*C*T*}T*C*T*T*G*C*A*A*A*C*{A*T*A}-3’ – SEQ ID NO : 70 (LNA 3-2) : 5’-{T*C*T*}T*C*T*T*G*C*A*A*A*C*A*{T*A}-3’ – SEQ ID NO : 71 Phosphorothioates = * LNA = {}

Claims

CLAIMS 1. An oligonucleotide agent capable of suppressing the expression of Mannose Receptor C-Type 2 (MRC2), for use in treating lymphedema.

2. The oligonucleotide agent for use according to claim 1, wherein the oligonucleotide agent comprises an antisense oligonucleotide (ASO).

3. The oligonucleotide agent for use according to claim 2, wherein the ASO is capable of specifically hybridising to MRC2 mRNA, optionally wherein the ASO displays at least 90% sequence complementarity to MRC2 mRNA, preferably at least 95%, more preferably 100%.

4. The oligonucleotide agent for use according to claim 2 or 3, wherein the ASO comprises one or more modifications selected from the group consisting of a modified internucleoside linkage, a modified nucleoside base, a modified sugar moiety, and combinations thereof.

5. The oligonucleotide agent for use according to any one of claims 2 to 4, wherein: i) the ASO comprises one or more modified internucleoside linkages selected from the group consisting of phosphorothioate, phosphorothioate Rp isomer, phosphorothioate Sp isomer, phosphorodithioate, methylphosphonate, methoxypropylphosphonate, and combinations thereof; ii) the ASO comprises peptide nucleic acid (PNA); iii) the ASO comprises one or more selected from the group consisting of 2’-O-methyl modified ribose (2’-OMe), 2’-O-methoxyethyl modified ribose (2’-MOE), 2’-deoxy-2’-fluoro modified ribose (2’-F), 2’-arabino-fluoro modified ribose (2’-Ara-F), 2’-O-benzyl modified ribose, 2’-O-methyl-4-pyridine modified ribose (2’-O-CH2Py(4)), a constrained ethyl ribose (cEt), a ribose comprising a 2’-O,4’-C-methylene bridge (Locked Nucleic Acid, LNA), and combinations thereof; iv) the ASO comprises one or more selected from the group consisting of tricyclo-DNA, phosphorodiamidate morpholino oligomer (PMO), unlocked nucleic acid (UNA), glycol nucleic acid (GNA), and combinations thereof; v) the ASO comprises one or more selected from the group consisting of 5’-methylcytidine, N6’-methyladenosine, 5’-fluoro-2’-deoxyuridine, pseudouridine, 2’-thiouridine, and combinations thereof; or vi) any combination of i) to v).

6. The oligonucleotide agent for use according to any one of claims 2 to 5, wherein the length of the ASO is between 12 and 60 nucleotides or modified nucleotides.

7. The oligonucleotide agent for use according to any one of claims 2 to 5, wherein the ASO is a gapmer.

8. The oligonucleotide agent for use according to claim 7, wherein the structure of the gapmer is as follows: Ax-By-Czwherein A and C are each independently ribonucleotides or modified ribonucleotides, such as optionally 2’-OMe ribonucleotides, 2’-MOE ribonucleotides, 2’-F ribonucleotides, cEt ribonucleotides, or LNA ribonucleotides, or a combination thereof; B are deoxyribonucleotides or modified deoxyribonucleotides, preferably unmodified deoxyribonucleotides; x and z each independently are 1-10; and y is 7-30.

9. The oligonucleotide agent for use according to claim 7 or 8, wherein the gapmer comprises one or preferably more modified internucleoside linkages, preferably wherein all internucleoside linkages of the gapmer are modified, optionally wherein at least one or more or all of the modified linkages are phosphorothioate linkages.

10. The oligonucleotide agent for use according to any one of claims 1 to 9, having a nucleobase sequence as set forth in any of SEQ ID NOs: 1 to 5, preferably wherein said oligonucleotide agent comprises a gapmer.

11. The oligonucleotide agent for use according to any of claims 1 to 10, wherein said oligonucleotide comprises a gapmer having a sequence as set forth in any of SEQ ID NOs: 6 to 9, SEQ ID NOs: 10 to 13 or 48, SEQ ID NOs: 14 to 17 or 49, SEQ ID NOs: 18 to 21 or 50, or SEQ ID NOs: 22 to 25 or 51.

12. The oligonucleotide agent for use according to claim 1, wherein the oligonucleotide agent comprises an RNA interference (RNAi) compound, optionally small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ssRNA, or any combination thereof.

13. The oligonucleotide agent for use according to any one of claims 1 to 12, wherein said MRC2 is human MRC2.

14. The oligonucleotide agent for use according to any one of claims 1 to 12, wherein said lymphedema is lymphedema in a human subject.

15. The oligonucleotide agent for use according to any one of claims 1 to 14, wherein the lymphedema is primary or secondary lymphedema, optionally wherein the secondary lymphedema is filariasis lymphedema or cancer-related lymphedema or cancer-treatment-related lymphedema, optionally wherein the cancer is breast cancer, a gynaecological cancer such as cervical, ovarian, or uterine cancer, melanoma, prostate cancer, testicular cancer, head and neck cancer, or lymphoma,optionally wherein the cancer treatment comprises chemotherapy, radiation therapy, surgery, or any combination thereof.

16. The oligonucleotide agent for use according to any one of claims 1 to 15, wherein the agent is to be administered subcutaneously, intradermally, systemically, to the lymphatic system, to one or more lymph nodes, or any combination thereof.

17. The oligonucleotide agent for use according to any one of claims 1 to 16, wherein the agent is to be administered simultaneously or sequentially, in either order, with one or more pro- lymphangiogenic factors, optionally with VEGF-C or an inducer of VEGF-C or with an inhibitor of ROCK, or with any combination thereof.

18. A pharmaceutical composition comprising an oligonucleotide agent capable of suppressing the expression of MRC2, optionally wherein the agent is as defined in any one of claims 2 to 12, for use in treating lymphedema.

19. A pharmaceutical composition comprising the oligonucleotide agent as defined in any one of claims 7-11.

20. The pharmaceutical composition according to claim 19 or the pharmaceutical composition for use according to claim 18, wherein the pharmaceutical composition further comprises one or more pro-lymphangiogenic factors, optionally VEGF-C or an inducer of VEGF-C or an inhibitor of ROCK, or any combination thereof.