WO/2005/089766 | NOVEL USE FOR PDE5 INHIBITORS |
WO/2023/049723 | PRC2 INHIBITORS FOR USE IN TREATING BLOOD DISORDERS |
WO/2021/180160 | BIFUNCTIONAL COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF |
WO2018126192A1 | 2018-07-05 | |||
WO1996038579A1 | 1996-12-05 | |||
WO1992006204A1 | 1992-04-16 |
US20200163967A1 | 2020-05-28 | |||
CH8765549A | ||||
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CLAIMS 1. A MEK1/2 inhibitor for use in the treatment of telangiectasia associated with hereditary haemorrhagic telangiectasia (HHT). 2. A MEK1/2 inhibitor for use according to claim 1, wherein the telangiectasia is nasal telangiectasia. 3. A MEK1/2 inhibitor for use according to claim 1 or 2, wherein said inhibitor treats or prevents HHT induced anaemia and/or haemorrhage. 4. A MEK1/2 inhibitor for use according to claim 3, wherein the HHT induced anaemia is associated with recurrent haemorrhages and/or the HHT induced haemorrhage are recurrent. 5. A MEK1/2 inhibitor for use according to claim 3 or 4, wherein the anaemia and/or haemorrhage is not responsive to dietary iron supplements. 6. A MEK1/2 inhibitor for use according to any one of claims 3-5, wherein the anaemia and/or haemorrhage would otherwise require treatment comprising surgery, an anti- angiogenic agent and/or blood transfusion. 7. A MEK1/2 inhibitor for use according to any one of the preceding claims, wherein said inhibitor is trametinib. 8. A MEK1/2 inhibitor for use according to claim 7, wherein the dose is less than 2mg/day. 9. A MEK1/2 inhibitor for use according to any one of the preceding claims, which is for oral, intravenous or subcutaneous administration. 10. A MEK1/2 inhibitor for use according to claim 9, wherein said inhibitor is trametinib for oral administration. 11. A MEK1/2 inhibitor for use according to any one of the preceding claims, which is administered at intervals daily, weekly, fortnightly, or monthly, preferably daily. 12. Use of a MEK1/2 inhibitor in the manufacture of a medicament for the treatment of telangiectasia associated with HHT. 13. A use according to claim 12, wherein said inhibitor treats or prevents HHT induced anaemia and/or haemorrhage. 14. A use according to claim 12 or 13, wherein said inhibitor is trametinib. 15. A method for treating telangiectasia associated with HHT, the method comprising administrating a therapeutically effective amount of a MEK1/2 inhibitor to a patient in need thereof. 16. A method according to claim 15, wherein said inhibitor treats or prevents HHT induced anaemia and/or haemorrhage. 17. A method according to claim 15 or 16, wherein said inhibitor is trametinib. 18. A method of identifying a patient as suitable for use of a MEK1/2 inhibitor for treating or preventing telangiectasia associated with HHT as defined in any one of claims 1 to 11, said method comprising determining and/or quantifying one or more of a patient’s: (a) red cell indices; (b) impaired activity; (c) lack responsiveness to dietary or oral iron supplements; and/or (d) lack of tolerance to bleeding and/or anaemia. |
PROTAC reagents Proteolysis targeting chimeras (also referred to as PROTACs or PROTAC reagents) may be used to inhibit MEK1/2 activity as described herein. PROTACs are heterobifunctional small molecules that simultaneously bind a target protein and ubiquitin ligase, enabling ubiquitination and degradation of the target. In more detail, a PROTAC reagent typically comprises a ligand for the target protein (in the case of the present invention, MEK1/2) and a ligand for an E3 ligase recognition domain. Through the use of such a PROTAC, an E3 ligase is recruited to the PROTAC-bound MEK1/2, inducing ubiquitin transfer from the E3 ligase complex to the target protein (in the case of the present invention, MEK1/2). Once the PROTAC has induced a sufficient degree of ubiquitination of the target, it is then recognised and degraded by the proteasome. As a non-limiting example, a PROTAC reagent may be produced by conjugating a ligand for an E3-ligase to a small molecule inhibitor as described herein (preferably trametinib) via a linker. In a preferred embodiment, a PROTAC reagent comprises a ligand for the E3 RING Cullin ligase von-Hippel Lindau protein (VHL) or cereblon - a part of a CRL4 E3 RING Cullin ligase complex, connected to a small molecule inhibitor of the invention via a linker. In some particularly preferred embodiments, the PROTAC reagent comprises a ligand for the E3 RING Cullin ligase von-Hippel Lindau protein (VHL) connected to trametinib, connected via a linker. In other particularly preferred embodiments, the PROTAC reagent comprises cereblon (a part of a CRL4 E3 RING Cullin ligase complex) and trametinib, connected via a linker. Because of their mechanism of action, PROTAC reagents simply need any ligand for the target protein. The functional pharmacology of the ligand, in the absence of the linker and E3 ligase ligand, is unimportant. Therefore in some embodiments a MEK1/2 inhibitory PROTAC reagent of the present invention may comprises a small molecule MEK1/2 agonist as the ligand. Double-stranded RNA Double-stranded RNA (dsRNA) molecules may be used to inhibit MEK1/2 activity as described herein. Using known techniques and based on a knowledge of the sequence of MEK1/2, dsRNA molecules can be designed to antagonise MEK1/2 by sequence homology-based targeting of the corresponding RNA sequence. Such dsRNAs will typically be small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs), or micro-RNAs (miRNAs). The sequence of such dsRNAs will comprise a portion that corresponds with that of a portion of the mRNA encoding MEK1/2. This portion will usually be 100% complementary to the target portion within the mRNA transcribed from the MEK1/2 gene, but lower levels of complementarity (e.g.90% or more or 95% or more) may also be used. Typically the % complementarity is determined over a length of contiguous nucleic acid residues. A dsRNA molecule of the invention may, for example, have at least 80% complementarity to the target portion within the mRNA transcribed from the MEK1/2 gene measured over at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or more nucleic acid residues, up to the dsRNA molecule having at least 80% complementarity the mRNA transcribed from the MEK1/2 gene of the invention over the entire length of the dsRNA molecule. In a preferred embodiment, the dsRNA is a shRNA. ShRNA can be delivered to a patient or a patients cells (such as endothelial cells or endothelial cell precursors) by any appropriate means. Suitable techniques are known in the art and include the use of plasmid, viral and bacterial vectors to deliver the shRNA. Typically, the shRNA is delivered using a viral vector delivery system. In a preferred embodiment, the viral vector is a lentiviral vector. Generally, once the shRNA has been delivered to an endothelial cell or endothelial precursor cell, it is then transcribed in the nucleus and processed. The resulting pre-shRNA is exported from the nucleus and then processed by dicer and loaded into the RNA-induced silencing complex (RISC). The sense (passenger) strand is degraded. The antisense (guide) strand directs RISC to mRNA that has a complementary sequence. In the case of perfect complementarity, RISC cleaves the mRNA. In the case of imperfect complementarity, RISC represses translation of the mRNA. In both of these cases, the shRNA leads to target gene silencing. A variant sequence may have at least 80% sequence identity to an shRNA sequence of the invention, measured over any appropriate length of sequence. Typically the % sequence identity is determined over a length of contiguous nucleic acid or amino acid residues. A variant sequence of the invention may, for example, have at least 80% sequence identity to a sequence of the invention measured over at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or more nucleic acid or amino acid residues. For example, a variant shRNA molecule of the invention may have at least 80% sequence identity with an shRNA molecule of the invention measured over at least 10, at least 20, at least 30, at least 40, at least 50, at least 60 or more nucleic acid residues, up to the variant shRNA molecule having at least 80% sequence identity with the shRNA molecule of the invention over the entire length of the variant shRNA molecule. Antisense RNA Single-stranded DNA (ssDNA) molecules, also known as antisense RNA, may be used to inhibit MEK1/2 activity as described herein. Using known techniques and based on a knowledge of the sequence of the MEK1/2 gene, antisense RNA molecules can be designed to antagonise the MEK1/2 gene by sequence homology-based targeting of the corresponding RNA. The sequence of such antisense will comprise a portion that corresponds with that of a portion of the mRNA transcribed from the MEK1/2 gene. This portion will usually be 100% complementary to the target portion within the transcribed mRNA but lower levels of complementarity (e.g.90% or more or 95% or more) may also be used. Aptamers Aptamers may be used to inhibit MEK1/2 activity as described herein. Aptamers are generally nucleic acid molecules that bind a specific target molecule. Aptamers can be engineered completely in vitro, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications. These characteristics make them particularly useful in pharmaceutical and therapeutic utilities. As used herein, "aptamer" refers in general to a single or double stranded oligonucleotide or a mixture of such oligonucleotides, wherein the oligonucleotide or mixture is capable of binding specifically to a target. Oligonucleotide aptamers will be discussed here, but the skilled reader will appreciate that other aptamers having equivalent binding characteristics can also be used, such as peptide aptamers. In general, aptamers may comprise oligonucleotides that are at least 5, at least 10 or at least 15 nucleotides in length. Aptamers may comprise sequences that are up to 40, up to 60 or up to 100 or more nucleotides in length. For example, aptamers may be from 5 to 100 nucleotides, from 10 to 40 nucleotides, or from 15 to 40 nucleotides in length. Where possible, aptamers of shorter length are preferred as these will often lead to less interference by other molecules or materials. Aptamers may be generated using routine methods such as the Systematic Evolution of Ligands by Exponential enrichment (SELEX) procedure. SELEX is a method for the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules. It is described in, for example, US 5,654, 151, US 5,503,978, US 5,567,588 and WO 96/38579. The SELEX method involves the selection of nucleic acid aptamers and in particular single stranded nucleic acids capable of binding to a desired target, from a collection of oligonucleotides. A collection of single- stranded nucleic acids (e.g., DNA, RNA, or variants thereof) is contacted with a target, under conditions favourable for binding, those nucleic acids which are bound to targets in the mixture are separated from those which do not bind, the nucleic acid-target complexes are dissociated, those nucleic acids which had bound to the target are amplified to yield a collection or library which is enriched in nucleic acids having the desired binding activity, and then this series of steps is repeated as necessary to produce a library of nucleic acids (aptamers) having specific binding affinity for the relevant target. Peptidomimetics Peptidomimetics may be used to inhibit MEK1/2 activity as described herein. Peptidomimetics are compounds which mimic a natural peptide or protein with the ability to interact with the biological target and produce the same biological effect. Peptidomimetics may have advantages over peptides in terms of stability and bioavailability associated with a natural peptide. Peptidomimetics can have main- or side-chain modifications of the parent peptide designed for biological function. Examples of classes of peptidomimetics include, but are not limited to, peptoids and β-peptides, as well as peptides incorporating D-amino acids. Antibodies Antibodies may be used to inhibit MEK1/2 activity as described herein. As used herein, the term antibody encompasses the use of a monoclonal antibody or polyclonal antibody, as well as the antigen-binding fragments of a monoclonal or polyclonal antibody, or a peptide which binds to MEK1/2 with specificity. The antibody may be a Fab, F(ab’)2, Fv, scFv, Fd or dAb. Therapeutic Indications The invention provides a MEK1/2 inhibitor for use in a method of treating and/or preventing telangiectasia associated with HHT. The MEK1/2 inhibitor for use in said method of therapy may be any MEK1/2 inhibitor as described herein. Preferably the MEK1/2 inhibitor is one which is suitable for oral administration, particularly trametinib. Typically the method of therapy comprises administering a MEK1/2 inhibitor (as described herein) to a patient or subject. The MEK1/2 inhibitor typically results in a reduction in MEK1/2 activity, as described herein. Said reduction in MEK1/2 activity may be quantified relative to a control, as described herein. The activity of a MEK1/2 inhibitor may be determined by quantitative and/or qualitative analysis, and may be measured directly or indirectly. A MEK1/2 inhibitor of the invention may elicit a decrease in the number and/or size (e.g. diameter and/or volume) of telangiectasia in a HTT patient. By way of non-limiting example, a reference to decreasing the number and/or size (e.g. diameter and/or volume) of telangiectasia may be understood to mean that, the number and/or size (e.g. diameter and/or volume) of telangiectasia is decreased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, up to total (100%), as compared with the control. Typically the number and/or size (e.g. diameter and/or volume) of telangiectasia is decreased by at least 50%, preferably at least 70% inhibition or more compared with the control. A MEK1/2 inhibitor of the invention may decrease the frequency, severity and/or duration of haemorrhages associated with telangiectasia (i.e. HHT-associated haemorrhages) in a patient, such as the average (mean) frequency (how often haemorrhage occurs), intensity (amount of blood lost), duration (how long an individual haemorrhage lasts) and/or severity of said haemorrhages. Severity of haemorrhage may be quantified as a product of the intensity, frequency and duration of haemorrhage, referred to as haemorrhage adjusted iron requirements (HAIR), as per the calculations described in Finnamore et al. (PLoS One 2013;8(10):e76516), which is herein incorporated by reference in its entirety) and as illustrated in Figure 4. Typically, mild haemorrhage results in a haemorrhage adjusted iron requirement that can still be met by usual dietary daily intakes of iron, and could correspond to a short (2- 5 minute), low intensity, “dripping” nosebleed once or twice a week. Typically, moderate haemorrhage results in a haemorrhage adjusted iron requirement that can be met by low dose supplements of iron (35mg/day), and could correspond to longer (10-20 minute) and/or more frequent (several times a week) nosebleeds, still usually of low intensity (“dripping”). Typically, severe haemorrhage results in a haemorrhage adjusted iron requirement that cannot be met by tolerated doses of oral iron supplements, and could correspond to longer (>20 minute), more frequent (daily or several times a day) nosebleeds, that are usually of high intensity (“pourers” or “gushers”). By way of non-limiting example, treatment with a MEK1/2 inhibitor according to the invention may reduce haemorrhage from severe to moderate or mild, or from moderate to mild. In numerical terms, mild HAIR may be no greater than the reference nutrient intake (RNI) for iron which is 8.7 mg/day for men and postmenopausal women, and 14.8 mg/day for premenopausal women (Department of Health. Dietary reference values for food energy and nutrients for the United Kingdom. London: HMSO; 1991), and severe HAIR may not be expected to be met by oral iron of approximately 65mg/day, with moderate HAIR falling in between (i.e. between 8.7mg/day to 65 mg/day mg/day for men and postmenopausal women and between 14.8mg/day to 65 mg/day mg/day for premenopausal women). Exemplary numerical HAIR values for mild/moderate/severe haemorrhage are illustrated in Figure 4. By way of a further non-limiting example, treatment with a MEK1/2 inhibitor according to the invention may result in a decrease in the frequency of haemorrhages (e.g. nosebleeds) to 1 a week or less, 1 every two weeks or less, 2 or 3 a month or less, 1 a month or less, or less frequently. By way of a further non-limiting example, treatment with a MEK1/2 inhibitor according to the invention may result in a decrease in the intensity of haemorrhages (e.g. nosebleeds) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, up to total (100%) inhibition, as compared with the control. Typically the intensity of haemorrhages (e.g. nosebleeds) is decreased by at least 50%, preferably at least 70%, more preferably at least 80%, compared with the control. By way of a further non-limiting example, treatment with a MEK1 inhibitor according to the invention may result in a decrease in the duration of haemorrhages (e.g. nosebleeds) by at least 5 minutes, by at least 10 minutes, by at least 15 minutes, by at least 30 minutes, by at least 1 hour, or more. By way of a further non-limiting example, treatment with a MEK1 inhibitor according to the invention may result in a decrease in the severity of haemorrhages (e.g. nosebleeds) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, up to total (100%), as compared with the control. Typically the severity of haemorrhages (e.g. nosebleeds) is decreased by at least 50%, preferably at least 70%, more preferably at least 80%. A MEK1/2 inhibitor of the invention may decrease anaemia associated with telangiectasia (i.e. HHT-associated anaemia) in a patient. A decrease in anaemia associated with telangiectasia may be quantified as a decrease in one or more symptoms of anaemia, as described herein, or by an increase in the patient’s haemoglobin, red cell indices, or by the improvement in iron indices e.g. blood iron, transferrin saturation index and/or ferritin levels. By way of non-limiting example, a MEK1/2 inhibitor of the invention may increase a patient’s haemoglobin levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, compared with a control. Typically a MEK1/2 inhibitor of the invention may increase a patient’s haemoglobin levels by at least 20%, at least 50%, preferably at least 70%, more preferably at least 80% of maximum possible to achieve a normal haemoglobin. Alternatively, a MEK1/2 inhibitor of the invention may allow a patient’s haemoglobin levels to be kept essentially constant (rather than being increased), but without the need for invasive treatments such as iron or blood transfusions. In some preferred embodiments, a MEK1/2 inhibitor of the invention may increase a patient’s haemoglobin levels to within the normal range of haemoglobin levels (e.g. matched for age and sex). A MEK1/2 inhibitor of the invention may maintain a patient’s haemoglobin at a clinically acceptable level without the need for invasive treatments such as iron or blood transfusions. Treatment with a MEK1/2 inhibitor according to the invention may reduce the frequency with which a patient requires more invasive treatments, such as blood transfusions, iron transfusions or i.v. administration of anti-angiogenic agents. By way of a non-limiting example, treatment with a MEK1/2 inhibitor according to the invention may result in a decrease in the frequency of invasive treatment(s) (e.g. blood transfusion) required by said patient to less than 1 every 4 weeks, less than 1 every 6 weeks, less than 1 every 8 weeks, less than 1 every 12 weeks, or more. In some embodiments, treatment with a MEK1/2 inhibitor according to the invention abrogates the need for a patient requires more invasive treatments, such as blood transfusions, iron transfusions or i.v. administration of anti-angiogenic agents (such as those described herein, including bevacizumab, thalidomide). The effects of treatment with a MEK1/2 inhibitor may be determined by quantitative and/or qualitative analysis, suitable methods and techniques are known in the art. By way of non-limiting example, size and/or number of telangiectasia may be determined by visual and endoscopic inspection; highly sensitive imaging (such as scanning by computerised tomography (CT), magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) or positron emission tomography (PET)), a patient’s haemoglobin level may be quantified by any appropriate test, such as a standard clinical full blood count. By way of a further non-limiting example, data regarding the frequency, severity and/or duration of haemorrhages (e.g. nosebleeds) may be captured using tools such as the Epistaxis Severity Score; Haemorrhage Adjusted Iron Requirement (HAIR); and standard quality of life (QoL) questionnaires, such as the International Quality of Life Assessment questionnaire, version 1.1 (IQOLA 1.1). The duration of action of a MEK1/2 inhibitor according to the invention may be for at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, or more. Typically this is assessed relative to the last administration of the MEK1/2 inhibitor. In the context of the therapeutic uses and methods of the invention, a “subject” or “patient” (these terms are used interchangeably herein) is any animal or patient that would benefit from the treatment of HHT-associated telangiectasia, HHT-induced haemorrhage and/or HHT-associated (HHT-induced) anaemia. Typical animal patients are mammals, such as primates, or horses. Preferably the patient is a human. Thus, the present invention provides a MEK1/2 inhibitor for use in the treatment and/or prevention of telangiectasia associated with HHT, such as nasal telangiectasia, GI telangiectasia, nasopharyngeal telangiectasia, endobronchial telangiectasia and/or tongue telangiectasia, or any combination thereof. Said inhibitor may treat or prevent HHT-associated (HHT-induced) anaemia and/or haemorrhage. Accordingly, the present invention provides a MEK1/2 inhibitor for use in the treatment and/or prevention of HHT-associated (HHT-induced) anaemia and/or HHT-associated (HHT-induced) haemorrhage. The HHT-induced anaemia may be associated with recurrent haemorrhages and/or the HHT induced haemorrhage may be recurrent, as defined herein. In some embodiments, the anaemia and/or haemorrhage, particularly when recurrent, is not responsive to oral iron supplements as described herein. Thus, as described herein, the present invention is particularly useful in treating and/or preventing telangiectasia associated with HHT, HHT-associated (HHT-induced) anaemia, and/or HHT-associated (HHT-induced) haemorrhage which would otherwise require an invasive treatment such as treatment comprising surgery, an anti-angiogenic agent and/or blood transfusion. The invention also provides a method of treating and/or preventing telangiectasia associated with HHT, HHT-associated (HHT-induced) anaemia, and/or HHT-associated (HHT-induced) haemorrhage comprising administering a therapeutically effective amount of a MEK1/2 inhibitor as defined herein to a patient in need thereof. Preferably said MEK1/2 inhibitor is trametinib. Additionally, the present invention provides the use of a MEK1/2 inhibitor in the manufacture of a medicament for use in a method of treating and/or preventing telangiectasia associated with HHT, HHT-associated (HHT-induced) anaemia, and/or HHT-associated (HHT-induced) haemorrhage. Preferably said MEK1/2 inhibitor is trametinib. The therapeutic use or method of the invention may comprise administering a therapeutically effective amount of a MEK1/2 inhibitor of the invention (as defined herein), either alone or in combination with other therapeutic agents, to a patient. As used herein, the term “treatment” or “treating” embraces therapeutic or preventative/prophylactic measures. The MEK1/2 inhibitors of the invention may also be used as a preventative therapy. As used herein, the term “preventing” includes preventing the onset of symptoms associated with telangiectasia associated with HHT, HHT-associated (HHT-induced) anaemia, and/or HHT-associated (HHT-induced) haemorrhage (as described herein) and/or reducing the severity or intensity of said symptoms. A MEK1/2 inhibitor of the invention or a composition comprising a MEK1/2 inhibitor may be administered to a patient already having HHT, HHT-associated (HHT-induced) anaemia, and/or HHT-associated (HHT-induced) haemorrhage, and typically who is exhibiting one or more symptom as described herein. When administered to such a patient, a compound or composition of the invention can cure, delay, reduce the severity of, or ameliorate one or more symptoms, and/or prolong the survival of a patient beyond that expected in the absence of such treatment. The treatments and preventative therapies of the present invention are applicable to a variety of different patients of different ages. In the context of humans, the therapies are applicable to children (e.g. infants, children under 5 years old, older children or teenagers) and adults, particularly to adults. In the context of other animal subjects (e.g. mammals such as primates), the therapies are applicable to immature subjects and mature/adult subjects. The MEK1/2 inhibitor of the invention or a composition comprising a MEK1/2 inhibitor may be used in combination with one or more additional therapeutic agents or treatments, which typically may be selected from a conventional treatment for HHT. As a non-limiting example, a MEK1/2 inhibitor of the invention may be used in combination with an oral iron supplement, and/or an agent which protects against haemolysis. When used in combination with one or more additional therapeutic agents or treatments, a MEK1/2 inhibitor of the invention or a composition comprising a MEK1 inhibitor of the invention may be administered before, simultaneously with, or after the administration of the one or more additional therapeutic agent or treatment. As such, the invention also provide compositions comprising a MEK1/2 inhibitor and one or more additional therapeutic agents (e.g. an oral iron supplement or anti-haemolytic agent) as a combined preparation for simultaneous, separate or sequential use in a method of treating and/or preventing HHT, HHT-associated (HHT-induced) anaemia, and/or HHT- associated (HHT-induced) haemorrhage. Sequential administration may mean that the two products are administered immediately one after the other, or that the second product is administered within 1 minute, within two minutes, within three minutes, within four minutes, within five minutes, within 10 minutes, within 15 minutes, within 20 minutes, within 25 minutes, within 30 minutes, within 45 minutes, within one hour, or more of the first product being administered. Separate administration may mean that the second product is administered within one hour, within two hours, within three hours, within six hours, within 12 hours, within 24 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days or more of the first product being administered. In some embodiments, a MEK1/2 inhibitor of the invention or a composition comprising a MEK1/2 inhibitor is not used as part of a combination therapy. Thus, a MEK1/2 inhibitor of the invention or a composition comprising a MEK1/2 inhibitor may be used independently from any other therapeutic agents or treatments, such as any anti-angiogenic agents. In some embodiments, a MEK1/2 inhibitor of the invention or a composition comprising a MEK1/2 inhibitor is used independently from a PIK3 inhibitor. Pharmaceutical Compositions and Formulations The invention provides a pharmaceutical composition comprising a MEK1/2 inhibitor of the invention and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, propellant and/or salt. Preferably the MEK1/2 inhibitor is trametinib. Administration of MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) is generally by conventional routes e.g. oral, intravenous, subcutaneous, intraperitoneal, or mucosal routes. The administration may be by parenteral injection, for example, a subcutaneous, intradermal or intramuscular injection. For example, formulations comprising MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) may be particularly suited to administration orally. Administration of small molecule MEK1/2 inhibitors may be injection, such as intravenously, intramuscularly, intradermally, or subcutaneously, or preferably by oral administration (small molecules with molecule weight of less than 500 Da typically exhibiting oral bioavailability). Accordingly, MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid prior to injection may alternatively be prepared. The preparation may also be emulsified, or the peptide encapsulated in liposomes or microcapsules. Preferably MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) are prepared as for oral administration. A MEK1/2 inhibitor may be encapsulated within an oral dosage form. Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. The active ingredients (such as the MEK1/2 inhibitors of the invention) are often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants which enhance the effectiveness of the MEK1/2 inhibitor. Generally, the carrier is a pharmaceutically-acceptable carrier. Non-limiting examples of pharmaceutically acceptable carriers include water, saline, and phosphate-buffered saline. In some embodiments, however, where the composition comprises a compound or products of the invention, this may be in lyophilized form, in which case it may include a stabilizer, such as BSA. In some embodiments, it may be desirable to formulate the composition with a preservative, such as thiomersal or sodium azide, to facilitate long term storage. Examples of additional adjuvants which may be effective include but are not limited to: complete Freunds adjuvant (CFA), Incomplete Freunds adjuvant (IFA), Saponin, a purified extract fraction of Saponin such as Quil A, a derivative of Saponin such as QS-21, lipid particles based on Saponin such as ISCOM/ISCOMATRIX, E. coli heat labile toxin (LT) mutants such as LTK63 and/ or LTK72, aluminium hydroxide, N-acetyl-muramyl-L-threonyl- D-isoglutamine (thr-MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1'-2'- dipalmitoyl-sn-glycero-3-hydroxyphosphoryl oxy)-ethylamine (CGP 19835A, referred to as MTP-PE), and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and cell wall skeleton (MPL+TDM+CWS) in a 2 % squalene/ Tween 80 emulsion, the MF59 formulation developed by Novartis, and the AS02, AS01, AS03 and AS04 adjuvant formulations developed by GSK Biologicals (Rixensart, Belgium). Examples of buffering agents include, but are not limited to, sodium succinate (pH 6.5), and phosphate buffered saline (PBS; pH 6.5 and 7.5). Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, maleic, and the like. Salts formed with the free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2- ethylamino ethanol, histidine, procaine, and the like. Additional formulations which are suitable for other modes of administration include suppositories and, in some cases, formulations suitable for distribution as aerosols. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. A MEK1/2 inhibitor or composition of the present invention (e.g. trametinib or a composition comprising trametinib) may be administered at daily, weekly, fortnightly or monthly intervals. Typically a MEK1/2 inhibitor or composition of the present invention (e.g. trametinib or a composition comprising trametinib) is for daily administration. The dosage ranges for administration of the MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) are those to produce the desired therapeutic effect. It will be appreciated that the dosage range required depends on the precise nature of the MEK1/2 inhibitor or composition, the route of administration, the nature of the formulation, the age of the patient, the nature, extent or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician. Variations in these dosage levels can be adjusted using standard empirical routines for optimisation. In some embodiments, the dose of MEK1/2 inhibitor, particularly trametinib is lower than the standard dose of said MEK1/2 inhibitor used as a chemotherapeutic. By way of non- limiting example, a MEK1/2 inhibitor (e.g. trametinib) may be used according to the invention at a dose of less than 2mg/day (2mg qd), less than 1.5mg/day (1.5mg qd), less than 1mg/day (1mg qd), or less than 0.5mg/day (0.5mg qd). Lower doses may be preferred to reduce the peak plasma concentration and/or elimination half-life of the MEK1/2 inhibitor, since a trametinib dose of 2mg/day results in a peak plasma concentration (Cmax) of 22.2 ng/mL, and elimination half-life of 3.9-4.8 days. In some embodiments, the frequency of MEK1/2 inhibitor, particularly trametinib is lower than the standard frequency of said MEK1/2 inhibitor used as a chemotherapeutic. By way of non-limiting example, a MEK1/2 inhibitor (e.g. trametinib) may be used according to the invention at a daily dose, alternate daily dose or three times weekly dose. Again , lower doses may be preferred to reduce the peak plasma concentration and/or elimination half-life of the MEK1/2 inhibitor, since a dose of 2mg/day results in a peak plasma concentration (Cmax) of 22.2 ng/mL, and elimination half-life of 3.9-4.8 days. The MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) may be administered for less than 8 weeks, for 8-52 weeks; for example, 12-48 weeks, 16-44 weeks, 20-40 weeks, or 24-36 weeks or more as a chronic treatment, preferably for the life of the patient. The duration of action of a MEK1/2 inhibitor according to the invention may be for at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, or more. Typically this is assessed relative to the last administration of the MEK1/2 inhibitor. The MEK1/2 inhibitors or compositions of the present invention (e.g. trametinib or a composition comprising trametinib) may be administered in a manner that prolongs the duration of the bioavailability of the MEK1/2 inhibitor, increases the duration of action of the MEK1/2 inhibitor and the release time frame of the MEK1/2 inhibitor by an amount selected from the group consisting of at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, and at least a month, over that of the MEK1/2 inhibitor in the absence of the duration-extending administration. Optionally, the duration of any or all of the preceding effects is extended by at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks or at least a month. The invention provides compositions comprising a MEK1/2 inhibitor (as described herein) and one or more additional therapeutic agents or treatments, Said one or more additional therapeutic agent or treatment may typically be selected from a conventional treatment for HHT. A composition of the invention may comprise a MEK1/2 inhibitor of the invention and an agent which supports red blood cell synthesis, and/or an agent which protects against haemolysis. As a non-limiting example, a composition of the invention may comprise a MEK1/2 inhibitor and one or more of a B group vitamin (such as thiamine and/B12), folate, L-thyroxine, or an antibiotic. Screening The invention also provides a method of identifying a patient as suitable for use of a MEK1/2 inhibitor for treating and/or preventing telangiectasia associated with HHT, HHT- associated haemorrhage and/or HHT-associated anaemia, as described herein. Identifying a patient as suitable for a treatment of the invention may also be determined by assessing clinical indicators of haemorrhage and/or anaemia. For example, a clinician’s categorisation of a patient’s clinical symptoms (using standard clinical classification/categorisation criteria) may be used to determine whether a patient is suitable for treatment. It is within the routine skill of a clinician to use standard techniques, such as those described herein, to identify patients suitable for treatment according to the present invention based on cut-off/threshold values or other clinically-relevant criteria. By way of non-limiting example, a patient may be identified on the basis of one or more of: (i) red cell indices; (ii) impaired activity; (iii) lack of responsiveness to dietary or oral iron supplements; and/or (iv) lack of tolerance of patients to bleeding and/or anaemia. Red cell indices which may be used to identify a patient as suitable for treatment according to the invention include. The lower limit of a normal haemoglobin is considered about 115g/L (11.5g/dL), lower limit of haematocrit as about 0.35, lower limit of mean corpuscular volume (MCV) as about 83.5fL, lower limit of mean corpuscular haemoglobin (MCH) as about 27.5pg, and lower limit of mean corpuscular haemoglobin concentration (MCHC) as about 315g/L (31.5g/dL). In some embodiments, the combination of any two values below the lower limit of normal range despite tolerable doses of oral iron treatment may be used to identify a patient as suitable for treatment. These indices may also be associated with evidence of any one or more iron indices below the lower limit of the normal range which is usually considered as about 10µmol/L for iron, about 20% for transferrin saturation index and about 20µg/L for ferritin. Alternatively or in addition, arterial oxygen content values may be used to identify a patient as suitable for treatment according to the invention. Arterial oxygen content values which may be used to identify a patient as suitable for treatment according to the invention include provision for patients who need a higher than normal haemoglobin to maintain arterial oxygen content (CaO 2 ) due to low oxygen saturation (SaO 2 ) of haemoglobin in arterial blood, either because of pathology such as HHT-associated pulmonary AVMs, or due to barometric falls in partial pressure of oxygen at altitude. In both settings, higher red cell counts, haemoglobin and haematocrit is required to maintain a normal CaO 2 where the median value for non-iron deficient individuals with HHT was 18.8mls of oxygen per dL, and CaO 2 calculated by [haemoglobin] x [SaO 2 ] x 1.34 with 1.34 representing the mls of oxygen carried by one gram of haemoglobin. For an individual or patient with a normal arterial SaO 2 of 97%, a normal CaO 2 can be delivered with a normal haemoglobin of 12.3g/dL. For an individual with a low arterial SaO2, a normal CaO2 can only be delivered by a haemoglobin above the upper limit of normal which is quoted as 15g/dL (150g/L). For an individual with an arterial SaO2 of 93% (the median value for a pulmonary AVM patient on presentation), a normal CaO2 requires a haemoglobin of 15.1g/dL (151g/L), for an individual with an SaO2 of 80%, a normal CaO2 requires a haemoglobin of 17.5g/dL (175g/L), and for an individual with an SaO2 of 65% (the lowest steady state in our cohort), a normal CaO2 requires a haemoglobin of 21.6g/dL (216g/L). Impaired activity criteria which may be used to identify a patient as suitable for treatment according to the invention include a patient being allocated with “impaired exercise tolerance” using a standard QoL questionnaire, such as the Veterans Specific Activity Questionnaire (VSAQ) (described in Gawecki et al. BMJ Open Resp. Res. (2019) 6:e000351, PMID 30956797, which is herein incorporated by reference in its entirety). A patient may be identified as suitable for treatment according to the invention if their VSAQ score is at least 2 points lower than their VSAQ score when not anaemic, or compared with the VSAQ score of a matched (e.g. age, sex, and prior exercise-matched) healthy control. Lack of responsiveness or failure to tolerate dietary or oral iron supplements may be used to identify a patient as suitable for treatment according to the invention include those described herein. Thus, a patient may be identified as suitable for treatment according to the invention if they are not responsive to dietary iron and/or oral iron supplements in the range of from about 25mg to about 200mg, such as from about 35mg to 100mg/day (e.g. a treatment regimen of a 35mg or 65mg oral dose 1-2 times per day), noting very few HHT patients are able to tolerate the “usual” treatment regime of 195mg (e.g. a treatment regimen of a 65mg oral dose 3 times per day). Lack of tolerance of patients to bleeding and/or anaemia criteria which may be used to identify a patient as suitable for treatment according to the invention include a patient identifying as having an unacceptable quality of life using a standard QoL questionnaire (such as those described herein). Other criteria include a patient not being amenable to local treatments because of the specific features or sites of telangiectasia, e.g. those near the back of the nares; on the tongue or lips; and in the nasopharynx or endobronchial tree. Accordingly, the invention provides a method of identifying a patient as suitable for use of a MEK1/2 inhibitor for treating and/or preventing telangiectasia associated with HHT, HHT- associated haemorrhage and/or HHT-associated anaemia, as described herein, which comprises determining and/or quantifying one or more of a patient’s (i) red cell indices; (ii) impaired activity; (iii) lack responsiveness to dietary or oral iron supplements; and/or (iv) lack of tolerance to bleeding and/or anaemia. Kits The invention further provides a kit comprising a MEK1/2 inhibitor or composition of the present invention (e.g. trametinib or a composition comprising trametinib). Said kit may further comprise one or more additional therapeutic agent or treatment, as described herein. Components of a kit are generally sterile and in sealed vials or other containers. Kits may be employed in therapy, diagnostic analysis or other applications as described herein. A kit may contain instructions for use of the components, e.g., for a treatment or method in accordance with the present invention. Ancillary materials to assist in or to enable performing such a treatment or method may be included within a kit of the invention. Each component of the kits is generally in its own suitable container. Thus, these kits generally comprise distinct containers suitable for each component (each binding member present). Further, the kits may comprise instructions for performing the treatment or method, and/or for interpreting and analysing data resulting from the performance of the treatment or method. SEQUENCE HOMOLOGY Any of a variety of sequence alignment methods can be used to determine percent identity, including, without limitation, global methods, local methods and hybrid methods, such as, e.g., segment approach methods. Protocols to determine percent identity are routine procedures within the scope of one skilled in the art. Global methods align sequences from the beginning to the end of the molecule and determine the best alignment by adding up scores of individual residue pairs and by imposing gap penalties. Non-limiting methods include, e.g., CLUSTAL W, see, e.g., Julie D. Thompson et al., CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position- Specific Gap Penalties and Weight Matrix Choice, 22(22) Nucleic Acids Research 4673-4680 (1994); and iterative refinement, see, e.g., Osamu Gotoh, Significant Improvement in Accuracy of Multiple Protein. Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments, 264(4) J. MoI. Biol.823-838 (1996). Local methods align sequences by identifying one or more conserved motifs shared by all of the input sequences. Non-limiting methods include, e.g., Match-box, see, e.g., Eric Depiereux and Ernest Feytmans, Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences, 8(5) CABIOS 501 -509 (1992); Gibbs sampling, see, e.g., C. E. Lawrence et al., Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment, 262(5131 ) Science 208-214 (1993); Align-M, see, e.g., Ivo Van WaIIe et al., Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences, 20(9) Bioinformatics:1428-1435 (2004). Thus, percent sequence identity is determined by conventional methods. See, for example, Altschul et al., Bull. Math. Bio.48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-19, 1992. Briefly, two amino acid sequences are aligned to optimize the alignment scores using a gap opening penalty of 10, a gap extension penalty of 1, and the "blosum 62" scoring matrix of Henikoff and Henikoff (ibid.) as shown below (amino acids are indicated by the standard one-letter codes). The "percent sequence identity" between two or more nucleic acid or amino acid sequences is a function of the number of identical positions shared by the sequences. Thus, % identity may be calculated as the number of identical nucleotides / amino acids divided by the total number of nucleotides / amino acids, multiplied by 100. Calculations of % sequence identity may also take into account the number of gaps, and the length of each gap that needs to be introduced to optimize alignment of two or more sequences. Sequence comparisons and the determination of percent identity between two or more sequences can be carried out using specific mathematical algorithms, such as BLAST, which will be familiar to a skilled person. ALIGNMENT SCORES FOR DETERMINING SEQUENCE IDENTITY A R N D C Q E G H I L K M F P S T W Y V A 4 R -1 5 N -2 0 6 D -2 -2 1 6 C 0 -3 -3 -3 9 Q -1 1 0 0 -3 5 E -1 0 0 2 -4 2 5 G 0 -2 0 -1 -3 -2 -2 6 H -2 0 1 -1 -3 0 0 -2 8 I -1 -3 -3 -3 -1 -3 -3 -4 -3 4 L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4 K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5 M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5 F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6 P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7 S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4 T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5 W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -211 Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7 V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4 The percent identity is then calculated as: Total number of identical matches __________________________________________ x 100 [length of the longer sequence plus the number of gaps introduced into the longer sequence in order to align the two sequences] Substantially homologous polypeptides are characterized as having one or more amino acid substitutions, deletions or additions. These changes are preferably of a minor nature, that is conservative amino acid substitutions (see below) and other substitutions that do not significantly affect the folding or activity of the polypeptide; small deletions, typically of one to about 30 amino acids; and small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue, a small linker peptide of up to about 20-25 residues, or an affinity tag. CONSERVATIVE AMINO ACID SUBSTITUTIONS Basic: arginine lysine histidine Acidic: glutamic acid aspartic acid Polar: glutamine asparagine Hydrophobic: leucine isoleucine valine Aromatic: phenylalanine tryptophan tyrosine Small: glycine alanine serine threonine methionine In addition to the 20 standard amino acids, non-standard amino acids (such as 4- hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline and α -methyl serine) may be substituted for amino acid residues of the polypeptides of the present invention. A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, and unnatural amino acids may be substituted for polypeptide amino acid residues. The polypeptides of the present invention can also comprise non-naturally occurring amino acid residues. Non-naturally occurring amino acids include, without limitation, trans-3-methylproline, 2,4-methano-proline, cis-4-hydroxyproline, trans-4-hydroxy-proline, N-methylglycine, allo- threonine, methyl-threonine, hydroxy-ethylcysteine, hydroxyethylhomo-cysteine, nitro- glutamine, homoglutamine, pipecolic acid, tert-leucine, norvaline, 2-azaphenylalanine, 3- azaphenyl-alanine, 4-azaphenyl-alanine, and 4-fluorophenylalanine. Several methods are known in the art for incorporating non-naturally occurring amino acid residues into proteins. For example, an in vitro system can be employed wherein nonsense mutations are suppressed using chemically aminoacylated suppressor tRNAs. Methods for synthesizing amino acids and aminoacylating tRNA are known in the art. Transcription and translation of plasmids containing nonsense mutations is carried out in a cell free system comprising an E. coli S30 extract and commercially available enzymes and other reagents. Proteins are purified by chromatography. See, for example, Robertson et al., J. Am. Chem. Soc.113:2722, 1991; Ellman et al., Methods Enzymol.202:301, 1991; Chung et al., Science 259:806-9, 1993; and Chung et al., Proc. Natl. Acad. Sci. USA 90:10145-9, 1993). In a second method, translation is carried out in Xenopus oocytes by microinjection of mutated mRNA and chemically aminoacylated suppressor tRNAs (Turcatti et al., J. Biol. Chem.271:19991-8, 1996). Within a third method, E. coli cells are cultured in the absence of a natural amino acid that is to be replaced (e.g., phenylalanine) and in the presence of the desired non-naturally occurring amino acid(s) (e.g., 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine, or 4- fluorophenylalanine). The non-naturally occurring amino acid is incorporated into the polypeptide in place of its natural counterpart. See, Koide et al., Biochem.33:7470-6, 1994. Naturally occurring amino acid residues can be converted to non-naturally occurring species by in vitro chemical modification. Chemical modification can be combined with site-directed mutagenesis to further expand the range of substitutions (Wynn and Richards, Protein Sci. 2:395-403, 1993). A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, non-naturally occurring amino acids, and unnatural amino acids may be substituted for amino acid residues of polypeptides of the present invention. Essential amino acids in the polypeptides of the present invention can be identified according to procedures known in the art, such as site-directed mutagenesis or alanine- scanning mutagenesis (Cunningham and Wells, Science 244: 1081-5, 1989). Sites of biological interaction can also be determined by physical analysis of structure, as determined by such techniques as nuclear magnetic resonance, crystallography, electron diffraction or photoaffinity labeling, in conjunction with mutation of putative contact site amino acids. See, for example, de Vos et al., Science 255:306-12, 1992; Smith et al., J. Mol. Biol.224:899-904, 1992; Wlodaver et al., FEBS Lett.309:59-64, 1992. The identities of essential amino acids can also be inferred from analysis of homologies with related components (e.g. the translocation or protease components) of the polypeptides of the present invention. Multiple amino acid substitutions can be made and tested using known methods of mutagenesis and screening, such as those disclosed by Reidhaar-Olson and Sauer (Science 241:53-7, 1988) or Bowie and Sauer (Proc. Natl. Acad. Sci. USA 86:2152-6, 1989). Briefly, these authors disclose methods for simultaneously randomizing two or more positions in a polypeptide, selecting for functional polypeptide, and then sequencing the mutagenized polypeptides to determine the spectrum of allowable substitutions at each position. Other methods that can be used include phage display (e.g., Lowman et al., Biochem.30:10832-7, 1991; Ladner et al., U.S. Patent No.5,223,409; Huse, WIPO Publication WO 92/06204) and region-directed mutagenesis (Derbyshire et al., Gene 46:145, 1986; Ner et al., DNA 7:127, 1988). SEQUENCE INFORMATION Where an initial Met amino acid residue or a corresponding initial codon is indicated in any of the following SEQ ID NOs, said residue/codon is optional. SEQ ID NO: 1 – human MEK1 nucleic acid sequence of NCBI Accession No. NM_002755 (version 4, i.e. NM_002755.4, accessed 22 January 2022) agtccctccc agggccgctt cgcagagcgg ctaggagcac ggcggcggcg gcactttccc cggcaggagc tggagctggg ctctggtgcg cgcgcggctg tgccgcccga gccggaggga ctggttggtt gagagagaga gaggaaggga atcccgggct gccgaaccgc acgttcagcc cgctccgctc ctgcagggca gcctttcggc tctctgcgcg cgaagccgag tcccgggcgg gtggggcggg ggtccactga gaccgctacc ggcccctcgg cgctgacggg accgcgcggg gcgcacccgc tgaaggcagc cccggggccc gcggcccgga cttggtcctg cgcagcgggc gcggggcagc gcagcgggag gaagcgagag gtgctgccct ccccccggag ttggaagcgc gttacccggg tccaaaatgc ccaagaagaa gccgacgccc atccagctga acccggcccc cgacggctct gcagttaacg ggaccagctc tgcggagacc aacttggagg ccttgcagaa gaagctggag gagctagagc ttgatgagca gcagcgaaag cgccttgagg cctttcttac ccagaagcag aaggtgggag aactgaagga tgacgacttt gagaagatca gtgagctggg ggctggcaat ggcggtgtgg tgttcaaggt ctcccacaag ccttctggcc tggtcatggc cagaaagcta attcatctgg agatcaaacc cgcaatccgg aaccagatca taagggagct gcaggttctg catgagtgca actctccgta catcgtgggc ttctatggtg cgttctacag cgatggcgag atcagtatct gcatggagca catggatgga ggttctctgg atcaagtcct gaagaaagct ggaagaattc ctgaacaaat tttaggaaaa gttagcattg ctgtaataaa aggcctgaca tatctgaggg agaagcacaa gatcatgcac agagatgtca agccctccaa catcctagtc aactcccgtg gggagatcaa gctctgtgac tttggggtca gcgggcagct catcgactcc atggccaact ccttcgtggg cacaaggtcc tacatgtcgc cagaaagact ccaggggact cattactctg tgcagtcaga catctggagc atgggactgt ctctggtaga gatggcggtt gggaggtatc ccatccctcc tccagatgcc aaggagctgg agctgatgtt tgggtgccag gtggaaggag atgcggctga gaccccaccc aggccaagga cccccgggag gccccttagc tcatacggaa tggacagccg acctcccatg gcaatttttg agttgttgga ttacatagtc aacgagcctc ctccaaaact gcccagtgga gtgttcagtc tggaatttca agattttgtg aataaatgct taataaaaaa ccccgcagag agagcagatt tgaagcaact catggttcat gcttttatca agagatctga tgctgaggaa gtggattttg caggttggct ctgctccacc atcggcctta accagcccag cacaccaacc catgctgctg gcgtctaagt gtttgggaag caacaaagag cgagtcccct gcccggtggt ttgccatgtc gcttttgggc ctccttccca tgcctgtctc tgttcagatg tgcatttcac ctgtgacaaa ggatgaagaa cacagcatgt gccaagattc tactcttgtc atttttaata ttactgtctt tattcttatt actattattg ttcccctaag tggattggct ttgtgcttgg ggctatttgt gtgtatgctg atgatcaaaa cctgtgccag gctgaattac agtgaaattt tggtgaatgt gggtagtcat tcttacaatt gcactgctgt tcctgctcca tgactggctg tctgcctgta ttttcgggat tctttgacat ttggtggtac tttattcttg ctgggcatac tttctctcta ggagggagcc ttgtgagatc cttcacaggc agtgcatgtg aagcatgctt tgctgctatg aaaatgagca tcagagagtg tacatcatgt tattttatta ttattatttg cttttcatgt agaactcagc agttgacatc caaatctagc cagagccctt cactgccatg atagctgggg cttcaccagt ctgtctactg tggtgatctg tagacttctg gttgtatttc tatatttatt ttcagtatac tgtgtgggat acttagtggt atgtctcttt aagttttgat taatgtttct taaatggaat tattttgaat gtcacaaatt gatcaagata ttaaaatgtc ggatttatct ttccccatat ccaagtacca atgctgttgt aaacaacgtg tatagtgcct aaaattgtat gaaaatcctt ttaaccattt taacctagat gtttaacaaa tctaatctct tattctaata aatatactat gaaataaaaa aaaaaggatg aaagcta SEQ ID NO: 2 – human MEK1 protein sequence of UniProt Accession No. Q02750 (sequence version 2, accessed 22 January 2022) MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELMFGCQVE GDAAETPPRP RTPGRPLSSY GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV SEQ ID NO: 3 – human MEK2 nucleic acid sequence of NCBI Accession No. NM_030662 (version 4, i.e. NM_030662.4, accessed 22 January 2022) ctctcggact cgggctgcgg cgtcagcctt cttcgggcct cggcagcggt agcggctcgc tcgcctcagc cccagcgccc ctcggctacc ctcggcccag gcccgcagcg ccgcccgccc tcggccgccc cgacgccggc ctgggccgcg gccgcagccc cgggctcgcg taggcgccga ccgctcccgg cccgccccct atgggccccg gctagaggcg ccgccgccgc cggcccgcgg agccccgatg ctggcccgga ggaagccggt gctgccggcg ctcaccatca accctaccat cgccgagggc ccatccccta ccagcgaggg cgcctccgag gcaaacctgg tggacctgca gaagaagctg gaggagctgg aacttgacga gcagcagaag aagcggctgg aagcctttct cacccagaaa gccaaggtcg gcgaactcaa agacgatgac ttcgaaagga tctcagagct gggcgcgggc aacggcgggg tggtcaccaa agtccagcac agaccctcgg gcctcatcat ggccaggaag ctgatccacc ttgagatcaa gccggccatc cggaaccaga tcatccgcga gctgcaggtc ctgcacgaat gcaactcgcc gtacatcgtg ggcttctacg gggccttcta cagtgacggg gagatcagca tttgcatgga acacatggac ggcggctccc tggaccaggt gctgaaagag gccaagagga ttcccgagga gatcctgggg aaagtcagca tcgcggttct ccggggcttg gcgtacctcc gagagaagca ccagatcatg caccgagatg tgaagccctc caacatcctc gtgaactcta gaggggagat caagctgtgt gacttcgggg tgagcggcca gctcatcgac tccatggcca actccttcgt gggcacgcgc tcctacatgg ctccggagcg gttgcagggc acacattact cggtgcagtc ggacatctgg agcatgggcc tgtccctggt ggagctggcc gtcggaaggt accccatccc cccgcccgac gccaaagagc tggaggccat ctttggccgg cccgtggtcg acggggaaga aggagagcct cacagcatct cgcctcggcc gaggcccccc gggcgccccg tcagcggtca cgggatggat agccggcctg ccatggccat ctttgaactc ctggactata ttgtgaacga gccacctcct aagctgccca acggtgtgtt cacccccgac ttccaggagt ttgtcaataa atgcctcatc aagaacccag cggagcgggc ggacctgaag atgctcacaa accacacctt catcaagcgg tccgaggtgg aagaagtgga ttttgccggc tggttgtgta aaaccctgcg gctgaaccag cccggcacac ccacgcgcac cgccgtgtga cagtggccgg gctccctgcg tcccgctggt gacctgccca ccgtccctgt ccatgccccg cccttccagc tgaggacagg ctggcgcctc cacccaccct cctgcctcac ccctgcggag agcaccgtgg cggggcgaca gcgcatgcag gaacgggggt ctcctctcct gcccgtcctg gccggggtgc ctctggggac gggcgacgct gctgtgtgtg gtctcagagg ctctgcttcc ttaggttaca aaacaaaaca gggagagaaa aagcaaa SEQ ID NO: 4 – human MEK2 protein sequence of UniProt Accession No. P36507 (sequence, accessed 22 January 2022) MLARRKPVLP ALTINPTIAE GPSPTSEGAS EANLVDLQKK LEELELDEQQ KKRLEAFLTQ KAKVGELKDD DFERISELGA GNGGVVTKVQ HRPSGLIMAR KLIHLEIKPA IRNQIIRELQ VLHECNSPYI VGFYGAFYSD GEISICMEHM DGGSLDQVLK EAKRIPEEIL GKVSIAVLRG LAYLREKHQI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DSMANSFVGT RSYMAPERLQ GTHYSVQSDI WSMGLSLVEL AVGRYPIPPP DAKELEAIFG RPVVDGEEGE PHSISPRPRP PGRPVSGHGM DSRPAMAIFE LLDYIVNEPP PKLPNGVFTP DFQEFVNKCL IKNPAERADL KMLTNHTFIK RSEVEEVDFA GWLCKTLRLN QPGTPTRTAV EXAMPLES The invention will be further clarified by the following examples, which are intended to be purely exemplary of the invention and are in no way limiting. Example 1 – Trametinib effectively treated haemorrhage and anaemia in HHT patient A patient over the age of 60 was suffering with both HHT and a progressive cancer. The patient’s HHT was caused by a loss-of-function variant (“mutation”) in the ENG gene encoding endoglin. The patient had been under review by the HHT services at Imperial College by the inventor for over a decade. Key features of the patient’s HHT included nosebleeds and transfusion-dependent anaemia, together with pulmonary arteriovenous malformations (PAVMs). The oncologist responsible for the patient’s cancer treatment initiated chemotherapy with trametinib according to a standard chemotherapeutic regimen. The patient reported only minor side effects corresponding to Grade 1 adverse events using the common terminology criteria for adverse events (CTCAE, version 5.0, November 27, 2017, NIH 2017). Prior to commencing treatment with trametinib, the patient had nosebleeds that varied between several times per week and multiple times per day, requiring specialist ENT treatments. In this respect, the patient was similar to ~50% of adult HHT populations, and thus exemplifies the HHT cohort. The patient was reviewed at regular intervals following initiation of trametinib. When reviewed by the HHT service after 10 months trametinib treatment, the patient spontaneously volunteered that since starting trametinib, nosebleeds had reduced in frequency to only from “time to time”. When questioned to determine frequency grouping, they suggested no more than once per month, corresponding to the 3rd lowest frequency grade of nosebleeds for HHT patients (see Figure 3A and B). In addition, the intensity of the patient’s nosebleeds had reduced to “brief trickles”. Prior to commencing trametinib, the patient had been receiving regular blood transfusions for many years for anaemia. In this respect, the patient was similar to ~5-10% of adult HHT populations. When reviewed after 10 months trametinib treatment, the patient stated that they had previously required blood (red cell) transfusions every 3 weeks for anaemia but since starting trametinib, far fewer were needed: Assessments had been extended to 8 weekly, and transfusions were not required even at extended assessment times (as shown in Figure 4A and B). Based on this assessment, a clinically important improvement in nosebleeds and anaemia resulted from trametinib treatment. The patient persisted with trametinib treatment, with treatment duration at time of filing being over 2 years’ continuous treatment. At 18 and 24 months, the improvements in nosebleeds (frequency and intensity) were maintained at approximately one a year, with a reduced haemorrhage adjusted iron requirement (HAIR) (not shown). Example 2 – Trametinib had no effect on the PAVMs of the HHT patient The effect of trametinib treatment on the patient’s AVMs was assessed in parallel. Thoracic CT scan images taken for clinical purposes were compared before Trametinib (-10 years (T-10yrs), -2 years (T-2ys), -1 month (T-1M)), and after Trametinib for 4 months (T+4M),10 months (T+10M) and 18 months (T+18M, data not shown). Blinded analysis of the CT scans was conducted by an expert Imperial Thoracic Radiologist to address the question of “whether the PAVMs have stayed the same, got better, or got worse?” The blinded analyser concluded that the venous sacs of some of the larger PAVMs have increased in size very slightly between T-2ys to T-1M. The changes (between T-1M and T+10M) were within the error of CT, but with a probable slight increase in size.” A specific venous sac (#7) was measured at 13mm (T-2 ys), 15mm (T-1M), 16mm (T+4M), 16.6mm (T+10M). Annotated CT scans are shown in Figure 5C. As quantified in Figure 5A and B, no PVAMs improved during the treatment, and some were slightly larger. Therefore, whilst treatment with trametinib elicited an improvement in HHT-associated haemorrhage (nosebleeds) and anaemia, pulmonary AVMs did not improve with trametinib treatment, and their natural history was not observably altered. less affected in HHT BOECs than non-canonical (SMAD-in TGFβ and BMP9 signalling are essential for development and viability. It has previously been reported that endoglin heterozygous mouse and human endothelial cells compensate by lowering expression of the ALK1 receptor encoded by ACVRL1; that ACVRL1 heterozygous human endothelial cells compensate by lowering expression of endoglin, but that intracellular signal transduction pathways below these receptors diverge. TGF-β and BMP ligands can signal through the canonical (SMAD4) pathway which includes 3 components encoded by HHT genes ACVRL1, ENG and SMAD4. There are also separate, SMAD4- independent signal transduction pathways which still rely on primary receptor binding by TGF- β and BMP ligands, and are thus also include components encoded by HHT genes ACVRL1 and ENG. HHT pathogenic variants have been reported to impede both canonical (SMAD4) and non-canonical (non-SMAD4) TGFβ/BMP9 signalling. However, even the effect of HHT pathogenic variants on steady-state gene expression is not as predictable as has been suggested in the art. The inventors hypothesised that when signalling through the canonical pathway is reduced because of heterozygous loss of ACVRL1, ENG or SMAD4, then in order to survive, cells compensatory mechanisms will be more effective than for the less specific non-canonical signalling pathways. This predicted that HHT endothelial cells heterozygous for ACVRL1 or ENG loss-of-function variants would display more normal responses of target genes for the canonical pathway, than for non-canonical pathways. To test this hypothesis, further RNASeq analysis of blood outgrowth endothelial cells (BOECs) from HHT patients was carried out. It has previously been shown that the Shovlin group established BOECs from controls and patients of all 3 HHT genotypes (ENG +/- , ACVRL1 +/- and SMAD4 +/- ); extracted RNA from replicate cultures; and developed novel methodologies to interpret primary alignment data generated by sequencing alignments to Homo sapiens human genome build 38 (GRCh38). None of the subsequent data are in the public domain. Normally, BMPs increase expression of ID1 by canonical pathways, and promote post- transcriptional processing of primary miR-21 transcript (pri-miR-21) into precursor miR-21 (pre-miR-21) by non-canonical pathways. The mean alignments to ID1 were 13,958 (SD 1,986) in control BOECs and 10,907 (SD 3,037) in ACVRL1 +/- and ENG +/- BOECs, i.e. the HHT BOEC alignments were reduced by 22% compared to control alignments for this canonical pathway (Figure 6A). The mean unique exact alignments to mature 3’ miR-21 were 13,520 (standard deviation [SD] 2,194) in control BOECs and 8,232 (SD 1061) in ACVRL1 +/- and ENG +/- BOECs, i.e. the HHT BOEC alignments were reduced by 39% compared control alignments for this non-canonical pathway, with similar patterns exhibited for alignments calculated in slightly less specific ways (Figure 6B). Taken together, these evaluations supported the possibility that the canonical signalling pathway was employing compensations downstream of the receptors. Example 4 – Compensation of steady-state, canonical TGFβ/BMP9 signalling in HHT BOECs by down-regulation of TGFβ/BMP9 signalling inhibitors The inventors hypothesised that compensatory mechanisms for the canonical pathway would include down regulation of TGFβ/BMP9 pathway inhibitors to “dampen the brakes”. To test this hypothesis, further RNAseq analysis of blood outgrowth endothelial cells (BOECs) from HHT patients was carried out, and the relative expression levels of TGFβ/BMP9 signalling inhibitors was investigated. For this, the RNASeq data from the Shovlin group’s blood outgrowth endothelial cells (BOECs) from controls and patients of all 3 HHT genotypes (ENG +/- , ACVRL1 +/ - and SMAD4 +/- ) was examined further. RNA had been extracted from replicate cultures; sequenced and aligned to Homo sapiens human genome build 38 (GRCh38), and unique gene reads normalised to total alignment counts per library initially further normalised using the Shovlin-group validated, lowest Gini Coefficient (GC) housekeeper gene RBM45 The data in Figure 7 are of RBM45-normalised alignments to the genes for all moieties defined in Miyazawa and Miyazono (Perspect Biol.2017, 9(3):a022095) except for SIK1, which is not considered a pathway inhibitor according to the technical consensus in 2022. Transcription of SMAD6 and SMAD7 was of particular interest, as these are the best- known of the canonical pathway inhibitors. Expression of SMAD6 and SMAD7 is upregulated by SMAD4 to provide negative feedback loops: SMAD6 preferentially inhibits SMAD signalling initiated by the BMP type 1 receptors ALK-3 and ALK-6, whereas SMAD7 inhibits both BMP9 and TGFβ-induced SMAD signalling. As shown in Figure 7, various inhibitors of TGFβ/BMP9 signalling, including SMAD6, SMAD7, SMURFs, CTBPs, TAB and OAF were down-regulated to different extents in BOECs with different HHT pathogenic variants: Fig.7a1: PPP1R15 encoding GADD34: reduced in all HHT BOECs Fig.7a2: SMAD6: greatest reduction seen in ENG+/- BOECs Fig.7a3: SMAD7: greatest reduction seen in ENG+/- BOECs Fig.7b: SMURF1: greatest reduction seen in ENG+/- BOECs Fig.7c: SMURF2: greatest reduction seen in SMAD4+/- BOECs Fig.7d: BAMBI: greatest reduction seen in ENG+/- and ACVRL1+/- BOECs Fig.7e-g: PPP1CA, PPP1CB, and PPP1CC encoding protein phosphatase 1 catalytic subunits alpha, beta, gamma: reduced most in ENG+/- BOECs Fig.7h: CTBP1: greatest reduction seen in ENG+/- BOECs Fig.7i: CTBP2: greatest reduction seen in ENG+/- BOECs Fig.7j: OAZ1: greatest reduction seen in SMAD4+/- BOECs Fig.7k: TOLLIP: observable reduction seen in ENG+/- and ACVRL1+/- BOECs Fig.7l: TAB1: greatest reduction seen in ENG+/- BOECs Taken together, the data provide strong evidence that HHT BOECs reduce inhibitors of the pathway affected by the HHT-causal variants, most likely as a compensatory mechanism in order to sustain essential signalling levels through SMAD4. In particular, reduction of SMAD6 and SMAD7 minimises SMAD signalling inhibition by these molecules, and so helps to compensate for reduced SMAD4 signalling resulting from the pathogenic SMAD4 or ENG variants. RNASeq data of the HHT BOECs compared with control BOECs, provided evidence that transcript levels of MAP3K1 (encoding MEKK1) were higher in HHT BOECs compared with the control BOECs, whereas the transcript levels of the other 14 MAP3K genes were similar or lower in HHT BOECs compared with the control BOECs (Figure 7m). Example 5 – Compensation of steady-state TGFβ/BMP9 signalling in HHT BOECs by up-regulation of SMAD4 signalling activators Following on from the results in Example 4, which suggest a compensatory mechanism in the HHT BOECs, the ability and specific mechanism by which HHT cells compensate for defects in TGFβ/BMP9 signalling was further investigated. In addition to downregulation of in TGFβ/BMP9 signalling inhibitors as demonstrated in Example 4, the inventors further hypothesised that the compensatory mechanisms in HHT BOECs would include upregulation of MEKK1 (encoded by MAP3K1), as MEKK1 has previously been shown to selectively phosphorylate SMAD2 and increase SMAD4 transcription in endothelial cells independently to TGFβ1. RNASeq was carried out on BOECs from HHT patients and healthy controls as described above. Having recognised that RBM45 was not as invariant in the BOECs as expected, the least variant low GC genes in BOECs under the experimental conditions (HNRNPK, COX4I1, IK, UBR2, UBE2Q1, SNW1, TXNL1, and KAT5) were used for DeSeq2 normalised expression. It is now evident that the RBM45-normalisations effectively normalise for PTC-related stress, whereas the DeSeq2-normalisations do not. As shown in Figure 8A irrespective of normalisation-method employed, MAP3K1 transcripts were observably increased in BOECs from HHT patients, particularly those with the ACVRL1 +/- or ENG +/- pathogenic variants. Furthermore, MAP3K1 transcripts were significantly increased on BMP9 stimulation (as shown in Figure 8B). Upregulation of MAP3K1 stimulates SMAD4 independent of TGFβ/BMP9 signalling. These data therefore implicate upregulation of MAP3K1 as a compensatory response in HHT BOECs. However, MAP3K1 has additional effects other than stimulating SMAD4 signalling. Therefore, as a next step the inventors investigated the effect of increased MAP3K1 signalling on other pathways. Example 6 – Up-regulation of MAP3K1 upregulates transcription of MEK1 and MEK2 SMAD2 phosphorylation/SMAD4 activation is not the main role of MEKK1 (encoded by MAP3K1), which is usually recognised as a MAP3K for the JNK pathway in the context of stress responses, and the MAPK pathway leading to activation of MEK1/2 (MAP2K1/2. MEK1 and MEK2 are dual-specificity kinases that uniquely activate extracellular signal regulated kinases ERK1 and ERK2 by threonine AND tyrosine phosphorylation, and ERKs are their sole known substrates. RNAseq was carried out on BOECs from HHT patients and healthy controls to investigate MEK1/MEK2 transcription levels, using RBM45 normalisation to normalise for PTC-related stress. As shown in Figure 9, MEK1 transcripts were observably increased in BOECs from HHT patients (Figure 9A), as were MEK2 transcripts (Figure 10A). As the available clinical data to-date relates to a patient with an ENG +/- pathogenic variant, the expression of MEK1 and MEK2 was further investigated in HHT BOECs with an ENG +/- pathogenic variant. MEK1 transcripts were observably increased in ENG +/- BOECs (Figure 9B), as were MEK2 transcripts (Figure 10B). Significantly, treatment with BMP9 had no effect on MEK1/2 transcript levels (Figure 9C and 10C). Taken together, the data provide evidence that ENG +/- HHT BOECs increase transcripts for MEK1 and MEK2. These gatekeepers for ERK1/2 phosphorylation, and in the setting of already increased, and particularly dynamic stress-increased MAP3K1 activity, are predictive of exuberant phosphorylation of ERK1/ERK2, which can in turn cause result in HHT- associated telangiectasia, HHT-associated haemorrhage and HHT-associated anaemia. Example 7 – BOECs from HHT patients have increased PTC transcripts compared with healthy BOECs To investigate the level of stress in BOECs from HHT patients compared with controls, all genes with Gini Coefficients (GCs) of less than 0.15 were identified, and these were aligned across all BOEC data sets. The 5 genes with the lowest reported GCs in all data – NXF1, RBM45, HNRNPK (Heterogeneous Nuclear Ribonucleoprotein K), COX4I1 (Cytochrome c oxidase subunit 4 isoform 1) and SF3B2 (Splicing Factor 3b Subunit 2) had been in wet laboratory experiments, and their rankings were displayed separately for clarity. The HHT BOECs were ranked according to their PTC persistence (which is a measure of cellular stress, with PTC persistence increasing as stress increases), and the transcript levels of these 5 genes plotted against PTC persistence (Figure 11). As shown in Figure 11, for HNRNPK, COX4I1 and SF3B2 there is similar variation in the levels of these transcripts across the HHT BOECs, regardless of PTC persistence. However, the level of NXF1 transcript was reduced in the HHT BOECs with the highest levels of PTC persistence, indicating that NXF1 is reduced in conditions of stress. Conversely, the level of RBM45 transcript was increased in the HHT BOECs with the highest levels of PTC persistence, indicating that RBM45 is increased in conditions of stress. Discussion The inventor’s own evaluation of over 1,500 HHT patients has demonstrated that HHT- associated telangiectasia which bleed are dynamic, with individual lesions growing and regressing, whereas pulmonary AVMs show no regression and either remain stable or slowly enlarge in adult life. Whereas some evidence suggests that interventions (e.g. dietary modifications) can have an effect on bleeding, in reviewing more than 900 pulmonary AVM patients, the inventor has observed only one case of spontaneous regression of a pulmonary AVM attributable to an intercurrent pulmonary embolus. Further, clinical experience in the field provides no evidence of any treatment that medically helps pulmonary AVMs. Rather, regression of pulmonary AVMs requires therapeutic embolization obliteration of all feeding arteries to a PAVM sac, or surgical removal, otherwise the sac derives new feeding arteries, and these are from both the pulmonary and the systemic circulation with significant risks of bleeding on acquiring systemic feeders. The data herein support the conclusion that upregulation of MAP3K1 leads to upregulation of MEK1/MEK2, and that this results in improvement in HHT-associated telangiectasia-associated haemorrhage and improvement in HHT-associated anaemia. HHT mutations do not constitutively activate the MEK1/MEK2 pathways, however the data herein suggest the pathways are impacted secondary to cellular compensations, whereby MEKK-1 (which is a RAF-independent MAP3 kinase (MAP3K) that phosphorylates SMAD4 independently to TGF-β) exhibits increased basal cellular transcript levels. This should not constitutively activate MAPK pathways or upregulate MEKK1-MEK1/2 signalling. However, MAP3K1 can be further upregulated during stress/injury responses (including those involving reactive oxygen species), which supports the inventor’s clinical observations that HHT- associated telangiectasia, HHT-associated haemorrhage and HHT-associated anaemia are dynamic, as stress may lead to transient increases in MAP3K1 signalling, and hence transient increases in MEK1/MEK2, exacerbating HHT-associated telangiectasia, HHT-associated haemorrhage and HHT-associated anaemia. Particularly, since MAP3K1 can be upregulated by reactive oxygen species (ROS) stress/injury responses, this supports the inventor’s clinical observations that HHT-associated haemorrhage can be precipitated by iron which induces ROS, and that endothelial cells (the cells which line telangiectasia) increase in the blood stream after iron treatment, and enter senescence or undergo non apoptotic cell death in culture after iron treatment, as ROS lead to transient increases in MAP3K1 signalling, and hence transient increases in MEK1/MEK2, exacerbating endothelial injury. Thus, exuberant signalling through the trametinib targets would be greater if cellular stress stimuli cascaded through MEKK1, and lower if any concurrent mitogenic signals (e.g. from angiogenic VEGF) were limited. These considerations appear highly relevant to the development of dynamic telangiectasia in HHT, as exemplified herein, distinct from established AVMs. Indeed, in the patient study presented herein, there was no discernible effect on pre-existing pulmonary AVMs. The available evidence therefore supports the therapeutic potential of MEK1/MEK2 inhibitors in the treatment of HHT-associated telangiectasia, HHT-associated haemorrhage and HHT-associated anaemia, distinct from AVMs. In particular, trametinib offers additional benefits as a potential therapeutic for treating HHT, as it can be delivered in a well-tolerated oral formulation better suited to regular lifestyles than requirements for intravenous medications.