Methods for determining the responsiveness of a patient to type I interferon therapy and use of type I interferon to treat a patient having a specified single nucleotide polymorphism

Abstract

Methods for determining the responsiveness of a patient to a therapy comprising the administration of a type I interferon, in order to make a decision to treat the patient with a type I interferon, and the use of SNP rs9984273 (C / T) in IFNAR2 as a marker for determining the responsiveness of a patient to said therapy.

Description

Technical Field

[0001] The present invention relates to a method for determining the responsiveness of a patient to a therapy comprising the administration of a type I interferon, so as to make a decision to treat a patient with a type I interferon, and the use of a specific single nucleotide polymorphism as a marker for determining the responsiveness of a patient to said therapy. The present invention also relates to the use of type I interferons to treat patients with specified single nucleotide polymorphisms. Background Art

[0002] Type I interferons (especially alpha and beta interferons) are our first line of defense in infection (Levy et al., 2003). As a countermeasure against acute injury, type I interferons enhance cell membrane and vascular integrity. Vascular leakage is an important feature of the following: sepsis; severe respiratory viral infections such as MERS, SARS and influenza; viral hemorrhagic fevers such as Ebola hemorrhagic fever; systemic inflammatory response syndrome (SIRS) and ischemia-reperfusion injury caused by major trauma or cardiovascular surgery. Type I interferons have the ability to upregulate CD73, a molecule that produces anti-inflammatory adenosine (Jalkanen and Salmi, 2006). CD73-derived adenosine enhances endothelial barrier function and leads to the prevention of vascular leakage, which is the dominant pathophysiological event in acute organ injury (Kiss et al., 2007), namely acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and multiple organ failure (MOF). Vascular leakage in acute lung injury (ARDS) allows plasma to extravasate into the alveolar space, leading to potentially life-threatening hypoxemia. Interferon beta-1a has been shown to reduce the effects of ARDS by reducing vascular leakage (Bellingan et al., 2014).

[0003] Like all protein-based biopharmaceuticals, in the use of type I interferons (e.g., alpha or beta interferons) as therapeutic agents, a major obstacle that must be overcome is its biological activity in individuals and exerting its expected effects. Genetic differences in molecular pathways threaten the activity and efficacy of polypeptides in drugs. Some of these changes are known to cause the loss or reduction of the drug biological activity of the target protein. When administering small amounts of hormone peptides, patient response to treatment is also critical.

[0004] Type I interferon is also widely used to treat multiple sclerosis (MS), but more than 50% of patients do not respond to the treatment. The reason for this is unclear (Mahurkar et al. 2016). Since MS is usually a slowly progressive disease, it takes an average of up to 2 years to clinically determine whether MS patients respond to treatment. The means of pre-determining whether a patient responds to interferon treatment are urgently needed in both MS and life-threatening acute conditions (such as ARDS and / or conditions associated with vascular leakage and organ dysfunction), where type I interferon can be used to enhance vascular integrity and prevent acute organ failure. Summary of the invention

[0005] An object of the present invention is to reduce or even eliminate the above-mentioned problems occurring in the prior art.

[0006] An object of the present invention is to provide a method for making a clinical decision to treat a patient with type I interferon, and predicting the outcome and response in a disease and / or condition requiring drug intervention with type I interferon. An object is to provide a marker for predicting the responsiveness of a patient to a therapy comprising the administration of type I interferon.

[0007] By having a predictive test for treatment response, physicians can easily and effectively optimize the care of patients.It is therefore an object of the present invention to provide a combination of genetic testing and pharmaceutical intervention with type I interferons to aid physicians in decision making.

[0008] Further, it is an object of the present invention to provide treatment with drug intervention based on patient selection. In particular, it is an object of the present invention to provide a treatment method with type I interferon for a specifically identified group of patients, ie a personalized therapy.

[0009] In order to achieve in particular the objects presented above, the invention is characterized by what is presented in the appended independent claims. Some preferred embodiments of the invention will be described in the other claims.

[0010] The embodiments and advantages mentioned in this text relate, where applicable, both to the method according to the invention and to the use according to the invention, even if this is not necessarily mentioned specifically.

[0011] An exemplary method according to the invention is for determining the responsiveness of a patient to treatment with a type I interferon, optionally concomitantly with a corticosteroid, the method comprising

[0012] - determining the presence or absence of the single nucleotide polymorphism (SNP) rs9984273 (C / T) in the interferon alpha and beta receptor subunit 2 (IFNAR2) in chromosome 21 from a sample obtained from the patient, and

[0013] - Classifying patients according to the presence or absence of said SNP, wherein

[0014] i) the presence of the SNP is indicative of responsiveness to treatment with or without concomitant corticosteroids, including type I interferons, or

[0015] ii) the absence of the SNP indicates non-responsiveness to treatment with concomitant corticosteroids, including type I interferons, and moderate responsiveness to treatment without concomitant corticosteroids, including type I interferons.

[0016] The present invention also relates to the use of a single nucleotide polymorphism (SNP) rs9984273 (C / T) in the subunit 2 (IFNAR2) of the interferon alpha and beta receptor in chromosome 21 and / or a SNP in linkage disequilibrium with SNP rs9984273 (C / T) for a marker, the marker being used to determine the responsiveness of a patient to a therapy comprising administration of type I interferon and optionally concomitant administration of a corticosteroid, i.e. the SNP can be used as a marker in patient selection for a treatment comprising type I interferon and optionally concomitantly with a corticosteroid. In a preferred embodiment of the present invention, a single nucleotide polymorphism (SNP) rs9984273 (C / T) in the subunit 2 (IFNAR2) of the interferon alpha and beta receptor in chromosome 21 and / or a SNP in linkage disequilibrium with SNPrs9984273 (C / T) is used as a marker in patient selection for a treatment concomitantly with a corticosteroid, comprising type I interferon.

[0017] Further, the present invention relates to a composition comprising type I interferon as an active ingredient, which is used for preventing and / or treating a disease or condition in an individual that requires or benefits from pharmaceutical intervention with type I interferon, wherein the individual has a single nucleotide polymorphism (SNP) rs9984273 (C / T) detected in subunit 2 of the interferon α and β receptor (IFNAR2) on chromosome 21 and / or a SNP detected that is in linkage disequilibrium with SNP rs9984273 (C / T).

[0018] At present, it has been observed that patients who receive type I interferon therapy and have single nucleotide polymorphism (SNP) rs9984273 (C / T) in subunit 2 (IFNAR2) of interferon alpha and beta receptor have significantly better results than patients who do not contain the SNP rs9984273 (C / T) and receive interferon therapy. The result showed that SNP rs9984273 (chromosome 21: chromosome position 34635065) marker is relevant to the response to type I interferon therapy. The sequence containing this polymorphic marker is the glucocorticoid receptor binding site in the IFNAR2 gene. In large-scale phase III randomized placebo-controlled studies, it has been observed that patients with CT rather than TT in IFNAR2 are enriched in responders, and they also have better survival in ARDS. Therefore, it has been observed that the SNP rs9984273 (C / T) in IFNAR2 and / or the SNP in linkage disequilibrium with SNP rs9984273 (C / T) can be used as a marker, to assist in making the clinical decision of starting or not starting the drug intervention of type I interferon in the patient suffering from the disease or illness that needs or benefits from I type interferon use. This discovery allows to carry out the treatment method of individualized patients according to the existence or absence of SNP rs9984273 (C / T) in IFNAR2. The existence or absence of SNPrs9984273 (C / T) in IFNAR2 can be simply determined by using specific genome test, and the result of test can be used for estimating the result and response in the disease or illness that needs to be intervened with I type interferon.

[0019] Further, it has been observed that the use of glucocorticoids with type I interferons (such as interferon alpha or interferon beta) does not affect the therapeutic response in patients with SNP rs9984273 (C / T) in IFNAR2. Although used with glucocorticoids, in patients with SNP rs9984273 (C / T) in IFNAR2, there is a responsiveness to type I interferons such as interferon alpha or interferon beta drug interventions. Although used with glucocorticoids, the presence of SNPrs9984273 (C / T) in IFNAR2 in patients provides a therapeutic method of raising CD73 by using type I interferons. The presence of SNP rs9984273 (C / T) in IFNAR2 in patients can also be used as a marker to assist in making a clinical decision to start or not start the glucocorticoid administration combined with type I interferon treatment.

[0020] According to one aspect of the invention, a combination of genetic testing and type I interferon therapy can be used to prevent and / or treat acute organ damage (ARDS, AKI, SIRS, and MOF) and severe viral infections. One such treatment is intravenous interferon beta-1a, which is considered to be beneficial, for example, in the treatment of acute organ damage (ARDS, AKI, SIRS, and MOF) and severe viral infections.

[0021] According to another aspect of the invention, the combination of genetic testing and type I interferon treatment can be used to prevent and / or treat vascular endothelial disease in humans with sepsis, severe acute viral infections, humans undergoing major cardiovascular surgery resulting in ischemia-reperfusion injury, and the disease states known as AKI, ARDS, SIRS, MOF, and MS.

[0022] According to another aspect of the invention, the combination of genetic testing and type I interferon treatment can be used to prevent and / or treat malignant diseases in humans, including hairy cell leukemia, malignant melanoma, follicular lymphoma, condyloma acuminatum, AIDS-related Kaposi's sarcoma, chronic hepatitis C, acute hepatitis C and chronic hepatitis B.

[0023] According to the present invention, SNP rs9984273 (C / T) in IFNAR2 and / or SNPs in linkage disequilibrium with SNP rs9984273 (C / T) can be used as prognostic biomarkers in the above-mentioned conditions / diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Shown are Kaplan-Meier survival curves for patients with ARDS who received intravenous interferon-β-1a (FP-1201-lyo) or placebo in a phase III clinical study.

[0025] Figure 2 shows the single nucleotide polymorphism (SNP) rs9984273 (C / T) in IFNAR2, which is designated according to the present invention as a decisive factor to make a clinical decision to treat a patient with or without type I interferon,

[0026] Figures 3a and 3b show the Kaplan-Meier survival curves of ARDS patients with or without (SNP) rs9984273 (C / T) in IFNAR2 who received intravenous interferon-β-1a in a phase III clinical study (0 = no polymorphism, 1 = presence of polymorphism), and

[0027] Figures 4 and 5 show the results of the multivariate logistic regression model for the Phase III clinical study. DETAILED DESCRIPTION

[0028] Terms and Definitions

[0029] The term "patient" or "individual" refers to a human being.

[0030] the term "Treatment" or "treating" This should be understood to include complete cure of the disease as well as improvement or alleviation of the disease.

[0031] The term "prevention" should be understood to include complete prevention, protection against, as well as reducing the risk of an individual developing the disease or condition.

[0032] Inventions and Discoveries

[0033] In a large phase III randomized placebo-controlled study investigating the use of intravenous interferon beta-1a in the treatment of acute respiratory distress syndrome (ARDS), it was not found to be superior to placebo.

[0034] The protocol for this study is described in more detail in Bellingan et al. 2017. The Phase III trial study was conducted as a double-blind, 1-to-1 randomized, parallel-group trial in which the efficacy and safety of intravenously administered recombinant human interferon beta-1a were investigated compared with placebo in the treatment of adult patients with ARDS. The study, which enrolled 300 patients, was conducted in 64 hospital intensive care units (ICUs) in Belgium, the Czech Republic, Finland, France, Germany, Italy, Spain, and the United Kingdom. Patients were randomly assigned to receive 10 μg of recombinant human interferon beta-1a or placebo administered intravenously once daily for 6 days and monitored for 28 days or until discharge from the intensive care unit. The primary endpoint was a composite endpoint that included death from any cause at 28 days and the number of days free of mechanical ventilation within 28 days among survivors. Although earlier Phase I / II studies showed reduced mortality, in this study, treatment with recombinant human interferon beta-1a did not result in reduced mortality or increased ventilator-free days compared with placebo. The Kaplan-Meier survival curves of the trial results are presented in Figure 1 Therefore, a more detailed analysis of the study results and treated patients is now performed.

[0035] In a more detailed analysis of the results of the Phase III randomized placebo-controlled study, it was observed that study subjects who received intravenous interferon beta-1a and had the single nucleotide polymorphism (SNP) rs9984273 (C / T) in the interferon alpha and beta receptor subunit 2 (IFNAR2) had significantly better outcomes than subjects who did not have the SNP rs9984273 (C / T) and were treated with interferon, as Figure 3a This is shown in Figure 3bIn the placebo group presented in , not seen. No matter whether they have described SNP rs9984273 (C / T), in the placebo group, experimenter's result is no different. Further, as explained in detail below, in the multivariate logistic regression model adjusted for severity of disease, it has been shown that the use of corticosteroids simultaneously is independently related to mortality, and the combination of SNP rs9984273 (C / T) and interferon treatment has a very significant effect on survival.

[0036] In order to analyze the results of the above-mentioned Phase III randomized placebo-controlled study in more detail, a linear step-down multivariate regression model was performed to study the most significant factors affecting the results on the 28th day (D28) after initial treatment. The variables included in the model were selected according to univariate analysis. The variables with a test P value <0.15 were input into the model. These were the overlapping use of corticosteroids during the interferon beta treatment period in the pilot study (i.e., from the 0th day to the 7th day), and the presence of the C / T polymorphism (INFAR2, polymorphism ID: rs9984273) in the subunit 2 of the interferon alpha and beta receptors. The continuous digital APACHE II score was used to adjust the severity of the disease because it also had a correlation with mortality in the univariate analysis.

[0037] The results of the multivariable logistic regression model for the phase III study are presented in Figure 4 and 5 middle. Figure 4 The table presented is from the group of patients treated with interferon, while Figure 5 The table presented in is from the group of patients treated with placebo. In the table, SNP: 1 = gene present, 0 = gene not present and corticosteroid effect: cstart2 = corticosteroid adjusted during dosing adjusted for APACHE score (AP30).

[0038] Multivariate regression models showed that patients treated with interferon beta-1a and carrying the SNP rs9984273 (C / T) were 5.7 times more likely to survive at D28 than those without the mutation (p = 0.0057), while patients who received glucocorticoids (cstart2) during the treatment period were 7.6 times more likely to die at D28 (odds ratio 0.13, p = 0.0008). In the placebo group, a similar detrimental effect of corticosteroid use during the first few days of treatment was seen (3.5 times more likely to die at D28, p = 0.06), but no survival effect was seen in the placebo group for the C / T polymorphism. This means that the C / T polymorphism in subunit 2 of the interferon alpha and beta receptor (INFAR2, polymorphism ID: rs9984273) and interferon beta-1a treatment together are the most favorable combination for patient outcome and efficacy of interferon treatment, i.e. the most predictive value for survival is the combination of having the identified SNP and receiving type I interferon treatment.

[0039] Embodiments of the present invention

[0040] As presented above, the findings of the present invention provide methods for classifying patients as more likely to respond to type I interferon therapy.

[0041] Methods for determining a patient's responsiveness to a therapy comprising administration of a Type I interferon and optionally concomitant administration of a corticosteroid include:

[0042] - Obtain samples from patients,

[0043] - determining the presence or absence of a single nucleotide polymorphism (SNP) rs9984273 (C / T) in the interferon alpha and beta receptor subunit 2 (IFNAR2) in chromosome 21 of the patient from a sample obtained from the patient, and

[0044] - Classifying patients according to the presence or absence of said SNP, wherein

[0045] i) the presence of said SNP is indicative of responsiveness to a therapy comprising administration of a type I interferon to said patient, with or without concomitant administration of a corticosteroid, or

[0046] ii) the absence of said SNP is indicative of non-responsiveness to therapy with concomitant administration of corticosteroids, and moderate responsiveness to said therapy without concomitant administration of corticosteroids.

[0047] According to one embodiment of the invention, a method for determining the responsiveness of a patient to a therapy comprising treatment with a type I interferon concomitantly with a corticosteroid comprises

[0048] - determining the presence or absence of the single nucleotide polymorphism (SNP) rs9984273 (C / T) in the interferon alpha and beta receptor subunit 2 (IFNAR2) in chromosome 21 from a sample obtained from the patient, and

[0049] - Classifying patients according to the presence or absence of said SNP, wherein

[0050] i) the presence of the SNP is indicative of responsiveness to a therapy comprising treatment with a type I interferon and a corticosteroid, or

[0051] ii) the absence of said SNP is indicative of non-responsiveness to therapy comprising treatment with type I interferon and corticosteroids.

[0052] The method according to the invention is simply based on determining the presence or absence of the single nucleotide polymorphism (SNP) rs9984273 (C / T) in a sample obtained from a patient. The SNP rs9984273 (C / T) in question is located in the subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21 (Homo sapiens: chromosome 21: chromosome position 34635065). It is listed in PubMed The full text is cited in , and no functional role for this SNP has been found until now. Figure 2 A detailed description of the location of the single nucleotide polymorphism (C / T) in question on the subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21 is also presented in. Patients with the SNP rs9984273 (C / T) have a C instead of a T in at least one of the genes.

[0053] The presence or absence of SNP rs9984273 (C / T) in the sample can be analyzed by SNP rs9984273 (C / T) in the subunit 2 (IFNAR2) of the interferon α and β receptors in detecting chromosome 21 and / or the SNP in linkage disequilibrium with SNP rs9984273 (C / T). According to one embodiment of the present invention, the presence or absence of SNP rs9984273 (C / T) in the sample and / or the SNP in linkage disequilibrium with SNP rs9984273 (C / T) can be determined by commercially available assay and measuring methods. The present invention is not limited to any concrete method or assay, but all suitable assays and / or methods can be used for amplification and detection of the SNP in the genomic DNA sample. Genomic DNA can originate from various sample types derived from the patient, such as tissue, saliva, blood or serum samples. For example, the presence of the SNP can be determined by contacting the sample with an oligonucleotide probe that recognizes SNP rs9984273 (C / T) and / or a SNP in linkage disequilibrium with SNP rs9984273 (C / T). A more detailed analysis of the patient group in the above-mentioned Phase III study was performed by using Taqman ® SNP genotyping assay (ThermoFisher Scientific; assay ID C_2443264_10) to detect the presence of SNP rs9984273 (C / T). More detailed information is presented in

[0054] Pre-designed TaqMan ® The SNP genotyping assay includes two allele-specific TaqMan ® Probe, it contains unique fluorescent dye and the PCR primer pair of detection specific SNP target.The present invention is not limited to this specific mentioned assay method for identifying the SNP.According to another embodiment of the present invention, can be by utilizing polymerase chain reaction and identification polymorphism SNP rs9984273 (C / T) and / or with SNP rs9984273 (C / T) in linkage disequilibrium specific restriction enzyme, make sample contact with oligonucleotide probe, determine the existence of the SNP.Suitable probe may be different due to, for example, sequence length to be detected.

[0055] In sample, the existence or non-existence of SNP rs9984273 (C / T) can be determined by detecting SNP rs9984273 (C / T) by using suitable probe like this.Alternately, the existence or non-existence of SNP rs9984273 (C / T) can be determined by detecting the SNP that is in linkage disequilibrium with SNP rs9984273 (C / T) in sample.Linkage disequilibrium means that there are two (or more) polymorphisms (its probability is more than 50%) simultaneously in the genetic sample.It also means that the physical distance between two (or more) different loci of these polymorphisms that are in linkage disequilibrium is very short, which means that these loci are not inherited independently of each other, but have the high probability (> 50%) of their inheritance together. Therefore, the screening method for a patient may include determining the presence or absence of a single nucleotide polymorphism (SNP) in a sample, wherein the SNP is SNPrs9984273 (C / T) in IFNAR2 and / or a SNP that is in linkage disequilibrium with SNP rs9984273 (C / T).

[0056] When the existence of SNPrs9984273 (C / T) has been detected from the patient, it indicates the responsiveness of the patient to therapy, and the therapy comprises the use of the type interferon to the patient, with or without the concomitant administration of corticosteroid. However, the non-existence of SNP described in the sample indicates the non-responsiveness of the concomitant administration of corticosteroid and the appropriate responsiveness of the concomitant administration of corticosteroid, if the patient without SNPrs9984273 (C / T) is treated by type interferon, then it should not be accompanied by corticosteroid and complete. By determining the existence or non-existence of the SNP, the doctor can decide to start or not start the use of type interferon. Further, the SNP can also be used as a marker, to assist in making the clinical decision of starting or not starting the use of the corticosteroid combined with type interferon treatment.

[0057] According to the present invention, the patient with the presence of SNP rs9984273 (C / T) in the sample has a survival probability of> 0.8, preferably> 0.85, or more preferably> 0.9 with therapy, wherein the therapy comprises administering to the patient's type I interferon, with or without the concomitant administration of corticosteroids. Therefore, the screening method according to the present invention significantly improves the patient's survival probability, because treatment can be individualized in the early stages of therapy.

[0058] In the present application, the term type I interferon refers to all forms of interferon beta and interferon alpha and their subtypes. In a preferred embodiment according to the present invention, interferon beta can be interferon beta-1a, interferon beta-1b and / or interferon beta-2 (i.e. interleukin-6). In a preferred embodiment according to the present invention, type I interferon comprises interferon beta-1a. In an embodiment according to the present invention, interferon alpha can be selected from interferon alpha-1, interferon alpha-2, interferon alpha-8, interferon alpha-10, interferon alpha-14 and interferon alpha-21. It is assumed that the screening method according to the present invention is suitable for screening any patient suffering from a disease or condition, and the disease or condition requires or benefits from drug intervention with type I interferon.

[0059] According to one embodiment of the present invention, when therapy also comprises the administration of the corticosteroid in combination with type I interferon, the corticosteroid is selected from glucocorticoid. According to one embodiment of the present invention, the glucocorticoid can be hydrocortisone, prednisone, prednisolone, methylprednisolone, betamethasone and / or dexamethasone.

[0060] According to the present invention, a composition comprising type I interferon as an active ingredient is used to prevent and / or treat a disease or condition in an individual that requires or benefits from type I interferon drug intervention. According to one embodiment of the present invention, the pharmaceutical preparation of the composition further comprises a suitable pharmaceutically acceptable carrier, which comprises excipients and adjuvants that facilitate the processing of the active compound into a preparation that can be used pharmaceutically. The composition comprises a pharmacologically effective amount of type I interferon. The expression " Pharmacologically effective amount " is intended to include any amount of type I interferon sufficient to cause the desired therapeutic result. The therapeutic effect may depend on the genetic profile of the subject. The pharmaceutical composition according to the present invention can be administered by any means to achieve its intended purpose. For example, administration can be intravenous, intraarticular or subcutaneous.

[0061] The present invention is based on type I interferon drug therapy together with genetic testing performed before treatment decisions. The designated genetic test can also be used to predict patient outcomes and the need for interferon intervention in disease states that require a natural type I interferon response, such as severe life-threatening viral infections, such as EBOLA, MERS, influenza, avian influenza, swine flu, and other similar conditions that cause systemic inflammatory response syndrome (SIRS) and central organ dysfunction, i.e. acute kidney injury (AKI), acute respiratory distress syndrome (ARDS) and / or multiple organ failure (MOF); and ischemic and systemic inflammatory injuries caused by major trauma, multiple blood transfusions or cardiovascular surgery, such as open aortic reconstruction, open heart surgery, organ transplantation, or any other surgical intervention requiring extracorporeal circulation and aortic cross-clamping.

[0062] The present invention involving the administration of type I interferons can be used to treat a range of vascular endothelial diseases in humans. CD73, an endothelial exoenzyme that can produce local adenosine, is a key molecule in maintaining the endothelial cell barrier and lung function. Interferon-β increases CD73 expression, resulting in increased local adenosine. Many inflammatory conditions are known to result in the loss of CD73 from the surface of inflamed / injured endothelial cells, thus reducing the available adenosine content. The anti-inflammatory properties of adenosine are well known in the literature, and any condition known to result from the loss of local adenosine effects would benefit from upregulation of CD73 expression. If permanent help is desired, upregulation of CD73 should be based on de novo synthesis.

[0063] The present invention comprising the use of type I interferon is also applicable to preventing and / or treating ischemia-reperfusion injury caused by blood vessel or heart surgery, organ transplantation, stroke, myocardial infarction or acute coronary syndrome, or ischemia pretreatment before large blood vessel or heart surgery and organ transplantation. In addition, the present invention is applicable to preventing and / or treating ischemia-reperfusion injury in myocardial infarction and stroke.

[0064] The present invention involving the administration of type I interferons is useful for severe bacterial pneumonia and sepsis leading to systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF).

[0065] The present invention involving the administration of type I interferons is useful for severe viral respiratory or hemorrhagic infections leading to systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF).

[0066] The present invention involving the administration of type I interferons is suitable for treating multiple sclerosis (MS).

[0067] The present invention involving the administration of type I interferons, particularly interferon alpha, is useful for treating malignant diseases in humans including hairy cell leukemia, malignant melanoma, follicular lymphoma, condyloma acuminatum, AIDS-related Kaposi's sarcoma, chronic hepatitis C, acute hepatitis C, and chronic hepatitis B.

[0068] According to one embodiment of the present invention, the disease or condition requiring or benefiting from type I interferon drug intervention can be selected from

[0069] - Endothelial diseases,

[0070] - Acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), or other traumatic conditions,

[0071] - Ischemia-reperfusion injury,

[0072] - ischemic preconditioning before major vascular or cardiac surgery and organ transplantation,

[0073] - Acute pancreatitis,

[0074] - Acute kidney injury,

[0075] - Multiple organ failure (MOF),

[0076] - Severe respiratory or hemorrhagic viral infections, and

[0077] - Multiple sclerosis (MS).

[0078] In one embodiment of the method of treating a patient described herein, the patient suffers from a vascular endothelial disease or any other condition described in this application. Administration of type I interferon should be initiated as soon as possible after disease diagnosis and genetic testing.

[0079] According to one embodiment of the invention, a method for determining a patient's responsiveness to treatment with type I interferon, optionally accompanied by corticosteroids, is used to screen patients with ARDS and enables individualized treatment methods based on the presence or absence of SNPrs9984273 (C / T) in IFNAR2.

[0080] According to one embodiment of the present invention, a method for treating a patient comprises determining the presence or absence of SNPrs9984273 (C / T) in IFNAR2, and administering a composition comprising a type I interferon, optionally with or without corticosteroids.

[0081] The patient will receive an effective amount of type I interferon as the main active ingredient, the effective amount being sufficient to treat, improve or prevent the disease or condition in question. For any particular subject, the optimal effective amount and concentration of type I interferon will depend on various factors, including the age, size, health and / or sex of the patient, the nature and extent of the condition, and any possible further therapeutic agents used in combination with type I interferon, such as the simultaneous use of corticosteroids, which are declared to interfere with interferon activity. The effective amount delivered for a given situation can be determined by the judgment of the clinician and the genetic test performed.

[0082] References cited in this manual

[0083] Bellingan et al., The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir Med 2014, 2: 98–107.

[0084] Bellingan et al. Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial. Trials 2017, 18:536.

[0085] Jalkanen, S. and Salmi, M., VAP-1 and CD73, Endothelial cell surface enzymes in leukocyte extravasation. Asterioscler. Thromb. Vasc. Biol. 2008, 18-26.

[0086] Kiss et al., IFN-β protects from vacular leakage via up-reguölation of CD73. Eur. J. Immunology 2007, 37: 3334-3338.

[0087] Levy et al., Ringing the interferon alarm: differential regulation of gene expression at the interface between innate and adaptive immunity. Current Opinion in Immunology 2003,15:52-58.

[0088] Mahurkar et al., Response to interferon-beta treatment in multiplesclerosis patients: a genome-wide association study. The PharmacogenomicsJournal, March 2016, 1–7. Sequence Listing <110> Fallon Pharmaceuticals <120> Methods for determining the responsiveness of a patient to type I interferon therapy and type I interferon therapy Use of patients with specified single nucleotide polymorphisms <130> AP107638PC <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 1001 <212> DNA <213> Homo sapiens <400> 1 gaggctgagg cagagaattg cttgaacctg ggaggtggag gttgcagtga gccaagaccg 60 cactactgca ctccagcctg ggcaacagag cgagactccc gtctcaaaaa aaaaaaaaaa 120 aaaaaatagt aagcatacct catagagcag ttgcaaggga aaggtaaatt atatataaag 180 caccaagagt catgcccagc atatagtaag catggtgtaa ctgttagctg ttattattgc 240 tgtcatcatc atcaactgca tcatcattca atctcattaa gtttattttt tattttttta 300 gaggcaaggt ctcgctaagg gctggaatgc agtggctatt cacaggtgca gtcataatgc 360 actacagtct gaaactcctg agctcaaaca gtcgtcctc ctaagcttc ccagtagctg 420 ggattacaag cgtgcatccc tgtgccccag tgattaagtt ttattatgta gaaaataaag 480 agcaaacagt acagctgata yggactctct ctctcttttt tttttttttt aagaattttc 540 ataacttttt agcctggcca tttcctaacc tgccaccgtt ggaagccatg gatatggtgg 600 aggtcattta catcaacaga aagaagaaag tgtgggatta taattatgat gatgaaagtg 660 atagcgatac tgaggcagcg cccaggacaa gtggcggtgg ctataccatg catggactga 720 ctgtcaggcc tctgggtcag gcctctgcca cctctacaga atcccagttg atagacccgg 780 agtccgagga ggagcctgac ctgcctgagg ttgatgtgga gctccccacg atgccaaagg 840 acagccctca gcagttggaa ctcttgagtg ggccctgtga gaggagaaag agtccactcc 900 aggacccttt tcccgaagag gactacagct ccacggaggg gtctgggggc agaattacct 960 tcaatgtgga cttaaactct gtgtttttga gagttcttga t 1001 <210> 2 <211> 51 <212> DNA <213> Homo sapiens <400> 2 taaagagcaa acagtacagc tgatayggac tctctctctc tttttttttt t 51

Claims

1. Use of an oligonucleotide probe for detecting single nucleotide polymorphism (SNP) rs9984273 (C / T) in preparing a reagent for determining a method for determining the responsiveness of a patient to a treatment comprising type I interferon accompanied by a corticosteroid, the method comprising - determining the presence of the single nucleotide polymorphism (SNP) rs9984273 (C / T) in the subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21 from a sample obtained from said patient, and - classifying said patients according to the presence of said SNP, wherein The presence of the SNP is indicative of responsiveness to a treatment comprising type I interferon concomitantly with a corticosteroid, wherein the patient suffers from acute respiratory distress syndrome (ARDS) or a severe viral infection causing acute respiratory distress syndrome (ARDS).

2. The use according to claim 1, wherein type I interferon is selected from interferon beta, interferon alpha and any subtype thereof.

3. The use according to claim 2, wherein the type I interferon is interferon beta-1a.

4. The method according to any one of claims 1 to 3, wherein the corticosteroid is selected from glucocorticoids.

5. purposes according to claim 4, wherein the glucocorticoid is selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, betamethasone and / or dexamethasone.

6. The use according to any one of claims 1-3, wherein a patient having the presence of said SNP in a sample has a survival probability of >0.8 with said treatment.

7. The use according to any one of claims 1-3, wherein a patient having the presence of said SNP in a sample has a survival probability of >0.85 with said treatment.

8. The use according to any one of claims 1-3, wherein a patient having the presence of said SNP in a sample has a survival probability of >0.9 with said treatment.

9. Use of an oligonucleotide probe for detecting a single nucleotide polymorphism (SNP) rs9984273 (C / T) in the subunit 2 (IFNAR2) of the interferon α and β receptor in chromosome 21 as a marker in the preparation of a reagent for determining a patient responding to a treatment comprising type I interferon combined with a corticosteroid, wherein the patient suffers from acute respiratory distress syndrome (ARDS) or a serious viral infection causing acute respiratory distress syndrome (ARDS).

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