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EP-4735639-A1 - IFN-SIGNATURE AS A BIOMARKER FOR HERPES SIMPLEX ENCEPHALITIS RELATED SYMPTOMS

EP4735639A1EP 4735639 A1EP4735639 A1EP 4735639A1EP-4735639-A1

Abstract

A method for diagnosing a probability of a human patient with encephalopathy symptoms has or may develop a herpes simplex encephalitis (HSE) related symptom

Inventors

  • ARMANGUÉ SALVADOR, Thaís
  • DALMAU, JOSEP

Assignees

  • Hospital Sant Joan de Deu
  • Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer
  • Institució Catalana De Recerca I Estudis Avançats (ICREA)

Dates

Publication Date
20260506
Application Date
20240627

Claims (15)

  1. 1. A method for diagnosing a probability of a human patient with acute encephalopathy symptoms has or may develop a herpes simplex encephalitis (HSE) related symptom comprising the steps of: (i): measuring, in a blood sample obtained from the patient, the expression level of at least one type I interferon (IFN)-response gene (IRG) to obtain a patient type I IFN-signature; (ii): comparing the measured patient type I IFN-signature of step (i) to a control group of human persons with a reference control type I IFN-signature with the same IRG as in step (i); (iii): analyzing the compared data of step (ii) to identify if the patient type I IFN-signature of step (i) is deviating from the control IFN-signature of step (ii); and (iv): deciding if the possible deviation in step (iii) relates to an elevated patient IFN-signature of step (i) as compared to the control IFN-signature of step (ii) and if the patient IFN-signature of step (i) is elevated, then is the patient IFN-signature defined as a positive IFN-signature, indicating a relatively high probability for that the human patient has or may develop a HSE related symptom.
  2. 2. The method for diagnosing of claim 1 , wherein the at least one IRG of step (i) is at least one IRG selected from the group of genes consisting of the genes of the table below:
  3. 3. The method for diagnosing of claim 2, wherein the at least one IRG of step (i) is at least one IRG selected from the group of genes consisting of (Entrez gene symbol): IFI27, IFI44, IFI44L, ISG15, RSAD2, and SIGLEC1.
  4. 4. The method for diagnosing of any of the preceding claims, wherein the patient IFN-signature of step (i) is made based on measurement of at least 2 different IRGs, more preferably at least 3 different IRGs, even more preferably at least 4 different IRGs (such as at least 5 different IRGs), and most preferably at least 6 different IRGs.
  5. 5. The method for diagnosing of claim 4, wherein the at least 6 different IRGs are at least 6 different IRGs selected from the group of claim 2.
  6. 6. The method for diagnosing of claim 5, wherein the at least 6 different IRGs are at least 6 different IRGs selected from the group of claim 3.
  7. 7. The method for diagnosing of any of the preceding claims: - wherein the control group of human persons of step (ii) of claim 1 is a healthy control (HC) group; and - wherein the patient has HSE and the measuring in step (i) of claim 1 is done in a period from 10 to 40 days after HSE onset, preferably from 15 to 30 days after HSE onset, and more preferably at day 21 after HSE onset; and - wherein the HSE related symptoms of step (iv) of claim 1 is autoimmune encephalitis (AE) post-HSE or viral complications.
  8. 8. The method for diagnosing of claim 7, wherein the positive patient IFN-signature of step (iv) of claim 1 has a Z score between 1 .5 to 4, determined according to the method identified in the specification; and wherein the HSE related symptoms of step (iv) is autoimmune encephalitis (AE) post-HSE.
  9. 9. The method for diagnosing of any of the claims 7-8, wherein the method is of claim 4 and the Z score is median Z score.
  10. 10. The method for diagnosing of any of the claims 7-9, wherein the method is of claim 5 or is of claim 6.
  11. 11 . The method for diagnosing of any of the claims 1 -6: - wherein the control group of human persons of step (ii) of claim 1 is a group of persons with herpesviral meningitis (HSV meningitis); and - wherein the human patient with acute encephalopathy symptoms is a human patient with herpes simplex virus (HSV); and - wherein the measuring in step (i) of claim 1 is less than 7 days after HSV disease onset; and - wherein the HSE related symptoms of step (iv) of claim 1 is HSE.
  12. 12. The method for diagnosing of claim 11 , wherein the positive patient IFN-signature of step (iv) of claim 1 has a Z score of at least 2 times higher than the HSV meningitis control type I IFN-signature of step (ii) of claim 1 , determined according to the method identified in the specification.
  13. 13. The method for diagnosing of any of the claims 11-12, wherein the method is of claim 4 and the Z score is median Z score.
  14. 14 The method for diagnosing of claim 13, wherein the method is of claim 6.
  15. 15. The method for diagnosing of any of the preceding claims, wherein the measuring of the expression level in step (i) of claim 1 is done by measuring the mRNA levels of the respective IRGs.

Description

IFN-signature as a biomarker for herpes simplex encephalitis related symptoms Field of the invention The present invention relates to a method for diagnosing a probability of a human patient with acute encephalopathy symptoms has or may develop a herpes simplex encephalitis (HSE) related symptom. Background of the invention Herpes simplex virus (HSV) is a virus that produces different viral infection symptoms in humans. Infection with HSV is manifested with different related symptoms - such as e.g. watery blisters in the skin or mucous membranes, lesions heal with a scab characteristic, herpes viral meningitis (HSV meningitis), and herpes simplex encephalitis (HSE - alternatively termed herpes viral encephalitis). Accordingly, a patient with HSV may develop different symptoms/diseases - i.e., the art describes different methods for diagnosing a probability in a patient for developing different HSV related symptoms - such as e.g. HSV related diseases and/or complications. Encephalopathy refers to abnormal mental status secondary to any disorder. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome has many possible organic and inorganic causes - such as e.g. mitochondrial encephalopathy, glycine encephalopathy, herpes simplex encephalitis (HSE), etc. As known in the art - acute encephalopathy symptoms refer to symptoms of encephalopathy in a patient that have been developed in a relatively short time frame (e.g. hours or days). Encephalitis refers when encephalopathy is secondary to an inflammatory disorder of the brain (e.g. Autoimmune causes, virus, etc.). Most causes of encephalitis have an acute presentation (symptoms develop in e.g. hours or days). Herpes simplex encephalitis (HSE) (alternatively termed Herpesviral encephalitis) is the most frequent sporadic infectious encephalitis in high-income (or non-tropical) countries, with an incidence of 2-4 cases per million persons each year and causes a high morbidity and mortality. Distinction between HSE and other causes of acute encephalopathy is difficult and may hold up important management decisions as early treatment is essential to decrease the burden of neurological residual symptoms. Currently the distinction between HSE and other causes of acute encephalopathy is only possible with invasive medical tests (lumbar puncture evaluation of cerebrospinal fluid [CSF] to look for inflammatory signs and specific microbiological tests for HSV in CSF). In addition, microbiological tests for HSV diagnosis in CSF have low sensitivity (first 3 days of symptoms) and non-optimal specificity; and do not allow distinction of HSE and HSV meningitis. Furthermore, in a confirmed case of HSE, in addition to sequelae caused by the infection, more than 25% of patients develop new neurological symptoms within 1-2 months after HSE, many of them in association with auto-antibodies against neuronal surface proteins (termed autoimmune encephalitis (AE) post-HSE). Distinction between AE post-HSE and recrudescence of residual deficits or new manifestations related to persistent or reactivation of the viral infection also is difficult and may hold up treatment decisions. The article by Armangue T et al (Lancet Neurol. 2018;17(9):760-772) describes the presence of CSF neuronal antibodies at day 21 after HSE onset as a diagnostic predictor of AE post-HSE. Chronic or persistent activation of the type I interferon (IFN) pathway has been described in autoimmune disorders such as systemic lupus erythematous or autoinflammatory diseases such as monogenic type I interferonopathies including Aicardi-Goutieres Syndrome (AGS) Rice et al. (Lancet Neurol. 2013;12(12):1159-1169). In these diseases, the chronic activation of the type I IFN pathway has been measured with an “IFN-signature” which quantifies RNA of multiple genes in the blood that are induced by high levels of type I IFN - see e.g. the article of Kim et al. (J. Interferon & Cytokine Rech. 2018;38(4):171-185) and (Rice et. al 2013). As discussed in e.g., Kim et al. 2018 - the term “IFN-signature” is a well know term in the art, and it relates to measurement of elevation of interferon (IFN)-response genes (IRGs) expression (e.g. via measurement of elevated/higher RNA expression levels). According to the art - the term “type I IFN- signature” relates to measurement of elevation of type I IFN response genes (IRGs) expression. The article by Liu Benke et al (J Neurol Sciences 424 (2021) 117394) discloses a study showing that of serum CXCL 13, IL-6, BAFF, CXCL 10 and MMP was significantly increased on day 21 following Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) in subjects that developed autoimmune encephalitis over those that did not. Without being limited to theory - at the filing date of the present patent application - the present inventors were not aware of a single prior art document that directly and unambiguously desc