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JP-7855586-B2 - Methods for identifying individuals at high risk of developing coronavirus infection and treatments for such individuals.

JP7855586B2JP 7855586 B2JP7855586 B2JP 7855586B2JP-7855586-B2

Inventors

  • コスミツキ、ジャック
  • ホロウィッツ、ジュリー
  • フェレイラ、マヌエル アレン レベズ
  • アベカシス、ゴンサロ
  • バラス、アリス
  • ダマスク、エイミー

Assignees

  • リジェネロン・ファーマシューティカルズ・インコーポレイテッド

Dates

Publication Date
20260508
Application Date
20211203
Priority Date
20201203

Claims (20)

  1. The use of a therapeutic agent for treating or inhibiting coronavirus infection in the manufacture of a pharmaceutical product for treating a person who has contracted or is susceptible to developing coronavirus infection, wherein the treatment is: The polygene risk score (PRS) of the subject is obtained from or has been obtained from the subject, and a genotyping assay is performed on the biological sample to determine whether the subject has a genotype that includes at least one genetic variant related to susceptibility to and/or severity of coronavirus infection. This includes determining by The PRS score reflects i) the presence or absence of the at least one genetic variant in the target genotype , and ii) the homozygosity or heterozygosity of the target with respect to each of the at least one genetic variants. In the aforementioned procedure, if the subject has a PRS score below a desired threshold, the therapeutic agent that treats or inhibits the coronavirus infection is administered to the subject at a standard dose or the administration is continued. If the subject has a PRS score exceeding a desired threshold, the therapeutic agent that treats or inhibits the coronavirus infection is administered to the subject in an amount exceeding the standard dose, or administration is continued . If the PRS score exceeds the desired threshold , the subject has an increased risk of developing the coronavirus infection and/or an increased risk of developing a severe coronavirus infection. The aforementioned therapeutic agents include lopinavir/ritonavir, chloroquine, hydroxychloroquine, remdesivir, ribavirin, azithromycin, farapirivir, ivermectin, enfuvirtide, amantadine, rimantadine, preconalil, acyclovir, zidovudine, lamivudine, formivirsen, rifampicin, zanamivir, oseltamivir, peramivir, ifenprodil, faviravir/favipiravir, TMJ2 (TJ003234), and TZL. S-501, APN01, tocilizumab, galidesivir, sarilumab, SNG001, AT-100, colchicine, leronlimab, BPI-002, OYA1, artemisinin, OT-101, Sepsivac, darunavir and cobicistat, baricitinib, BXT-25, dexamethasone, duvelisib, interferon, antibody cocktail REGN-COV2, or anti-IL6 antibody, or any combination thereof. The at least one genetic variant associated with susceptibility to developing coronavirus infection and/or severity of coronavirus infection includes single nucleotide polymorphisms (SNPs) rs73064425, rs2531743, rs143334143, rs9411378, rs10735079, rs2109069, rs74956615, and rs2236757, The aforementioned use.
  2. The use according to claim 1, wherein the PRS score also reflects the association between the at least one genetic variant and susceptibility to coronavirus infection.
  3. The use according to claim 1, wherein the PRS score also reflects the association between the at least one genetic variant and the severity of coronavirus infection.
  4. The use according to claim 1, wherein the PRS score also reflects the association between the at least one genetic variant and susceptibility to coronavirus infection and the severity of coronavirus infection.
  5. The use according to any one of claims 1 to 4, wherein the severity of the coronavirus infection is characterized by hospitalization, cytokine storm, shortness of breath, pneumonia, organ failure, septic shock, chest pain or chest tightness, and/or speech impairment or motor loss.
  6. A use according to any one of claims 1 to 5 , The PRS score is combined with a comorbidity score based on the number of comorbidities the subject has ; If the subject's PRS score and comorbidity score combined fall below a desired threshold, the subject is administered or continues to be administered the therapeutic agent that treats or inhibits the coronavirus infection at a standard dose; If the subject's PRS score and comorbidity score combined exceed a desired threshold, the subject is administered or continues to be administered with the therapeutic agent that treats or inhibits the coronavirus infection in an amount exceeding the standard dose ; Herein, the use of the PRS score and the comorbidity score together exceeding the desired threshold indicates that the subject has an increased risk of developing the coronavirus infection and/or an increased risk of developing a severe coronavirus infection.
  7. The use according to claim 6 , wherein the subject has one to five comorbidities, one to four comorbidities, one to three comorbidities, or two or three comorbidities .
  8. The use according to claim 6 or 7, wherein the comorbidity score reflects the presence or severity of comorbidities, including hypertension, coronary artery disease, heart failure, type 2 diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease (COPD ), or Alzheimer 's disease.
  9. The use according to any one of claims 1 to 8 , wherein the therapeutic agent is an antibody cocktail of anti-IL-6 antibodies, REGN-COV2, or a combination thereof.
  10. The use according to any one of claims 1 to 9, wherein the genotyping assay comprises sequencing at least a portion of the nucleotide sequence of a genomic nucleic acid molecule in the biological sample, at least a portion of the nucleotide sequence of an mRNA molecule in the biological sample, or at least a portion of the nucleotide sequence of a cDNA molecule generated from the mRNA molecule in the biological sample.
  11. The use according to any one of claims 1 to 10, wherein the genotyping assay comprises sequencing at least a portion of the nucleotide sequence of a region of at least one nucleic acid molecule and/or an adjacent nucleic acid molecule encoding LZTFL1, SLC6A20, CCHCR1, ABO, OAS3, DPP9, RAVER1 , and/or IFNAR2.
  12. The use according to claim 11, wherein the genotyping assay comprises sequencing the entirety of at least one nucleic acid molecule encoding LZTFL1, SLC6A20, CCHCR1, ABO, OAS3, DPP9, RAVER1, and/or IFNAR2 , and/or the entirety of a region of an adjacent nucleic acid molecule .
  13. The aforementioned genotype determination assay, a) Amplifying at least a portion of the region of the at least one nucleic acid molecule and/or an adjacent nucleic acid molecule that encodes LZTFL1, SLC6A20, CCHCR1, ABO, OAS3, DPP9, RAVER1, and/or IFNAR2, b) Labeling the amplified nucleic acid molecule with a detectable label, c) Contacting the labeled nucleic acid molecule with a support containing a mutation-specific probe, d) Detecting the detectable sign, The use according to claim 11, including the use described in claim 11 .
  14. The aforementioned genotype determination assay, Contacting at least one nucleic acid molecule encoding LZTFL1, SLC6A20, CCHCR1, ABO, OAS3, DPP9, RAVER1, and/or IFNAR2, and/or a region of an adjacent nucleic acid molecule , with a mutation-specific probe containing a detectable label, To detect the aforementioned detectable sign, The use according to claim 11, including the use described in claim 11 .
  15. The use according to any one of claims 1 to 14 , wherein the coronavirus infection includes Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), or Coronavirus Disease 2019 (COVID-19).
  16. The use according to any one of claims 1 to 15 , wherein the procedure further comprises testing the subject for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  17. The use of a polygene risk score (PRS) to assess the risk of a subject developing coronavirus infection or developing severe coronavirus infection, wherein the assessment is: The determination of the polygene risk score (PRS) of the subject is made by obtaining or having obtained a biological sample from the subject, and by performing or having performed a genotyping assay on the biological sample to determine whether the subject has a genotype that includes at least one genetic variant related to susceptibility to and/or severity of coronavirus infection, The PRS score reflects i) the presence or absence of the at least one genetic variant, and ii) the homozygosity and heterozygosity of the subject for each of the at least one genetic variants. If the subject has a PRS score below the desired threshold, the subject has a reduced risk of developing coronavirus infection or severe coronavirus infection, and if the subject has a PRS score above the desired threshold, the subject has an increased risk of developing coronavirus infection or severe coronavirus infection. The at least one genetic variant associated with susceptibility to developing coronavirus infection and/or severity of coronavirus infection includes single nucleotide polymorphisms (SNPs) rs73064425, rs2531743, rs143334143, rs9411378, rs10735079, rs2109069, rs74956615, and rs2236757, The aforementioned use.
  18. The use according to claim 17 , wherein the PRS score also reflects the association between the at least one genetic variant and susceptibility to coronavirus infection.
  19. The use according to claim 17 , wherein the PRS score also reflects the association between the at least one genetic variant and the severity of coronavirus infection.
  20. The use according to claim 17 , wherein the PRS score also reflects the association between the at least one genetic variant and susceptibility to coronavirus infection and the severity of coronavirus infection.

Description

This disclosure provides methods for treating subjects who have or are susceptible to coronavirus infection, methods for identifying subjects who have or are at high risk of developing coronavirus infection, and methods for diagnosing coronavirus infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in Wuhan, China at the end of 2019 and causes coronavirus disease 2019 (COVID-19). Symptoms of COVID-19 range from flu-like symptoms such as fever, cough, and headache, to respiratory failure, acute immune reaction, and death, although it is estimated that most infected individuals show little to no symptoms, even if they are present. As of September 2020, the disease had over 30 million known cases and over 940,000 known deaths worldwide, with many more cases and deaths likely undetected. Known risk factors include, in particular, male gender, older age, race, obesity, cardiovascular and renal disease, chronic obstructive pulmonary disease (COPD), and dementia. One characteristic of COVID-19 infection is that it can be fatal for some individuals, while others of comparable age and overall health may be completely asymptomatic. Increased risk of severe illness is associated, among other risk factors, with sex (male), race, age, and obesity. While the rationale for such differences remains unclear at present, the ability to predict the severity of symptoms in individuals with COVID-19 infection will be a valuable tool for identifying high-risk populations. The ability to identify, monitor, and, if necessary, isolate these populations will represent a significant advance in managing the current COVID-19 pandemic. This disclosure provides a method for treating a subject with a therapeutic agent that treats or inhibits coronavirus infection, wherein the subject is infected with or susceptible to developing coronavirus infection, and the method is determined by the following steps: i) determining a polygenetic risk score (PRS) of the subject, a) obtaining or having obtained a biological sample from the subject; and b) performing or having performed a genotyping assay on the biological sample to determine whether the subject has a genotype that includes one or more genetic variants associated with susceptibility to and/or severity of coronavirus infection; wherein the PRS score is determined by the presence or absence of genetic variants and the subject's gene type for each genetic variant. ii) If the subject's PRS score is below a desired threshold, administer or continue administering a standard dose of a treatment agent that treats or inhibits coronavirus infection to the subject, and/or monitor the subject for the onset of coronavirus infection and/or the progression of coronavirus infection; or iii) If the subject has a PRS score above a desired threshold, administer or continue administering a standard dose of a treatment agent that treats or inhibits coronavirus infection to the subject at the same or a higher dose, wherein the presence of a PRS score above a desired threshold indicates an increased risk of the subject developing coronavirus infection and/or developing severe coronavirus infection. This disclosure provides a method for identifying subjects at increased risk of developing coronavirus infection or severe coronavirus infection, the method comprising determining a polygenic risk score (PRS) of the subject, by: a) obtaining or having obtained a biological sample from the subject; and b) performing or having performed a genotyping assay on the biological sample to determine whether the subject has a genotype containing one or more genetic variants associated with susceptibility to and/or severity of coronavirus infection; wherein the PRS score reflects the presence or absence of genetic variants and the subject's homozygosity and heterozygosity for each genetic variant; if the subject's PRS score is below a desired threshold, the subject has a reduced risk of developing coronavirus infection or severe coronavirus infection; and if the subject's PRS score is above a desired threshold, the subject has an increased risk of developing coronavirus infection or severe coronavirus infection. The accompanying drawings incorporated herein, and constituting part thereof, illustrate several embodiments and are useful in illustrating the principles of this disclosure together with the description of this disclosure. This study shows an association between a high COVID-19 genetic risk score (GRS) and hospitalization or severe disease progression in COVID-19-positive patients with one or more established COVID-19 risk factors.This data shows COVID-19 positive patients and COVID-19 patients requiring hospitalization, categorized by age, sex, and confirmed COVID-19 comorbidities across several cohorts.This shows the sample sizes for various COVID-19 patient categories across several cohorts.Same as above.This shows genetic variants that have been shown to be associated with COVID-19