Biomarkers of amyotrophic lateral sclerosis and uses thereof
Patent Information
- Application Number
- HK62026126644
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-03-21
- Filing Date
- 2026-07-24
- Publication Date
- 2026-09-18
- Estimated Expiration
- 2044-03-19
Smart Images
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Abstract
Description
This invention relates to biomarkers and their application in treatment screening for patients with amyotrophic lateral sclerosis (ALS). The invention also relates to the assessment of ALS disease severity, treatment of ALS patients, and monitoring of ALS treatment efficacy. Abstract
Claims
WHAT IS CLAIMED IS:
1. A method of treating amyotrophic lateral sclerosis (ALS) comprising:(a) collecting a serum sample from a patient diagnosed with ALS before administering a first ALS therapy;(b) administering the first ALS therapy to the patient;(c) collecting a serum sample from the patient after administering the first ALS therapy;(d) measuring concentration of at least one biomarker in the serum samples collected from the patient before and after administering the first ALS therapy, wherein the at least one biomarker is selected from the group consisting of oxidized low-density lipoprotein receptor 1 (0LR1), oxidized low-density lipoprotein (ox-LDL), 4-hydroxynonenal (4-HNE), soluble CD 14 (sCD14), lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), interleukin 17F (IL-17F), interleukin 17C (IL-17C), monocyte chemoattractant protein- 1 MCP-1 (CCL2), and interleukin- 18 (IL- 18);(e) comparing the concentration of the at least one biomarker in the serum sample collected from the patient after administering the first ALS therapy to a baseline, wherein the concentration of the at least one biomarker in the serum sample collected from the patient before administering the first ALS therapy is the baseline; and(f) administering a second ALS therapy to the patient if the concentration of at least one biomarker after administering the first ALS therapy is at least one-fold different than the baseline.
2. The method of claim 1 further comprising collecting serum samples on a serial basis for the duration of the ALS therapy, wherein the serum samples are collected at least once a week, at least once every two weeks, or at least once a month.
3. The method of claim 1 or claim 2, wherein the second ALS therapy is administered to the patient if the concentration of at least 2, at least 3, at least 4, or at least 5 biomarkers are at least one-fold different than the baseline.
4. The method of any one of claims 1-3, wherein the second ALS therapy is administered to the patient if the concentration of at least one biomarker is at least one-fold higher than the baseline.
5. The method of any one of claims 1-4, wherein the second ALS therapy is administered to the patient if the concentration of at least one biomarker is at least one-fold less than the baseline.
6. The method of any one of claims 1-5, wherein the second ALS therapy is administered to the patient if the concentration of at least one biomarker is at least one-fold higher than the baseline and at least one additional biomarker is at least one-fold lower than the baseline.
7. The method of any one of claims 1-6, wherein the second ALS therapy is administered to the patient if the concentration of CCL2, IL- 18, or both are at least one-fold lower than the baseline.
8. The method of claim 7, wherein the second ALS therapy administered to the patient is the same as the first ALS therapy administered.
9. The method of any one of claims 1-6, wherein the second ALS therapy is not administered to the patient if the concentration of CCL2, IL-18, or both are at least one-fold higher than the baseline.
10. The method of any one of claims 5-8, wherein the second ALS therapy administered to the patient is not the same as the first ALS therapy administered if the concentration of CCL2, IL- 18, or both are at least one-fold higher than the baseline.
11. The method of any one of claims 1-10, wherein the serum sample is collected from the patient at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least after 4 weeks of administering the first ALS therapy.
12. The method of any one of claims 1-11, wherein the first ALS therapy is the same as the second ALS therapy administered.
13. The method of any one of claims 1-11 , wherein the first ALS therapy is different from the second ALS therapy administered.
14. The method of any one of claims 1-13, wherein the ALS therapy comprises one or more agents that targets inflammation and / or oxidative stress.
15. The method of any one of claims 1-14, wherein the ALS therapy comprises at least one gene therapy, wherein the gene therapy targets one or more mutations in genes SOD1, C9orf72, FUS, or any combination thereof.
16. The method of any one of claims 1-15, wherein the ALS therapy comprises a Treg infusion.
17. The method of any one of claims 1-16, wherein the ALS therapy comprises Relyvrio (AMXOO35), edaravone, riluzole, or any combination thereof.
18. The method of any one of claims 1-17, wherein the ALS therapy comprises IL-2.
19. The method of any one of claims 1-18, wherein the ALS therapy comprises IL-2 and Abatacept (CTLA-4 Ig).
20. The method of any one of claims 1-19, wherein the ALS therapy comprises an antiinflammatory agent.
21. The method of any one of claims 1-20, wherein the ALS therapy comprises an antioxidant agent.
22. The method of any one of claims 1-21, wherein the second ALS therapy comprises an anti-inflammatory agent if the concentration of CCL2, IL- 18, or both are at least one-fold higher than the baseline.
23. The method of any one of claims 1-22, wherein the second ALS therapy comprises an anti-antioxidant agent if the concentration of ox-LDL, 0LR1 or both are at least one-fold higher than the baseline.
24. The method of any one of claims 1-23, wherein the method further comprises determining an Appel ALS clinical score (AALS) for the patient before and after administering the first ALS therapy.
25. The method of claim 24, wherein the second ALS therapy is administered to the patient if the concentration of at least one biomarker is at least one-fold different than the baseline and the AALS score for the patient the same or lower than the AALS score for the patient before administering the first ALS therapy.
26. The method of any one of claims 1-25, wherein the concentration of the at least one biomarker is determined by enzyme linked-immunosorbent assay (ELISA), protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, protein immunostaining, electrophoresis analysis, competitive binding assay, functional protein assay, protein microarray, high-performance liquid chromatography (HPLC), mass spectrometry, liquid chromatography-mass spectrometry (LC / MS), capillary electrophoresis (CE)-MS, cytometric bead array analysis, immunonephelometric assays, fluorescence activated cell sorting (FACS) analysis, microscopic analysis, microarray, or any combination thereof.
27. A method for selecting a patient for amyotrophic lateral sclerosis (ALS) therapy, the method comprising:(a) determining whether a concentration of at least one biomarker in a serum sample collected from a patient diagnosed with or suspected of having ALS is less than, equal to, or greater than, a reference concentration;(b) wherein the at least one biomarker is selected from the group consisting of oxidized low- density lipoprotein receptor 1 (0LR1), oxidized low-density lipoprotein (ox-LDL), monocyte chemoattractant protein- 1 MCP-1 (CCL2), interleukin- 18 (IL- 18), and any combination thereof; and,(c) selecting the patient for ALS therapy if at least one biomarker is equal to or less than the reference concentration.
28. The method of claim 27, further comprising administering the ALS therapy to the selected patient.
29. The method of claim 27 or 28, wherein the ALS therapy comprises Relyvrio (AMXOO35), edaravone, riluzole, Treg infusion, IL-2, or any combination thereof.
30. The method of any one of claims 27-29, wherein the patient is selected for ALS therapy if at least two or more biomarkers are equal to or less than the reference concentration.
31. The method of claim 30, wherein the at least two or more biomarkers are CCL2 and IL-18.
32. The method of any one of claims 27-31, wherein the patient is naive to ALS therapy.
33. The method of any one of claims 27-32, wherein the patient has previously received at least one ALS therapy.
34. The method of any one of claims 27-33, wherein the patient has received at least one ALS therapy and is selected for a subsequent administration of the same ALS therapy if at least one biomarker is equal to or less than the reference concentration.
35. The method of claim 34, wherein the ALS therapy is a Treg infusion, IL-2, or a combination thereof.
36. The method of any one of claims 27-35, wherein the reference concentration is an average concentration of the biomarker measured in serum samples collected from at least 10 healthy subjects having the same age, gender, and ethnicity as the patient.
37. The method of any one of claims 27-36, wherein the concentration of the at least one biomarker is determined by enzyme linked-immunosorbent assay (ELISA), protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, protein immunostaining, electrophoresis analysis, competitive binding assay, functional protein assay, protein microarray, high-performance liquid chromatography (HPLC), mass spectrometry, liquid chromatography-mass spectrometry (LC / MS), capillary electrophoresis (CE)-MS, cytometric bead array analysis, immunonephelometric assays, fluorescence activated cell sorting (FACS) analysis, microscopic analysis, microarray, or any combination thereof.
38. A kit for detecting and quantifying the level of one or more ALS biomarkers in a serum sample obtained from a patient having or suspected of having ALS, wherein the ALS biomarkers are selected from the group consisting of oxidized low-density lipoprotein receptor 1 (0LR1), oxidized low-density lipoprotein (ox-LDL), monocyte chemoattractant protein-1 MCP-1 (CCL2), interleukin- 18 (IL- 18), and any combination thereof.
39. The kit of claim 38, wherein the kit comprises a solid surface having an antibody or a fragment thereof comprising a binding epitope for the ALS biomarkers 0LR1, ox-LDL, IL-17C, CCL2, IL-18, or any combination thereof, and at least one reagent for detecting formation of a biomarker-antibody complex.
40. The kit of claim 38 or claim 39 for use in selecting a patient for an ALS therapy.
41. The kit of any one of claims 38-40 for use in monitoring effectiveness of an ALS therapy, wherein effectiveness can be assessed during the course of or after completing an ALS therapy regimen.
42. A method of treating treatment-responsive ALS, comprising administering to a patient diagnosed with treatment-responsive ALS a therapeutically effective amount of an ALS therapy, wherein the treatment-responsive ALS is characterized as having at least one biomarker equal to or less than a reference concentration,wherein the at least one biomarker is selected from the group consisting of oxidized low- density lipoprotein receptor 1 (0LR1), oxidized low-density lipoprotein (ox-LDL), monocyte chemoattractant protein- 1 MCP-1 (CCL2), and interleukin- 18 (IL- 18); and, wherein the reference concentration is an average concentration of the biomarker measured in serum samples collected from at least 10 healthy subjects having the same age, gender, and / or ethnicity as the patient.
43. The method of claim 42, wherein treatment-responsive ALS is characterized as having at least two biomarkers equal to or less than a reference concentration.
44. The method of claim 43, wherein the at least two or more biomarkers are CCL2 and IL-18.
45. The method of any one of claims 42-44, wherein the ALS therapy comprises Relyvrio (AMXOO35), edaravone, riluzole, Treg infusion, IL-2, or any combination thereof.
46. The method of claim 45, wherein the ALS therapy is a Treg infusion, IL-2, or a combination thereof.
47. A method of determining whether a patient diagnosed with ALS is indicated as likely to be responsive to ALS treatment, comprising detecting the concentration of at least one biomarker compared to a reference concentration in a serum sample collected from the patient, wherein the at least one biomarker having a concentration equal to or less than the reference concentration indicates that the patient is likely to be responsive to ALS treatment, wherein the at least one biomarker is selected from the group consisting of oxidized low- density lipoprotein receptor 1 (OLR1), oxidized low-density lipoprotein (ox-LDL), monocyte chemoattractant protein- 1 MCP-1 (CCL2), and interleukin- 18 (IL- 18); and, wherein the reference concentration is an average concentration of the biomarker measured in serum samples collected from at least 10 healthy subjects having the same age, gender, and / or ethnicity as the patient.
48. The method of claim 47, wherein at least two biomarkers having a concentration equal to or less than a reference concentration indicates that the patient is likely to be responsive to ALS treatment.49 The method of claim 48, wherein the at least two or more biomarkers are CCL2 and IL-18.
50. The method of any one of claims 47-49, wherein the ALS therapy comprises Relyvrio (AMXOO35), edaravone, riluzole, Treg infusion, IL-2, or any combination thereof.
51. The method of claim 50, wherein the ALS therapy is a Treg infusion, IL-2, or a combination thereof.