METHODS AND COMPOSITIONS FOR TREATING CYTOKINE STORM, ARDS, AND ACUTE LUNG INJURY USING BETA-GLUCOCEREBROSIDASE

Abstract

The present invention relates to methods and compositions for treating a subject with a condition selected from: i) an on-going cytokine storm, ii) acute respiratory distress syndrome (ARDS), and/or iii) acute lung injury (ALI), using a composition comprising β-glucocerebrosidase, or a vector encoding β-glucocerebrosidase. In certain embodiments, the condition is caused by COVID-19 virus infection or other viral infection.

Claims

1. A method of treating a subject comprising: administering or providing a composition to a subject, wherein said composition comprises β-glucocerebrosidase, and wherein said subject has a condition selected from: i) an on-going cytokine storm, ii) acute respiratory distress syndrome (ARDS), and/or iii) acute lung injury (ALI).

2. (canceled)

3. The method of claim 1, wherein said subject is a human.

4. The method of claim 1, wherein said condition is ALI.

5. The method of claim 1, wherein said condition is an on-going cytokine storm.

6. The method of claim 1, wherein said condition is ARDS.

7-8. (canceled)

9. The method of claim 1, wherein said composition is in the form of an aqueous solution and wherein said administering is via intravenous injection into said subject.

10. The method of claim 1, wherein said administering is via said subject's airway.

11. The method of claim 1, wherein said composition is administered via said subject's airway using a nebulizer or inhaler.

12-15. (canceled)

16. A system or kit comprising: a) an airway administration device, and b) a composition comprising β-glucocerebrosidase.

17. The system or kit of claim 16, wherein said airway administration device comprises an inhaler or nebulizer.

18. The system or kit of claim 16, wherein said composition is present inside said airway administration device.

Description

DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1. Treating COVID19 with glucocerebrosidase. Impaired respiratory capacity from virus infection leads to hypoxia, which upregulates the synthesis of β-glucosylceramide. Virus replication also induces cell death, resulting in subsequent release of β-glucosylceramide. β-glucosylceramide is an endogenous ligand recognized by a variety of immune cells, including macrophages, dendritic cells and neutrophils, serving as a danger signal to indicate tissue damage. Upon recognition of β-glucosylceramide, immune cells are activated to produce copious amount of cytokine, engendering cytokine storm and further tissue damage. This cycle results in a feedforward loop that amplifies lung injury and sustains cytokine production, culminating in cytokine storm and multi-organ failure in ARDS. Glucocerebrosidase is administered to a COVID-19 infected subject to reduce the cytokine storm and/or ARDS and acute lung injury.

DEFINITIONS

[0011] As used herein, the terms “host,” “subject” and “patient” refer to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, etc.) that is studied, analyzed, tested, diagnosed or treated. As used herein, the terms “host,” “subject” and “patient” are used interchangeably, unless indicated otherwise. In certain embodiments, the subject is a human (e.g., a human with a viral infection, such as COVID-19 infection or a human that otherwise has ARDS or ongoing cytokine storm or acute lung injury).

DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to methods and compositions for treating a subject with a condition selected from: i) an on-going cytokine storm, ii) acute respiratory distress syndrome (ARDS), and/or iii) acute lung injury (ALI), using a composition comprising β-glucocerebrosidase, or a vector encoding β-glucocerebrosidase. In certain embodiments, the condition is caused by COVID-19 virus infection or other viral infection.

[0013] Provided here is treatments using glucocerebrosidase, or a vector encoding glucocerebrosidase, for treating a subject with a cytokine storm, acute respiratory distress syndrome (ARDS) and/or acute lung injury (ALI), which are critical conditions that frequently culminate in death. Diseases in which aforementioned critical conditions may arise include, but are not limited to, viral infection-induced disease, such as SARS, MERS, COVID19, and flu; bacterial or fungal pneumonia; and therapy-induced cytokine storm and multi-organ failure such those seen in CAR-T therapies; lung injuries resulted from inhalation of smoke or toxic gas; and transfusion-related acute lung injury (TRALI).

[0014] There is no proven therapeutics that has demonstrated efficacy in preventing mortality in patients undergoing cytokine storm and ARDS, especially for patients with COVID19. In clinical practice, anti-IL-6 biologics are currently being used off label to treat patients whose serum cytokines register an exorbitant levels. At the time the cytokine storm sets in, multi-organ failure can reach an irreversible point, rendering therapeutic intervention aiming at controlling the cytokine storm futile.

[0015] The use of glucocerebrosidase, or a vector encoding glucocerebrosidase may be superior to current therapy as it targets an upstream biological event leading to the onset of cytokine storm and subsequent ARDS and multi-organ failure. Therefore, the intervention described by the current invention can prevent cytokine storm and multi-organ failure.

[0016] Gaucher's disease patients were shown to exhibit pulmonary manifestations, described as ground-glass opacity in CT scan. This radiologic feature is similar to the findings from patients with severe viral infection-associated pneumonia (e.g. COVID19). Gaucher's disease can be effectively treated by enzyme replacement therapy using recombinant human GBA, which removes the deposited β-GluCer. In addition to Gaucher's disease, accumulation of β-GluCer is also found in ischemic tissues. The synthesis of β-GluCer was shown to be regulated by O.sub.2 saturation, with hypoxic condition promoting the production of β-GluCer. Relevant to this regulatory mode, β-GluCer level is increased in the lung in response to stress. Bronchoalveolar lavage fluid of elastase-exposed mice (lung injury) showed elevated level of β-GluCer. Consistently, elevated level of β-GluCer is found in the bronchoalveolar lavage fluid of pneumonia patients undergoing acute respiratory distress syndrome. Additionally, obesity has been shown to increase the level of β-GluCer.

[0017] Mechanistically, β-GluCer is released by dying cells. Extracellular β-GluCer can be recognized by immune cells expressing a C-type lectin receptor, MINCLE. Activation of myeloid MINCLE pathway initiates NF-kB signaling and promotes the cytokine production, including IL-6, TNFa and IL-1β. In work conducted during development of the presnet invention, it was shown that β-GluCer can activate Mincle on T cells to drive Th17 polarization and drive Th17-mediated inflammation. As a result, increased level of β-GluCer can amplify inflammatory responses, leading to massive cell death and tissue damage.

[0018] Cytokine storm, or cytokine release syndrome is a fatal pathogenic event commonly seen in patients with sepsis, viral infection or drug reaction. The most famous disease where cytokine storm has been noted is COVID19, which is caused by the pathogen SARS-CoV2, a novel coronavirus. Representing an immune overdrive, cytokine storm often culminates in multi-organ failure and death. The trigger of cytokine storm varies from condition to condition. However, a feedforward loop that sustains and amplifies the production/release of cytokines is required to enable the production of copious amount of cytokine. Breaking the feedforward loop is required for attenuating the cytokine storm. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. ARDS is the leading cause of mortality in viral infection-induced diseases, including COVID19, SARS, MERS and flu. Known risk factor for ARDS include old age and overweight.

[0019] In certain embodiments, glucocerebrosidase, or a vector encoding glucocerebrosidase, are used administered to subject with COVID-19 infection or other respiratory virus infection. As shown in the hypothetical model in FIG. 1, impaired respiratory capacity from virus infection leads to hypoxia, which upregulates the synthesis of β-glucosylceramide. Virus replication also induces cell death, resulting in subsequent release of β-glucosylceramide. β-glucosylceramide is an endogenous ligand recognized by a variety of immune cells, including macrophages, dendritic cells and neutrophils, serving as a danger signal to indicate tissue damage. Upon recognition of β-glucosylceramide, immune cells are activated to produce copious amount of cytokine, engendering cytokine storm and further tissue damage. This cycle results in a feedforward loop that amplifies lung injury and sustains cytokine production, culminating in cytokine storm and multi-organ failure in ARDS.

[0020] In certain embodiments, provided here methods to treat cytokine storm and ARDS using recombinant glucocerebrosidase or a vector encoding glucocerebrosidase. In particular embodiments, the method involve infusion of a recombinant human glucocerebrosidase into patients at risk for or suffering from cytokine storm or ARDS. In certain embodiments, patients with the following conditions may be treated with the current invention: Viral infection-induced disease (e.g., SARS, MERS, COVID19, and flu), bacterial or fungal pneumonia; therapy-induced cytokine storm and multi-organ failure such those seen in CAR-T therapies; lung injuries resulted from inhalation of smoke or toxic gas; and transfusion-related acute lung injury (TRALI).

[0021] In one example, glucocerebrosidase, or a vector encoding glucocerebrosidase, is used to treat COVID-19 infection as shown in FIG. 1. COVID19 patients with mild symptoms who are deemed to be at a high risk of progression may be treated with infusion of recombinant glucocerebrosidase to prevent disease progression. The method of determining the risk for disease aggravation can be based on the attending physician's clinical assessment or based on a laboratory assay that determines (1) the level of β-GluCer in the blood or bronchoalveolar lavage fluid; and/or (2) serum cytokine levels. COVID19 patients with severe symptoms can be treated with infusion of recombinant glucocerebrosidase to prevent ARDS or cytokine release syndrome. COVID19 patients in critical condition may be treated with infusion of recombinant glucocerebrosidase as a rescuing therapy.

REFERENCES

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[0033] All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described compositions and methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the present invention.