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METHODS OF TREATING OR PREVENTING NEUROLOGICAL DISEASESJan 4, 2019 -
Mesoblast, Inc.The present disclosure provides a method for treating an inflammatory neurological disease comprising administering a population of cells enriched for STRO-1+ cells and/or progeny thereof and/or soluble factors derived therefrom.
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Description ·
Claims ·
Patent History ·
Patent HistoryDescription
RELATED APPLICATIONThis application claims priority from U.S. patent application Ser. No. 61/493,073 entitled “Methods of treating or preventing neurological diseases”, filed on 3 Jun. 2011. The entire contents of that application are hereby incorporated by reference.
SEQUENCE LISTINGA sequence listing is filed in electronic form with this application. The entire contents of the sequence listing is hereby incorporated by reference.
FIELDThe present disclosure relates to methods for treating or preventing neurological diseases.
BACKGROUNDInflammatory neurological diseases are a class of conditions in which a subject's immune system targets or attacks components of the neurological system. These diseases can result from the immune system attacking, for example, neurons, Schwann cells or other cells of the nervous system myelin or neurotransmitters. In some cases, the inflammatory neurological disease may be a complication or a component of an existing disease, e.g., Exemplary inflammatory neurological diseases include multiple sclerosis, systemic lupus erythematosus (SLE), Guillain-Barre syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, transverse myelitis, leukodystrophy or progressive multifocal leukoencephalopathy.
MS is one of the more common inflammatory neurological diseases. It is an inflammatory and demyelinating degenerative disease of the human central nervous system (CNS). It is a worldwide disease that affects approximately 300,000 people in the United States alone. The majority of people affected by MS (about 70%-80% of cases) show onset between 20 and 40 years of age. MS is a heterogeneous disorder based on clinical course, magnetic resonance imaging (MRI) scan assessment, and pathology analysis of biopsy and autopsy material. The disease manifests itself in a large number of possible combinations of deficits, including spinal cord, brainstem, cranial nerve, cerebellar, cerebral, and cognitive syndromes. Progressive disability is the fate of most patients with MS. About half of MS patients require a cane to walk within 15 years of disease onset.
MS presents in most cases (about 80%) with clinical relapses characterized by fully or partially-reversible focal neurological deficits. This form of MS is known as relapsing-remitting MS (RRMS), and is dominated by inflammation and oedema. Active inflammation of the CNS is visualized as gadolinium enhancing white matter lesions on MRI. After a median of about 39 years, about half of RRMS cases gradually accumulate irreversible neurologic deficits in the absence of clinical relapses or new white matter lesions as detected by MRI. This stage of disease is known as secondary progressive MS (SPMS) or chronic disease. The 20% of patients who do not present with RRMS present with progressive clinical deterioration from the onset of disease, which is known as primary progressive MS (PPMS), which is another form of chronic disease.
Currently, acute MS relapses are usually treated with high-dose, short-term intravenous corticosteroids. This treatment shortens relapse duration but does not improve the degree of recovery or the long-term course of disease. There are currently several approved disease-modifying therapies approved in USA, which are intended to lower the clinical relapse rate, extend the time to next relapse and/or reduce the accumulation of new lesions on MRI. However, these therapies are only moderately effective for treating MS, particularly during the relapsing-remitting phase. These treatments also merely retard the progression of disease and do not result in remyelination.
SLE is an inflammatory disease affecting various organ systems in the body. Subjects suffering from SLE can develop various neurological disorders such as headaches, personality changes, organic brain syndrome, peripheral neuropathies, sensory neuropathy, psychological problems including paranoia, mania, and schizophrenia, seizures, transverse myelitis, and paralysis and stroke. Some of these changes can be brought on by antiphospholipid antibodies (e.g., anti-cardiolipin antibodies), which can bind to cells of the central nervous system and disrupt function and/or thrombosis.
Common pharmalogical treatments for lupus include the use of corticosteroids or immunosuppressive drugs, both of which have undesirable side effects and merely treat the symptoms as they occur.
Other inflammatory neurological diseases are treated using, for example, immunosuppressive drugs, corticosteroids, plasmapheresis or intravenous immunoglobulin, each of which carry a risk of infection or other adverse side effect.
It will therefore be apparent to those skilled in the art that there is a need in the art for new therapies useful for treating inflammatory neurological diseases.
SUMMARYThe inventors have studied the effect of STRO-1
+ multipotential cell preparations in an accepted animal models of an inflammatory neurological disease, i.e., chronic paralytic experimental inflammatory encephalomyelitis (EAE). The inventors found that STRO-1
+ cells administered after induction of EAE reduced the severity of the disease.
The inventors also found that STRO-1
+ cells prevented an immune response against an antigen by T cells derived from an animal previously immunized with the antigen.
The present disclosure provides a method for treating or preventing an inflammatory neurological disease, the method comprising administering to the subject a population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom.
In one example, the inflammatory neurological disease is associated with or caused by a T cell response to an inflammatory stimulus.
In one example, the method comprises administering a population of cells enriched for STRO-1
bright cells and/or progeny thereof and/or soluble factors derived therefrom.
In one example, the inflammatory neurological disease is selected from the group consisting of multiple sclerosis, systemic lupus erythematosus, Guillain-Barre syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, transverse myelitis, leukodystrophy and progressive multifocal leukoencephalopathy.
In one example, the disease is systemic lupus erythematosus.
In another example, the disease is multiple sclerosis. In one example, the disease is a chronic progressive form of multiple sclerosis. In another example, the disease is a relapsing-remitting form of multiple sclerosis.
In one example, the method comprises administering a population of cells enriched for STRO-1
bright cells and/or progeny thereof and/or soluble factors derived therefrom. In one example, the progeny are additionally enriched for STRO-1
bright cells.
Exemplary cells and/or progeny additionally express tissue non-specific alkaline phosphatase (TNAP) and/or heat shock protein 90β (HSP90β
and/or CD146.
In one example, the population of cells is derived from bone marrow or dental pulp.
In one example, the population enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom are administered systemically. For example, the population of cells enriched for Stro-1
+ cells and/or progeny cells thereof and/or soluble factors derived therefrom may be administered intravenously, intra-arterially, intramuscularly, subcutaneously, into an aorta, into an atrium or ventricle of the heart or into a blood vessel connected to an organ affected by the inflammatory neurological disease. For example, the population and/or progeny and/or soluble factors are administered intravenously.
In another example, the population enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom are administered into cerebral spinal fluid or into the central nervous system.
In a further example, the population enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom are administered to a site of disease, e.g., to a site of myelin degeneration.
In the case of a relapsing-remitting disease (e.g., relapsing-remitting MS), the cells can be administered during disease relapse to prevent or delay relapse of the disease.
In one example, the method comprises administering an effective amount of the population enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom. In one example, the effective amount is an amount sufficient to increase the number of regulatory T (Treg) cells in the subject and/or at the site of pathogenesis.
An exemplary method described herein according to any example, comprises administering a dose of the population and/or the progeny and/or the soluble factors sufficient to improve a clinical measure of the inflammatory neurological disease and/or to reduce or prevent an immune response against an antigen associated with the inflammatory neurological disease.
In one example, the method comprises administering an effective dose or a therapeutically effective dose of the population and/or progeny and/or soluble factors.
In one example, the method comprises administering between 1×10
4 to 5×10
6 STRO-1
+ cells and/or progeny thereof per kg. For example, the method comprises administering between 1×10
5 to 1×10
6 STRO-1
+ cells and/or progeny thereof per kg. For example, the method comprises administering between 2×10
5 to 8×10
5 STRO-1
+ cells and/or progeny thereof per kg. For example, the method comprises administering about 2×10
5 STRO-1
+ cells and/or progeny thereof per kg or about 4×10
5 STRO-1
+ cells and/or progeny thereof per kg or about 8×10
5 STRO-1
+ cells and/or progeny thereof per kg.
In one example, a method described herein according to any example, comprises administering a low dose of STRO-1
+ cells and/or progeny thereof. For example, the low dose of STRO-1
+ cells and/or progeny thereof comprises between 1×10
3 and 3×10
5 STRO-1
+ cells and/or progeny thereof per kg.
In one example, the population and/or the progeny and/or the soluble factors are administered a plurality of times. For example, the population and/or the progeny and/or the soluble factors are administered a plurality of times in one week or once every four or more weeks.
In one example, the population and/or the progeny and/or the soluble factors are administered during a remission of an inflammatory neurological condition.
In another example, the population enriched for STRO-1
+ cells and/or progeny thereof are genetically-engineered to express a molecule to block stimulation of T cells and/or the soluble factors are from such genetically-modified cells.
In another example, the population enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors therefrom are administered with a compound to block stimulation of T cells.
The population enriched for STRO-1
+ cells and/or progeny cells can be autogeneic or allogeneic and/or the soluble factors can be derived from autogeneic or allogeneic cells. In one example, the population of cells and/or progeny cells are allogeneic and/or the soluble factors are derived from autogeneic cells.
In one example, the population enriched for STRO-1
+ cells and/or progeny cells have been culture expanded prior to administration and/or prior to obtaining the soluble factors.
In another example, a method described herein further comprises administering an immunosuppressive agent. The immunosuppressive agent may be administered for a time sufficient to permit said transplanted cells to be functional.
The present disclosure also provides a method for preventing an immune response in response to an antigen, the method comprising administering to the subject a population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom.
In one example, the immune response is a T cell-mediated immune response. An exemplary T cell-mediated immune response comprises T cell proliferation.
In one example, the T cell-mediated immune response is suppressed in response to a specific antigen and a T cell-mediated immune response in response to another antigen is not suppressed.
In one example, the subject has previously raised an immune response to the antigen and the population, progeny and/or soluble factors suppress a further immune response to the antigen.
In one example, the population, progeny and/or soluble factors are administered after the subject raises an immune response to the antigen to thereby prevent a further immune response to the antigen.
In one example, the immune response is suppressed for at least about 24 days following administration of the population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom.
The present disclosure also provides a method for inducing tolerance to an antigen in a subject, the method comprising administering to the subject a population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom.
In one example of a method described herein the antigen or the specific antigen is one against which an inflammatory response is raised. For example, the inflammatory response is causative of an inflammatory neurological disease.
In one example of a method described herein according to any example, the population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom is administered with a compound that treats or prevents an inflammatory neurological disease. An exemplary compound is glatiramer acetate and/or beta interferon.
The compound can be mixed with the population and/or progeny and/or soluble factors or administered at the same time and/or administered before or after the population and/or progeny and/or soluble factors (e.g., such that the compound and the population and/or progeny and/or soluble factors are providing a benefit at the same time).
The present disclosure also provides a population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom for use in the treatment or prevention of an inflammatory neurological disease and/or for suppressing a T cell-mediated immune response against an antigen and/or for inducing tolerance to an antigen.
The present disclosure also provides for use of a population of cells enriched for STRO-1
+ cells and/or progeny thereof and/or soluble factors derived therefrom in the manufacture of a medicament for treating or preventing an inflammatory neurological disease and/or for suppressing a T cell-mediated immune response against an antigen and/or for inducing tolerance to an antigen.
Each example of the disclosure shall be taken to apply mutatis mutandis to a method for reducing, delaying or preventing myelin destruction and/or an inflammatory response against myelin or a component thereof.
Each example of the disclosure shall be taken to apply mutatis mutandis to inflammation in the nervous system or a component thereof,
Each example of the disclosure shall be taken to apply mutatis mutandis to a method for inducing or promoting remyelination or neurite outgrowth.
ResultsControl C57B1/6J mice display similar phenotypic symptoms (progressive paralysis) to that of MS patients as well as showing extensive inflammation, demyelination and axonal loss/damage in the CNS.
As shown in FIG. 4, intravenously administered MPCs administered at the onset of EAE disease induction are able to inhibit the severity of the mean clinical disease scores over the course of 36 days compared to EAE animals treated with PBS.
FIG. 5 shows that MPC treatment induces a dose-dependent reduction in cumulative disease index in chronic progressive EAE (total area under the curve analysis of mean clinical disease score).
The effects of administration of the MPCs are summarized in Table 6:
TABLE 6 Summary of clinical outcome in mouse EAE model following treatment with MPCs Total MPC dose Total MPC dose 0.6 × 10
5 1.2 × 10
5 PBS (3 × 10
6 MPC/kg) (6 × 10
6 MPC/kg) Disease incidence 12/12 5/5 5/5 Day disease onset 13.92 ± 0.54 11.6 ± 0.6 13.8 ± 0.97 (range) (11-18) (10-13) (12-17) Death or severe 3/12 (25) 0/5 (0) 0/5 (0) disease (%) Maximum clinical 3.5 ± 0.26 3 2.6 ± 0.4 score Cumulative disease 62 ± 5.8 55.7 ± 2.1 44.3 ± 4.4 index (Area under curve)
Data in Table 6 show that all animals demonstrate neurological disease between 10-18 days following induction of EAE with MOG peptide 35-55. 25% (3/12) of control animals treated with PBS died in comparison to 0/15 animals treated with MPC The maximum clinical score was the highest in the control group and all MPC treated groups showed a lower maximal clinical score
The cumulative disease index which is the area under the curve (AUC) for the mean clinical score for the duration of 36 days were all lower for the MPC therapy groups compared to that observed for the control group indicating a robust and sustained EAE disease suppression by MPC.
These data show that in this model of a human inflammatory neurological condition human MPCs are effective in reducing the clinical severity of EAE.
Example 4Effect of MPCs on T Cell ProliferationMPC-treated mice and controls as described in Example 3 were culled on day 36 after disease induction (MOG35-55 immunization). Splenocytes were cultured in vitro with media alone or re-stimulated with MOG
35-55 and then T-cell proliferative responses were measured through [
3H]-thymidine incorporation. The specific proliferative responses to MOG were compared to the matched splenocytes cultured in media-alone (unstimulated). Splenocytes cultured in PMA/Ionomycin served to determine the non-specific (antigen-independent) stimulation of T cell proliferation.
Data presented in FIG. 6 demonstrate that T cell immune responses to secondary in vitro antigenic challenge with MOG are inhibited in comparison to T cells cultured from control animals. Data in FIG. 7 show that T cell immune responses in animals previously treated with MPC in vivo maintain potent responses to non-specific stimulation with PMA/ionomycin in vitro in comparison to T cells cultured from PBS-treated control animals. This exaggerated response to non-specific stimulation may reflect the xenogenic response to human antigens by mouse T-cells.
These data show that human MPCs reduce or prevent T cell immune response to a specific antigen (e.g., antigenic stimulation by MOG), even 24 days after the last administration of MPCs. The data indicate that STRO-1 enriched MPC induce tolerance to multiple sclerosis antigens.
Example 6In Vitro Effects of MPCsThe immunoregulatory properties of MPC are tested by proliferation assays, mixed lymphocyte reactions and cytokines production as described below.
Claims1. A method for improving motor function or delaying disease progression in a subject suffering from an inflammatory neurological disease, the method comprising administering to the subject a population of cells enriched for STRO-1+ multipotential cells.
2. The method of claim 1, wherein the inflammatory neurological disease is associated with or caused by a T cell response to an inflammatory stimulus.
3. The method of claim 1 comprising administering a population of cells enriched for STRO-1bright multipotential cells.
4. The method of claim 1, wherein the inflammatory neurological disease is selected from the group consisting of multiple sclerosis, systemic lupus erythematosus, Guillain-Barre syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, transverse myelitis, leukodystrophy and progressive multifocal leukoencephalopathy.
5. The method of claim 1, wherein the disease is systemic lupus erythematosus or multiple sclerosis.
6-7. (canceled)
8. The method of claim 1, wherein the population enriched for STRO-1+ multipotential cells is administered systemically.
9. (canceled)
10. The method of claim 1, comprising:
(i) administering an amount of the population enriched for STRO-1+ multipotential cells effective to increase the number of regulatory T (Treg) cells in the subject and/or at the site of pathogenesis of the disease;
(ii) administering between 2×106 to 8×106 STRO-1+ multipotential cells per kg;
(iii) administering between 3×106 to 6×106 STRO-1+ multipotential cells per kg; or
(iv) administering a low dose of STRO-1+ multipotential cells, wherein the low dose of STRO-1+ multipotential cells comprises between 0.1×106 and 3×106 STRO-1+ multipotential cells per kg or comprises about 3×106 STRO-1+ multipotential cells per kg.
11-15. (canceled)
16. The method of claim 1, wherein the population enriched for STRO-1+ multipotential cells are administered once weekly or less often or are administered once every four weeks or less often.
17. (canceled)
18. The method of claim 1, wherein the population enriched for STRO-1+ multipotential cells are genetically-engineered to express a molecule to block stimulation of T cells and/or the soluble factors are from such genetically-modified cells or wherein the population enriched for STRO-1+ multipotential cells are administered with a compound to block stimulation of T cells.
19. (canceled)
20. The method of claim 1, wherein the population enriched for STRO-1+ multipotential cells are autogeneic or allogeneic.
21. The method of claim 1, wherein the population enriched for STRO-1+ multipotential cells have been culture expanded prior to administration.
22. A method for preventing an immune response in response to an antigen, the method comprising administering to the subject a population of cells enriched for STRO-1+ multipotential cells.
23. The method of claim 22, wherein the immune response is a T cell-mediated immune response.
24. (canceled)
25. The method of claim 22, wherein the T cell-mediated immune response is suppressed in response to a specific antigen and a T cell-mediated immune response in response to another antigen is not suppressed.
26. The method of claim 22, wherein the subject has previously raised an immune response to the antigen and the population suppresses a further immune response to the antigen.
27. The method of claim 26, comprising administering the population after the subject raises an immune response to the antigen to thereby prevent a further immune response to the antigen.
28. The method of claim 22, wherein the immune response is suppressed for at least about 24 days following administration of the population of cells enriched for STRO-1+ multipotential cells.
29. A method for inducing tolerance to an antigen in a subject, the method comprising administering to the subject a population of cells enriched for STRO-1+ multipotential cells.
30. The method of claim 22, wherein the antigen is one against which an inflammatory response is raised.
31. The method of claim 30, wherein the inflammatory response is causative of an inflammatory neurological disease.
32. The method of claim 1, wherein the population of cells enriched for STRO-1+ multipotential cells is administered with a compound that treats or prevents an inflammatory neurological disease.
33-35. (canceled)
Patent History
Publication number: 20190201448
Type: Application
Filed: Jan 4, 2019
Publication Date: Jul 4, 2019
Applicant:
Mesoblast, Inc. (New York, NY)
Inventor:
Claude BERNARD (Clayton)
Application Number: 16/240,344
Classifications
International Classification: A61K 35/28 (20060101); C12N 5/0775 (20060101); A61K 38/21 (20060101);
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