P38 map kinase inhibitors for treating Friedreich's ataxia
Inventors
Wilson, Robert B. • Cotticell, Maria Grazia • Wang, Yongping • XIA, Shujuan • Kaur, Avinash • Tobias, John W.
Assignees
University of Pennsylvania Penn
Publication Number
US-12370180-B2
Publication Date
2025-07-29
Expiration Date
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Abstract
The invention provides p38 MAPK inhibitors that compensate for a frataxin deficiency or mutation and methods of using the same (e.g., to treat Friedreich's ataxia).
Core Innovation
The invention provides p38 mitogen-activated protein kinase (MAPK) inhibitors that compensate for a frataxin deficiency or mutation and methods of using the same, for example, to treat Friedreich's ataxia. In one aspect, methods for treating a subject at risk for developing Friedreich's ataxia or suffering from Friedreich's ataxia or reducing the symptoms thereof comprise administering to the subject a therapeutically effective amount of a p38 MAPK inhibitor. In another aspect, methods for compensating for a frataxin deficiency or mutation in a subject comprise administering to the subject a therapeutically effective amount of a p38 MAPK inhibitor. The invention also provides methods for compensating for a frataxin deficiency or mutation in a cell by administering an effective amount of a p38 MAPK inhibitor, and contemplates in vitro, in vivo, and ex vivo administration.
The background describes that mitochondrial dysfunction contributes to the pathology of numerous diseases and specifically that Friedreich's ataxia is an autosomal recessive disease caused by a triplet (GAA) repeat expansion in the first intron of the frataxin (FXN) gene leading to decreased frataxin protein levels. The decrease in frataxin function results in decreased iron-sulfur-cluster (ISC) assembly associated with mitochondrial dysfunction, mitochondrial iron accumulation, cytosolic iron depletion, and increased oxidative stress. The specification states there are currently no approved treatments for Friedreich's ataxia, and the invention addresses methods and compositions to compensate for frataxin deficiency or mutation and to treat or reduce symptoms of Friedreich's ataxia.
Claims Coverage
Five inventive features corresponding to independent method claims directed to therapeutic and cellular uses of p38 MAPK inhibitors are identified.
Administration of p38 MAPK inhibitors for treating Friedreich's ataxia
A method for treating a subject at risk for developing Friedreich's ataxia or suffering from Friedreich's ataxia or reducing the symptoms thereof comprising administering to the subject a therapeutically effective amount of a p38 MAPK inhibitor or a pharmaceutical composition thereof, wherein the p38 MAPK inhibitor is selected from a listed group of p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof.
Use of p38 MAPK inhibitors to compensate for frataxin deficiency or mutation in a subject
A method for compensating for a frataxin deficiency or mutation in a subject comprising administering to the subject a therapeutically effective amount of a p38 MAPK inhibitor or a pharmaceutical composition thereof, wherein the p38 MAPK inhibitor is selected from a listed group of p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof.
Compensation for frataxin deficiency or mutation in primary fibroblast cells
A method for compensating for a frataxin deficiency or mutation in a primary fibroblast cell comprising administering to the primary fibroblast cell an effective amount of a p38 MAPK inhibitor selected from a listed group of p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof.
Increasing frataxin gene expression or a phenotype thereof by p38 MAPK inhibition
A method for increasing frataxin gene expression or a phenotype thereof in a cell having a frataxin deficiency or mutation, comprising administering to the cell an effective amount of a p38 MAPK inhibitor or a pharmaceutically acceptable derivative thereof, wherein the p38 MAPK inhibitor is selected from a listed group of p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof.
Altering cytokine expression or secretion using p38 MAPK inhibitors
A method for altering cytokine expression or secretion in a cell having a frataxin deficiency or mutation, comprising administering to the cell an effective amount of a p38 MAPK inhibitor or a pharmaceutically acceptable derivative thereof, wherein the p38 MAPK inhibitor is selected from a listed group of p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof.
The independent claims cover administration of specified p38 MAPK inhibitors to treat Friedreich's ataxia, to compensate for frataxin deficiency or mutation in subjects and cells (including primary fibroblasts), to increase frataxin gene expression or related phenotypes, and to alter cytokine expression or secretion, with the p38 MAPK inhibitors recited as a defined group and pharmaceutically acceptable derivatives thereof.
Stated Advantages
Compensating for a frataxin deficiency or mutation in a subject or cell.
Treating a subject at risk for developing Friedreich's ataxia, suffering from Friedreich's ataxia, or reducing the symptoms thereof by administering p38 MAPK inhibitors.
Increasing frataxin gene expression or a phenotype thereof, which can produce decreases in iron accumulation, decreases in oxidative stress, or improvement of mitochondrial dysfunction, including increasing mitochondrial production of adenosine triphosphate (ATP).
Altering cytokine expression and/or secretion, including decreasing expression or secretion of cytokines such as IL6, IL8, GM-CSF, RANTES, IL1-beta, VEGF, MCP-1, IP10, and GRO.
Reversal of the growth defect of primary Friedreich's ataxia fibroblasts in mitochondrial stress medium by p38 MAPK inhibitors.
Anti-inflammatory activity of p38 MAPK inhibitors, including inhibition of the production of pro-inflammatory cytokines.
Documented Applications
Methods for treating a subject at risk for developing Friedreich's ataxia, suffering from Friedreich's ataxia, or reducing the symptoms thereof by administering a therapeutically effective amount of a p38 MAPK inhibitor.
Methods for compensating for a frataxin deficiency or mutation in a subject by administering a therapeutically effective amount of a p38 MAPK inhibitor.
Methods for compensating for a frataxin deficiency or mutation in a cell, including in vitro, in vivo, or ex vivo administration of a p38 MAPK inhibitor.
Methods for compensating for a frataxin deficiency or mutation in a primary fibroblast cell by administering a p38 MAPK inhibitor.
Methods for increasing frataxin gene expression or a phenotype thereof in a cell having a frataxin deficiency or mutation by administering a p38 MAPK inhibitor, including outcomes such as decreased oxidative stress, decreased mitochondrial iron, and increased mitochondrial ATP production.
Methods for altering cytokine expression or secretion in cells having a frataxin deficiency or mutation by administering p38 MAPK inhibitors, including decreasing levels of specified cytokines (IL6, IL8, GM-CSF, RANTES, IL1-beta, VEGF, MCP-1, IP10, and GRO).
Use of specific named p38 MAPK inhibitors and pharmaceutically acceptable derivatives thereof as therapeutic agents for the foregoing methods.
Formulation and administration of p38 MAPK inhibitors as pharmaceutical compositions with pharmaceutically acceptable carriers, diluents, binders, preservatives, various dosage forms, routes of administration, and controlled- or immediate-release embodiments.
Combination therapy embodiments comprising administration of p38 MAPK inhibitors in combination with one or more additional p38 MAPK inhibitors or with additional therapeutic agents.
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