Treatment of mitochondrial diseases
Inventors
MARTÍ SEVES, Ramon • GONZÁLEZ VIOQUE, Emiliano • BLÁZQUEZ BERMEJO, Cora • TORRES TORRONTERAS, Javier • CABRERA PÉREZ, Raquel • CÁMARA NAVARRO, Yolanda
Assignees
Centro de Investigacion Biomedica en Red CIBER • Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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Publication Number
US-11337980-B2
Publication Date
2022-05-24
Expiration Date
Abstract
The present invention provides a composition comprising one or more deoxyribonucleosides for use in the treatment of a mitochondrial DNA depletion and/or multiple deletions syndrome provided that the syndrome is not caused by a defect in the deoxyribonucleoside triphosphate (dNTP) metabolism. With the use of the invention there is a recovery in mitochondrial DNA levels independently from the severity of the patient's disease, which confers a great therapeutic value to the invention.
Core Innovation
The disclosed invention is a method for the treatment of a mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in POLG1 protein. The method comprises administering a therapeutically effective amount of a composition comprising deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine to a subject in need thereof, optionally with one or more pharmaceutically acceptable inhibitors of deoxynucleoside degradation.
The disclosed invention further provides a method of increasing mtDNA levels in vivo. This method comprises administering a composition comprising deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine to a cell having one or more mutations in the POLG1 protein, optionally with one or more pharmaceutically acceptable inhibitors of nucleoside degradation, thereby increasing the mtDNA level in vivo.
The provided context states that the approach uses canonical deoxyribonucleosides to restore mtDNA levels, and reports surprising findings in POLG-deficient patient fibroblasts, where mtDNA copy number recovers to healthy-order levels after depletion and subsequent post-withdrawal treatment with dNs and an inhibitor.
Claims Coverage
The document contains two independent claims. Across them, the coverage centers on treating POLG1 mutation-associated mitochondrial DNA depletion/deletion syndrome in a subject and increasing mtDNA levels in vivo in cells having POLG1 protein mutations by administering the four canonical deoxyribonucleosides, with optional inhibitors of nucleoside or deoxynucleoside degradation.
Treating POLG1 mutation-associated mitochondrial DNA depletion and/or deletion syndrome using a deoxyribonucleoside composition
A method for the treatment of a mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in the DNA polymerase subunit gamma-1 (POLG1) protein, comprising administering a therapeutically effective amount of a composition comprising deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine, optionally with one or more pharmaceutically acceptable inhibitors of deoxynucleoside degradation, to a subject in need thereof.
Increasing mtDNA levels in vivo in cells with POLG1 protein mutations using a deoxyribonucleoside composition
A method of increasing mtDNA levels in vivo, comprising administering a composition comprising deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine, optionally with one or more pharmaceutically acceptable inhibitors of nucleoside degradation, to a cell having one or more mutations in the POLG1 protein, thereby increasing the mtDNA level in vivo.
Overall, the claims cover POLG1-mutation-associated mitochondrial DNA depletion/deletion syndromes and in vivo mtDNA level increase by administering a composition of the four canonical deoxyribonucleosides, with optional pharmaceutically acceptable inhibitors of nucleoside or deoxynucleoside degradation.
Stated Advantages
Restores or increases mtDNA levels, with reported recovery of mtDNA copy number to healthy-order levels in POLG-deficient patient fibroblasts after depletion and post-withdrawal treatment with dNs plus an inhibitor.
Provides a treatment for mitochondrial DNA depletion and/or multiple deletions syndromes not caused by dNTP metabolism defects.
Documented Applications
Therapy for mitochondrial DNA depletion and/or deletion syndrome due to POLG1 protein mutations, including treatment of mitochondrial DNA depletion and multiple deletions syndromes not caused by dNTP metabolism defects.
In vivo increase of mtDNA levels by administering the deoxyribonucleoside composition to cells having one or more POLG1 protein mutations.
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