Treatment of mitochondrial diseases
Inventors
MARTÍ SEVES, Ramon • GONZÁLEZ VIOQUE, Emiliano • BLÁZQUEZ BERMEJO, Cora • TORRES TORRONTERAS, Javier • CABRERA PÉREZ, Raquel • CÁMARA NAVARRO, Yolanda
Assignees
Fundacio Hospital Universitari Vall D'hebron Institut De Recerca • Centro de Investigacion Biomedica en Red CIBER • Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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Publication Number
US-11998551-B2
Publication Date
2024-06-04
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 invention describes a therapy for treating mitochondrial DNA depletion and/or deletion syndromes caused by one or more mutations in the DNA polymerase subunit gamma-1 (POLG1) protein. It addresses mitochondrial diseases (MODS), including mitochondrial DNA depletion syndrome and mitochondrial DNA multiple deletion syndrome, where mtDNA loss is not due to dNTP metabolism defects.
The method comprises administering a therapeutically effective amount of a composition comprising deoxycytidine and deoxythymidine to a subject in need thereof, where the deoxycytidine and deoxythymidine are present in equal amounts by weight. The treatment is reported to restore mtDNA copy number to healthy-like levels and to treat mtDNA deletions in patient-derived fibroblasts carrying POLG mutations.
Canonical deoxyribonucleosides also demonstrate effects consistent with enhanced POLG activity and acceleration of mtDNA recovery following mtDNA depletion. The disclosure further includes formulation and delivery route options and optional co-administration of nucleoside-catabolism inhibitors to support nucleoside stability, including EHNA and other named inhibitors.
Claims Coverage
The independent claim coverage centers on a POLG1-mutation-associated mitochondrial DNA depletion/deletion syndrome treatment using an equal-weight composition of deoxycytidine and deoxythymidine. The further claim features refine the mutation set, add mtDNA polymerization-rate acceleration, restrict the patient phenotype, and specify delivery routes and optional nucleoside-catabolism inhibition including EHNA.
Equal-weight deoxycytidine and deoxythymidine composition for POLG1 mutation treatment
A method for treating a mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in the DNA polymerase subunit gamma-1 (POLG1) protein by administering a therapeutically effective amount of a composition comprising deoxycytidine and deoxythymidine to a subject in need thereof, wherein the deoxycytidine and deoxythymidine are present in equal amounts by weight.
POLG1 mutation selection
The method specifies the POLG1 mutations as one or more mutations chosen from R309C, W748S, V1177L, G848S, E1143, and E1143G, alone or in combination, with mutation positions defined relative to SEQ ID NO: 1.
Accelerating mitochondrial DNA polymerization rate
The method further includes treatment that accelerates the subject’s mitochondrial DNA (mtDNA) polymerization rate.
Selected clinical phenotype restriction (with absence of leukoencephalopathy)
The method is applied to a subject having a clinical phenotype selected from specified genetic and neurologic conditions, specifically in the absence of leukoencephalopathy.
Specified delivery routes
The composition is formulated for delivery using one of the selected routes: oral, rectal, parenteral, inhalation, topical, or ophthalmic delivery.
Optional inhibition of deoxynucleoside degradation using EHNA
The method uses erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) as the inhibitor of deoxyadenosine degradation.
Across the independent claim and its refinements, the core coverage is treatment of POLG1-mutation-associated mitochondrial DNA depletion/deletion syndrome by administering an equal-weight deoxycytidine/deoxythymidine composition, with further limitations on POLG1 mutation variants, an mtDNA polymerization-rate acceleration effect, restricted clinical phenotypes, specified delivery routes, and optional nucleoside-catabolism inhibition including EHNA.
Stated Advantages
Restores mtDNA copy number to healthy-like levels.
Treats mitochondrial DNA deletions.
Demonstrates enhanced POLG activity and acceleration of mtDNA recovery following mtDNA depletion.
Not dependent on dNTP metabolism defects.
Low cost.
No special storage requirements.
Documented Applications
Treatment of mitochondrial DNA depletion syndrome and mitochondrial DNA multiple deletion syndrome (MODS) due to POLG1 mutations.
Therapy applied in patient-derived fibroblasts carrying POLG mutations, with mtDNA copy number recovery and mtDNA deletion treatment described.
Use in additional MODS cases described as caused by other replication machinery/nucleotide-related gene defects by hyperstimulating polymerase gamma activity.
Formulation/delivery using oral, rectal, parenteral, inhalation, topical, or ophthalmic delivery routes.
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