# US 11,998,551 B2 · Treatment of mitochondrial diseases > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,551 B2 - Document ID: US11998551B2 - Status: Granted - Kind: B2 - Application number: 17/728,698 - Filed: 2022-04-25 - Published: 2023-03-02 - Granted: 2024-06-04 - Earliest claimed: 2015-06-05 - Assignees: Fundació Hospital Universitari Vall D'Hebron—Institut De Recerca; Centro De InvestigacióN BioméDica En Red - Applicants: Fundació Hospital Universitari Vall D'Hebron-Institut De Recerca; Centro De InvestigacióN BioméDica En Red - Inventors: Ramon Martí Seves; Emiliano González Vioque; Cora Blázquez Bermejo; Javier Torres Torronteras; Raquel Cabrera Pérez; Yolanda Cámara Navarro - Web page: https://patentgrep.com/patent/US11998551B2 ## CPC - A61K 31/52: Purines, e.g. adenine - A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid - A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine - A61K 31/7076: containing purines, e.g. adenosine, adenylic acid - A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 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 the step of administering a therapeutically effective amount of a composition comprising deoxycytidine and deoxythymidine to a subject in need thereof, thereby treating the mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in the POLG1 protein, and wherein the deoxycytidine and deoxythymidine are present in the composition in equal amounts by weight. ### Claim 2 (depends on 1) The method according to claim 1, wherein the one or more mutations are selected from the group consisting of R309C, W748S, V1177L, G848S, E1143, and E1143G or combinations thereof, the positions being referred with respect to SEQ ID NO: 1. ### Claim 3 (depends on 1) The method of claim 1, wherein the one or more mutations in the POLG1 protein are located in the POLG1 exonuclease domain, the POLG1 polymerase domain, the POLG1 linker region, or combinations thereof. ### Claim 4 (depends on 3) The method of claim 3, wherein the one or more mutations in the POLG1 protein are located in the POLG1 exonuclease domain. ### Claim 5 (depends on 3) The method of claim 3, wherein the one or more mutations in the POLG1 protein are located in the POLG1 polymerase domain. ### Claim 6 (depends on 3) The method of claim 3, wherein the one or more mutations in the POLG1 protein are located in the POLG1 linker region. ### Claim 7 (depends on 1) The method according to claim 1, wherein the composition further comprises one or more pharmaceutically acceptable inhibitors of degradation of deoxynucleosides. ### Claim 8 (depends on 7) The method according to claim 7, wherein the pharmaceutically acceptable inhibitor is an inhibitor of deoxyadenosine degradation. ### Claim 9 (depends on 8) The method of claim 8, wherein the inhibitor of deoxyadenosine degradation is erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). ### Claim 10 (depends on 1) The method of claim 1, wherein the treating comprises acceleration in the subject's mitochondrial DNA (mtDNA) polymerization rate. ### Claim 11 (depends on 1) The method of claim 1, wherein the subject has a clinical phenotype selected from the group consisting of autosomal recessive and dominant adult-onset progressive external ophthalmoplegia (PEO), myoclonic epilepsy, myopathy, sensory ataxia (MEMSA) syndrome, mitochondrial recessive ataxia syndrome (MIRAS), sensory ataxia, neuropathy, dysarthria, ophthalmoplegia (SANDO) syndrome, hepatocerebral MDS (Alpers-Huttenlocher syndrome), and mitochondrial genome maintenance exonuclease 1 (MNGIE) in the absence of leukoencephalopathy. ### Claim 12 (depends on 1) The method of claim 1, wherein the subject has Alpers-Huttenlocher syndrome. ### Claim 13 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 the step of administering a therapeutically effective amount of a composition comprising deoxycytidine and deoxythymidine to a subject in need thereof, thereby treating the mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in the POLG1 protein, wherein the deoxycytidine and deoxythymidine are present in the composition in an equimolar ratio. ### Claim 14 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 the step of administering a therapeutically effective amount of a composition comprising deoxycytidine and deoxythymidine to a subject in need thereof, thereby treating the mitochondrial DNA depletion and/or deletion syndrome due to one or more mutations in the POLG1 protein, wherein the deoxycytidine and deoxythymidine are present in the composition in equimolar amounts. ### Claim 15 (depends on 1) The method of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients or carriers. ### Claim 16 (depends on 1) The method of claim 1, wherein the composition is formulated for delivery by a method selected from the group consisting of oral delivery, rectal delivery, parenteral delivery, delivery by inhalation, topical delivery or ophthalmic delivery. ### Claim 17 A method of increasing mtDNA levels in vivo, comprising administering a composition comprising deoxycytidine and deoxythymidine, and optionally 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, wherein deoxycytidine and deoxythymidine are present in the composition in equal amounts by weight.