# US 11,110,111 B2 · Deoxynucleoside therapy for diseases caused by unbalanced nucleotide pools including mitochondrial DNA depletion syndromes > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,110,111 B2 - Document ID: US11110111B2 - Status: Granted - Kind: B2 - Application number: 16/583,852 - Filed: 2019-09-26 - Published: 2020-02-06 - Granted: 2021-09-07 - Earliest claimed: 2015-06-17 - Assignees: The Trustees of Columbia University in the City of New York - Applicants: The Trustees of Columbia University in the City of New York - Inventors: Michio Hirano; Caterina Garone; Ramon Marti - Web page: https://patentgrep.com/patent/US11110111B2 ## CPC - A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine - A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration} - A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine - A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid - 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 21/00: Drugs for disorders of the muscular or neuromuscular system - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - 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 invention relates generally to a pharmacological therapy for human genetic diseases, specifically those characterized by unbalance nucleotide pools, more specifically mitochondrial DNA depletion syndromes, and more specifically, thymidine kinase 2 (TK2) deficiency. The pharmacological therapy involves the administration of at least one deoxynucleoside, or mixtures thereof. For the treatment of TK2 deficiency, the pharmacological therapy involves the administration of either deoxythymidine (dT) or deoxycytidine (dC), or mixtures thereof. This administration of deoxynucleosides is applicable to other disorders of unbalanced nucleotide pools, especially those found in mitochondrial DNA depletion syndrome. ## Claims ### Claim 1 A method of treating mitochondrial DNA depletion syndrome in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one deoxynucleoside, wherein the mitochondrial DNA depletion syndrome is characterized by at least one mutation in a gene chosen from the group consisting of: DGUOK; TYMP; and RRM2B, and the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day. ### Claim 2 (depends on 1) The method of claim 1, wherein the composition comprises two or more deoxynucleosides. ### Claim 3 (depends on 1) The method of claim 1, wherein the deoxynucleoside is chosen from the group consisting of deoxycytidine (dC), deoxythymidine (dT), deoxyadenosine (dA), deoxyguanosine (dG), and mixtures thereof. ### Claim 4 A method of treating mitochondrial DNA depletion syndrome in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one deoxynucleoside, wherein the mitochondrial DNA depletion syndrome is characterized by at least one mutation in a gene chosen from the group consisting of: DGUOK; TYMP; and RRM2B, and the therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day. ### Claim 5 A method of treating mitochondrial DNA depletion syndrome in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one deoxynucleoside, wherein the mitochondrial DNA depletion syndrome is characterized by at least one mutation in a gene chosen from the group consisting of: DGUOK; TYMP; and RRM2B, and, the therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day. ### Claim 6 (depends on 1) The method of claim 1, wherein the composition comprises more than one deoxynucleoside and the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of each deoxynucleoside in the composition. ### Claim 7 (depends on 1) The method of claim 1, wherein the composition comprises more than one deoxynucleoside and the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of the total deoxynucleoside in the composition. ### Claim 8 (depends on 1) The method of claim 1, wherein the composition is administered once daily, twice daily, three times daily, four times daily, five times daily or six times daily. ### Claim 9 (depends on 1) The method of claim 1, wherein the composition is administered orally, intrathecally, enterally, or intravenously. ### Claim 10 (depends on 9) The method of claim 9, wherein the composition is administered orally and comprises one or more deoxynucleosides mixed with cow's milk, human breast milk, infant formula or water. ### Claim 11 (depends on 1) The method of claim 1, further comprising administering to the subject an additional agent chosen from the group consisting of an inhibitor of thymidine phosphorylase and an inhibitor of cytidine deaminase. ### Claim 12 (depends on 1) The method of claim 1, wherein the therapeutically effective amount of the composition administered to the subject is increased over time. ### Claim 13 (depends on 12) The method of claim 12, wherein a first therapeutically effective amount of the composition administered to the subject is about 100 mg/kg/day of composition, and wherein the therapeutically effective amount of the composition is increased over time to 200 mg/kg/day, to 400 mg/kg/day, to 800 mg/kg/day, up to 1000 mg/kg/day. ### Claim 14 (depends on 1) The method of claim 1, wherein the composition comprises a pharmaceutically acceptable carrier. ### Claim 15 (depends on 1) The method of claim 1, further comprising monitoring the subject for an adverse effect after the administration of the composition, wherein if an adverse effect is observed, the therapeutically effective amount of the composition is decreased. ### Claim 16 (depends on 15) The method of claim 15, further comprising monitoring the subject for the observed adverse effect after the therapeutically effective amount of the composition is decreased, wherein if the adverse effect is no longer observed, the therapeutically effective amount of the composition is increased.