Treatment of mitochondrial diseases
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.
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 deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine, and optionally one or more pharmaceutically acceptable inhibitors of deoxynucleoside degradation, 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.
2. The method according to claim 1 , wherein the composition comprises one or more pharmaceutically acceptable inhibitors of degradation of deoxynucleosides.
3. 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.
4. The method according to claim 1 , wherein the composition does not contain any further nucleoside.
5. The method according to claim 2 , wherein the pharmaceutically acceptable inhibitor is an inhibitor of deoxyadenosine degradation.
6. The method of claim 5 , wherein the inhibitor of deoxyadenosine degradation is erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA).
7. The method of claim 1 , wherein the one or more mutations in the POLG1 protein are located in the POLG1 exonuclease domain, the polymerase domain, the linker region or combinations thereof.
8. The method of claim 7 , wherein the one or more mutations in the POLG1 protein are located in the POLG1 exonuclease domain.
9. The method of claim 7 , wherein the one or more mutations in the POLG1 protein are located in the POLG1 polymerase domain.
10. The method of claim 7 , wherein the one or more mutations in the POLG1 protein are located in the POLG1 linker region.
11. The method of claim 1 , wherein the treating comprises acceleration in the subject's mtDNA polymerization rate.
12. The method of claim 1 , wherein the subject has a clinical phenotype selected from the group consisting of autosomal recessive and dominant adult-onset PEO, myoclonic epilepsy, myopathy, sensory ataxia (MEMSA) syndrome, ataxia-neuropathy spectrum including mitochondrial recessive ataxia syndrome (MIRAS), and sensory ataxia, neuropathy, dysarthria, ophthalmoplegia (SANDO) syndrome, and hepatocerebral MDS (Alpers-Huttenlocher syndrome) or features of MNGIE in the absence of leukoencephalopathy.
13. The method of claim 1 , wherein the subject has Alpers-Huttenlocher syndrome.
14. The method of claim 1 , wherein the deoxyadenosine, deoxyguanosine, deoxycytidine, and deoxythymidine are present in the composition in an equimolar ratio.
15. The method of claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients or carriers.
16. 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.
17. A method of increasing mtDNA levels in vivo, comprising administering a composition comprising deoxyadenosine, deoxyguanosine, 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.