HRP20200949T1 - Deoksinukleozidna terapija bolesti uzrokovanih neurevnoteženim fondovima nukleotida, uključujući sindrome manjka mitohondrijske dna - Google Patents
Deoksinukleozidna terapija bolesti uzrokovanih neurevnoteženim fondovima nukleotida, uključujući sindrome manjka mitohondrijske dna Download PDFInfo
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- HRP20200949T1 HRP20200949T1 HRP20200949TT HRP20200949T HRP20200949T1 HR P20200949 T1 HRP20200949 T1 HR P20200949T1 HR P20200949T T HRP20200949T T HR P20200949TT HR P20200949 T HRP20200949 T HR P20200949T HR P20200949 T1 HRP20200949 T1 HR P20200949T1
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- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 201000002697 mitochondrial DNA depletion syndrome Diseases 0.000 title 1
- 239000002773 nucleotide Substances 0.000 title 1
- 125000003729 nucleotide group Chemical group 0.000 title 1
- 238000002560 therapeutic procedure Methods 0.000 title 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims 13
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 claims 8
- 230000002411 adverse Effects 0.000 claims 6
- 230000000694 effects Effects 0.000 claims 6
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 claims 5
- 102100027624 Thymidine kinase 2, mitochondrial Human genes 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- 108010036893 thymidine kinase 2 Proteins 0.000 claims 4
- 238000012544 monitoring process Methods 0.000 claims 3
- UCKYOOZPSJFJIZ-FMDGEEDCSA-N (4r)-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 UCKYOOZPSJFJIZ-FMDGEEDCSA-N 0.000 claims 2
- 229940123974 Cytidine deaminase inhibitor Drugs 0.000 claims 2
- 229940122020 Thymidine phosphorylase inhibitor Drugs 0.000 claims 2
- 230000007812 deficiency Effects 0.000 claims 2
- 206010012735 Diarrhoea Diseases 0.000 claims 1
- 235000020247 cow milk Nutrition 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010016766 flatulence Diseases 0.000 claims 1
- 235000013350 formula milk Nutrition 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 210000004251 human milk Anatomy 0.000 claims 1
- 235000020256 human milk Nutrition 0.000 claims 1
- 210000003205 muscle Anatomy 0.000 claims 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical group N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 claims 1
- 229960002952 tipiracil Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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Claims (23)
1. Deoksicitidin (dC), namijenjen upotrebi u postupku liječenja nedostatka timidin-kinaze 2 (TK2) kod ljudskog subjekta kojem je to potrebno, naznačen time što se navedeni postupak sastoji u primjeni terapijski djelotvorne količine deoksitimidina (dT) i navedenog deoksicitidina (dC).
2. Deoksitimidin (dT), namijenjen upotrebi u postupku liječenja nedostatka timidin-kinaze 2 (TK2) kod ljudskog subjekta kojem je to potrebno, naznačen time što se navedeni postupak sastoji u primjeni terapijski djelotvorne količine deoksicitidina (dC) i navedenog deoksitimidina (dT).
3. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što se terapijski djelotvorna količina kreće
a) između 100 mg/kg dnevno i 1000 mg/kg dnevno svakog deoksinukleozida u pripravku; ili:
b) između 200 mg/kg dnevno i 800 mg/kg dnevno svakog deoksinukleozida u pripravku; ili:
c) između 250 mg/kg dnevno i 400 mg/kg dnevno svakog deoksinukleozida u pripravku.
4. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što se terapijski djelotvorna količina svakog deoksinukleozida u pripravku kreće između 100 mg/kg dnevno i 400 mg/kg dnevno.
5. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što se terapijski djelotvorna količina svakog deoksinukleozida u pripravku kreće između 250 mg/kg dnevno i 400 mg/kg dnevno.
6. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što se terapijski djelotvorna količina kreće
a) između 100 mg/kg dnevno i 1000 mg/kg dnevno ukupnih deoksinukleozida u pripravku; ili:
b) između 200 mg/kg dnevno i 800 mg/kg dnevno ukupnih deoksinukleozida u pripravku; ili:
c) između 250 mg/kg dnevno i 400 mg/kg dnevno ukupnih deoksinukleozida u pripravku.
7. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što omjer između deoksicitidina (dC) i deoksitimidina (dT) je 50/50, 5/95, 10/90, 15/85, 20/80, 25/75, 30,70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10 ili 95/5.
8. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 7, naznačeni time što je navedeni omjer između deoksicitidina (dC) i deoksitimidina (dT) 50/50.
9. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što se pripravak primjenjuje jednom dnevno, dva puta dnevno, tri puta dnevno, četiri puta dnevno, pet puta dnevno ili šest puta dnevno.
10. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što se pripravak primjenjuje oralno, intratekalno, enteralno ili intravenski.
11. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 10, naznačeni time što se pripravak primjenjuje oralno; te što navedeni pripravak dodatno sadrži kravlje mlijeko, majčino mlijeko, formulu za dojenčad ili vodu.
12. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što dodatno uključuju primjenu na subjektu inhibitora timidin-fosforilaze.
13. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 12, naznačeni time što je inhibitor timidin-fosforilaze tipiracil.
14. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što dodatno uključuju primjenu na subjektu inhibitora citidin-deaminaze.
15. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 14, naznačeni time što je inhibitor citidin-deaminaze tetrahidrouridin [THU].
16. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što se terapijski djelotvornu količinu pripravka primijenjenu na subjektu povećava s vremenom; gdje prva terapijski djelotvorna količina pripravka koju se primjenjuje na subjektu može biti otprilike 100 mg/kg dnevno pripravka, te što se terapijski djelotvornu količinu pripravka povećava s vremenom do 200 mg/kg dnevno, do 400 mg/kg dnevno, do 800 mg/kg dnevno, te do 1000 mg/kg dnevno.
17. dC ili dT, namijenjeni upotrebi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što pripravak sadrži farmaceutski prihvatljivi nosač.
18. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što postupak liječenja dodatno uključuje praćenje subjekta nakon primjene pripravka, što se sastoji u:
a. promatranju snage i kontrole mišića;
b. promatranju razlika u visini i težini;
c. promatranju pokretljivosti; i
d. određivanju poboljšavanja stanja kod subjekta ako u bilo kojem od promatranja (a)-(c) dolazi do povećanja nakon primjene pripravka, te određivanju da nema poboljšavanja ako je u bilo kojem od promatranja (a)-(c) stanje isto ili dolazi do smanjenja nakon primjene pripravka.
19. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 18, naznačeni time što ako se u koraku (d) odredi da nema poboljšavanja, terapijski djelotvornu količinu pripravka se povećava.
20. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 1 odnosno 2, naznačeni time što postupak liječenja dodatno uključuje praćenje subjekta na štetni učinak nakon primjene pripravka, gdje ako se opazi štetni učinak, terapijski djelotvornu količinu pripravka se smanjuje.
21. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 20, naznačeni time što dodatno uključuju praćenje subjekta na opaženi štetni učinak nakon smanjivanja terapijski djelotvorne količine pripravke, gdje ako se štetni učinak više ne opaža, terapijski djelotvornu količinu pripravka se povećava.
22. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 20, naznačeni time što je štetni učinak gastrointestinalna intolerancija.
23. dC ili dT, namijenjeni upotrebi u skladu s patentnim zahtjevom 20, naznačeni time što se štetni učinak bira iz skupine koju čine proljev i nadutost u trbuhu.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562180914P | 2015-06-17 | 2015-06-17 | |
| EP19156021.8A EP3505174B1 (en) | 2015-06-17 | 2016-06-17 | Deoxynucleoside therapy for diseases caused by unbalanced nucleotide pools including mitochondrial dna depletion syndromes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20200949T1 true HRP20200949T1 (hr) | 2020-10-02 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20191794TT HRP20191794T1 (hr) | 2015-06-17 | 2019-10-03 | Deoksinukleozidna terapija bolesti uzrokovanih neuravnoteženim nukleotidnim fondovima, uključujući sindrome gubitka mitohondrijske dna |
| HRP20200949TT HRP20200949T1 (hr) | 2015-06-17 | 2020-06-15 | Deoksinukleozidna terapija bolesti uzrokovanih neurevnoteženim fondovima nukleotida, uključujući sindrome manjka mitohondrijske dna |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20191794TT HRP20191794T1 (hr) | 2015-06-17 | 2019-10-03 | Deoksinukleozidna terapija bolesti uzrokovanih neuravnoteženim nukleotidnim fondovima, uključujući sindrome gubitka mitohondrijske dna |
Country Status (23)
| Country | Link |
|---|---|
| US (4) | US10471087B2 (hr) |
| EP (3) | EP3569236A1 (hr) |
| JP (3) | JP6599484B2 (hr) |
| KR (2) | KR20180039624A (hr) |
| CN (2) | CN107847512A (hr) |
| AU (3) | AU2016280293B2 (hr) |
| BR (2) | BR112017027079B1 (hr) |
| CA (1) | CA2989653A1 (hr) |
| CY (2) | CY1122605T1 (hr) |
| DK (2) | DK3505174T3 (hr) |
| ES (2) | ES2808148T3 (hr) |
| HK (1) | HK1252133A1 (hr) |
| HR (2) | HRP20191794T1 (hr) |
| HU (2) | HUE046399T2 (hr) |
| IL (3) | IL275256B2 (hr) |
| LT (2) | LT3310362T (hr) |
| MX (2) | MX2017016425A (hr) |
| PL (2) | PL3505174T3 (hr) |
| PT (2) | PT3505174T (hr) |
| RS (2) | RS60572B1 (hr) |
| RU (2) | RU2721492C2 (hr) |
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| US10292996B2 (en) * | 2015-03-26 | 2019-05-21 | The Trustees Of Columbia University In The City Of New York | Deoxyribonucleoside monophospate bypass therapy for mitochondrial DNA depletion syndrome |
| MX2017016425A (es) * | 2015-06-17 | 2018-12-11 | Univ Columbia | Terapia con desoxinucleosidos para enfermedades generadas por grupos de nucleotidos desequilibrados, inclusive sindromes de agotamiento del adn mitocondrial. |
| RU2731179C2 (ru) | 2015-12-22 | 2020-08-31 | Зодженикс Интернэшнл Лимитед | Фенфлураминовые композиции и способы их получения |
| EP3393470B1 (en) | 2015-12-22 | 2021-01-20 | Zogenix International Limited | Metabolism resistant fenfluramine analogs and methods of using the same |
| JP2019526544A (ja) | 2016-08-24 | 2019-09-19 | ゾゲニクス インターナショナル リミテッド | ５−ｈｔ２ｂアゴニストの形成を阻害するための製剤およびその使用方法 |
| WO2019051097A1 (en) | 2017-09-08 | 2019-03-14 | The Regents Of The University Of California | RNA-GUIDED ENDONUCLEASE FUSION POLYPEPTIDES AND METHODS OF USING SAME |
| US10682317B2 (en) | 2017-09-26 | 2020-06-16 | Zogenix International Limited | Ketogenic diet compatible fenfluramine formulation |
| IL277725B2 (en) * | 2018-04-12 | 2024-02-01 | Modis Therapeutics Inc | Pro-drugs of deoxynucleosides for the treatment of diseases resulting from an imbalance in the nucleotide reserves |
| US11571397B2 (en) | 2018-05-11 | 2023-02-07 | Zogenix International Limited | Compositions and methods for treating seizure-induced sudden death |
| AU2020334060A1 (en) | 2019-08-19 | 2022-03-24 | Zogenix, Inc. | Polymorphic forms of deoxycytidine, compositions comprising the same and uses |
| WO2021046355A1 (en) * | 2019-09-05 | 2021-03-11 | Mitorainbow Therapeutics, Inc. | Treating mitochondrial dna depletion disorders |
| CN115667505A (zh) | 2020-03-19 | 2023-01-31 | 因特利亚治疗公司 | 用于定向基因组编辑的方法和组合物 |
| US11612574B2 (en) | 2020-07-17 | 2023-03-28 | Zogenix International Limited | Method of treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
| US20220096514A1 (en) * | 2020-09-29 | 2022-03-31 | Zogenix International Limited | Methods of treating thymidine kinase 2 deficiency by administering deoxycytidine and deoxythymidine |
| EP4268829A1 (en) * | 2020-12-28 | 2023-11-01 | Yamasa Corporation | Muscular atrophy inhibitor and method for inhibiting muscular atrophy |
| CN117120060A (zh) * | 2021-03-26 | 2023-11-24 | 周格尼克斯-莫迪斯公司 | 含有嘌呤和嘧啶的水溶液及其用途 |
| CA3222484A1 (en) * | 2021-06-18 | 2022-12-22 | Daniel DIPIETRO | Prodrugs of deoxynucleosides for treatment of mitochondrial diseases caused by unbalanced nucleotide pools |
| WO2024015453A1 (en) * | 2022-07-12 | 2024-01-18 | Zogenix Mds, Inc. | Methods for increasing the bioavailability of nucleoside medicinal agents |
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| RU2300381C2 (ru) * | 1998-08-10 | 2007-06-10 | Айденикс (Кайман) Лимитед | β-L-2'-ДЕЗОКСИНУКЛЕОЗИДЫ ДЛЯ ЛЕЧЕНИЯ ГЕПАТИТА В |
| NZ513926A (en) * | 1999-02-23 | 2001-09-28 | Univ California | Methods of treatment of mitochondrial disorders |
| EA005890B1 (ru) * | 2000-05-26 | 2005-06-30 | Айденикс (Кайман) Лимитед | СПОСОБЫ ЛЕЧЕНИЯ ИНФЕКЦИЙ, ВЫЗЫВАЕМЫХ ВИРУСОМ ГЕПАТИТА ДЕЛЬТА, С ИСПОЛЬЗОВАНИЕМ β-L-2'-ДЕЗОКСИНУКЛЕОЗИДОВ |
| WO2012125848A2 (en) * | 2011-03-16 | 2012-09-20 | Baylor College Of Medicine | A method for comprehensive sequence analysis using deep sequencing technology |
| US10292996B2 (en) | 2015-03-26 | 2019-05-21 | The Trustees Of Columbia University In The City Of New York | Deoxyribonucleoside monophospate bypass therapy for mitochondrial DNA depletion syndrome |
| AU2016273340B2 (en) * | 2015-06-05 | 2021-09-09 | Centro De Investigación Biomédica En Red | Treatment of mitochondrial diseases |
| MX2017016425A (es) * | 2015-06-17 | 2018-12-11 | Univ Columbia | Terapia con desoxinucleosidos para enfermedades generadas por grupos de nucleotidos desequilibrados, inclusive sindromes de agotamiento del adn mitocondrial. |
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