(Hirano) Deoxypyrimidine monophosphate bypass therapy (核苷分流治療/ dCMP+dTMP) 提供粒線體 缺陷 小查理 希望

為救英罕見絕症寶寶 美國國會給他發綠卡 【大紀元2017年07月20日訊】（大紀元記者張婷綜合報導）英國罕見疾病患者小查理（Charlie Gard）的悲慘處境持續引起美國政府的關注。美國國會日前決定授予11個月大的小查理美國公民身分，以便他可以到美國接受治療。據英國《獨立報》報導，美國國會的這一決定可能會迫使負責治療小查理的倫敦大奧蒙德街醫院（Great Ormond Street Hospital）對小查理放手，使他能夠到美國接受核苷治療。內布拉斯加州（Nebraska）的代表福登伯裡（Jeff Fortenberry）表示，美國國會已經通過了一個修正案，授予小查理及其家人永久居民身分，這樣他可以到美國接受所需要的治療。小查理患有罕見的線粒體消損症（mitochondrial depletion disease），目前只能靠醫院各種設施支持而維持生命。倫敦大奧蒙德街醫院的醫生們不認為任何治療將會幫助小查理改善病情，相反可能會給他造成痛苦，不如拔掉呼吸機，讓小查理有尊嚴地死去。但小查理的父母堅決反對，他們查到美國通過一種名為核苷分流治療的先進療法，曾經成功治癒多位有線粒體缺陷的病人，於是要求讓小查理到美國治療，但醫院方面堅決反對，認為這種治療方法沒有得到國際承認，是在拿小查理做實驗。此事告到了英國法庭，法庭決定支持英國醫院的看法。哥倫比亞、康乃爾大學長老會醫院的神經科醫生西拉諾（Michio Hirano）本週飛往英國，親自為小查理做檢查。英國最高法院將會在本月晚些時候對小查理的案子做出裁決，法官表示，將會把海拉諾的診斷結果考慮進去。報導稱，小查理被授予美國公民身分可能意味著他的父母不會再需要來自英國醫院的許可，就可以帶他到美國去接受治療。而目前查理的父母則不敢擅自去美國。因為根據英國的法律，如果英國醫生認為父母可能會使孩子遭受痛苦，警察會上門逮捕父母。

責任編輯：林妍

Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency

Caterina Garone,1,2 Beatriz Garcia-Diaz,1 Valentina Emmanuele,1,3 Luis C Lopez,4 Saba Tadesse,1 Hasan O Akman,1 Kurenai Tanji,5 Catarina M Quinzii,1 and Michio Hirano1,* EMBO Mol Med. 2014 Aug; 6(8): 1016–1027.

Abstract Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2−/−) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2−/− mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2−/−200dCMP/dTMP) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency.

Introduction Encoded by the nuclear DNA gene TK2, thymidine kinase 2 (TK2) is a mitochondrial matrix protein that phosphorylates thymidine and deoxycytidine pyrimidine nucleosides to generate deoxythymidine monophosphate (dTMP) and deoxycytidine monophosphate (dCMP), which, in turn, are converted to deoxynucleotide triphosphates (dNTPs) required for mitochondrial DNA (mtDNA) synthesis. Autosomal recessive TK2 mutations cause severe mtDNA depletion and devastating neuromuscular diseases in infants and children, as well as mtDNA multiple deletions and progressive external ophthalmoplegia in adults (Saada et al, 2001; Tyynismaa et al, 2012). To elucidate the molecular pathogenesis of TK2 deficiency, we generated a homozygous Tk2 H126N knock-in mutant (Tk2−/−) mouse that manifests a phenotype strikingly similar to the human infantile encephalomyopathy (Akman et al, 2008). Between postnatal day 10 and 13, Tk2−/− mice rapidly develop fatal encephalomyopathy beginning with decreased ambulation, unstable gait, coarse tremor, and growth retardation that rapidly progress to early death at age 14–16 days (Dorado et al, 2011). A similar phenotype was observed in the Tk2 knockout mouse (Zhou et al, 2008). In the Tk2−/− mice, loss of Tk2 activity caused dNTP pool imbalances with low dTTP levels in brain and decreased dTTP and dCTP in liver, which, in turn, produce mtDNA depletion and defects of mitochondrial respiratory chain (RC) complexes I, III, IV, and V containing mtDNA-encoded subunits, most prominently in the brain and spinal cord (Dorado et al, 2011). Based on the understanding of the pathogenesis of Tk2 deficiency, we have assessed a rationale therapeutic strategy to bypass the enzymatic defect with oral dCMP and dTMP supplementation.