biostudies-literatureLopez-Gomez CEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD NIH HHSU.S. Department of DefenseJ. Willard and Alice S. Marriott FoundationNINDS NIH HHS640-652https://www.ebi.ac.uk/biostudies/studies/S-EPMC9307066biostudies-literatureUnknown90(4)<h4>Objective</h4>Autosomal recessive human thymidine kinase 2 (TK2) mutations cause TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with pyrimidine deoxynucleosides deoxycytidine and thymidine ameliorates mitochondrial defects and extends the lifespan of Tk2 knock-in mouse (Tk2^KI ) and compassionate use deoxynucleoside therapy in TK2 deficient patients have shown promising indications of efficacy. To augment therapy for Tk2 deficiency, we assessed gene therapy alone and in combination with deoxynucleoside therapy in Tk2^KI mice.<h4>Methods</h4>We generated pAAVsc CB6 PI vectors containing human TK2 cDNA (TK2). Adeno-associated virus (AAV)-TK2 was administered to Tk2^KI , which werAnnals of neurologySynergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency.PMC9307066P01 HD032062P01 HD080642U54 NS078059P01/HD32062FPA/W81XWH2010807Tadesse SLee EJKleiner GXie JAkman HOLopez-Gomez CGao GHirano MSanchez-Quintero MJfalseSynergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency.<h4>Objective</h4>Autosomal recessive human thymidine kinase 2 (TK2) mutations cause TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with pyrimidine deoxynucleosides deoxycytidine and thymidine ameliorates mitochondrial defects and extends the lifespan of Tk2 knock-in mouse (Tk2^KI ) and compassionate use deoxynucleoside therapy in TK2 deficient patients have shown promising indications of efficacy. To augment therapy for Tk2 deficiency, we assessed gene therapy alone and in combination with deoxynucleoside therapy in Tk2^KI mice.<h4>Methods</h4>We generated pAAVsc CB6 PI vectors containing human TK2 cDNA (TK2). Adeno-associated virus (AAV)-TK2 was administered to Tk2^KI , which wer2021-01-01T00:00:00Z2021 Oct2026-05-31T15:56:44.966Z2025-04-04T12:45:28.814ZS-EPMC93070663433832910.1002/ana.26185