Synergistic effect of deoxynucleosides and AAV gene therapy for thymidine kinase 2 deficiency
Synergistic effect of deoxynucleosides and AAV gene therapy for thymidine kinase 2 deficiency
Abstract Autosomal recessive thymidine kinase 2 (TK2) mutations causes TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with deoxycytidine and thymidine ameliorates mitochondrial defects and extends lifespan of Tk2 knock-in mouse (TK2?/?); however, efficacy is limited by age- and tissue-dependent expression of the cytosolic enzymes Tk1 and Dck. Thus, therapies aimed at systemic restoration of TK2 activity are needed. Here, we demonstrate that delivery of human TK2 cDNA to Tk2?/? mice using AAV9 efficiently rescued Tk2 activity in all the tissues tested except kidney, delayed disease onset, and increased lifespan. Sequential treatment of Tk2?/? mice with AAV9 first followed by AAV2 at different ages allowed us to reduce the viral dose while further prolonging the lifespan. Furthermore, addition of deoxycytidine and deoxythymidine supplementation to AAV9 + AAV2 treated Tk2?/? mice dramatically improved mtDNA copy numbers in liver and kidney, animal growth, and lifespan. These data indicate that combined pharmacological and gene therapies may be highly efficacious for human TK2 deficiency.
Sanchez-Quintero Maria J.、Lee Eung Jeon、Xie Jun、Gao Guangping、Kleiner Gulio、Akman Hasan Orhan、Lopez-Gomez Carlos、Hirano Michio
H. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical CenterH. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical CenterMicrobiology and Physiological Systems, University of Massachusetts Medical Center||Horae Gene Therapy Center, University of Massachusetts Medical CenterMicrobiology and Physiological Systems, University of Massachusetts Medical Center||Horae Gene Therapy Center, University of Massachusetts Medical CenterH. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical CenterH. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical CenterH. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical CenterH. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical Center
基础医学遗传学分子生物学
Adeno-associated virusdeoxynucleoside therapygene therapyMitochondrial DNA Depletion Syndromethymidine kinase 2TK2
Sanchez-Quintero Maria J.,Lee Eung Jeon,Xie Jun,Gao Guangping,Kleiner Gulio,Akman Hasan Orhan,Lopez-Gomez Carlos,Hirano Michio.Synergistic effect of deoxynucleosides and AAV gene therapy for thymidine kinase 2 deficiency[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2020.10.08.330969.点此复制
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