Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency
| Autor: | Carlos Lopez-Gomez, Hasan O. Akman, Michio Hirano, Jun Xie, Guangping Gao, Maria J. Sanchez-Quintero, Saba Tadesse, Gulio Kleiner, Eung Jeon Lee |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Compassionate Use Trials
Mitochondrial DNA Genetic enhancement DNA Mitochondrial Thymidine Kinase Article chemistry.chemical_compound Mice Mitochondrial myopathy Complementary DNA medicine Animals Humans Gene Kidney business.industry Mitochondrial Myopathies Genetic Therapy medicine.disease Mitochondria medicine.anatomical_structure Neurology chemistry Mutation Cancer research Deoxycytidine Neurology (clinical) Thymidine business |
| Zdroj: | Ann Neurol |
| ISSN: | 1531-8249 |
| Popis: | Objective 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 (Tk2KI ) 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 Tk2KI mice. Methods We generated pAAVsc CB6 PI vectors containing human TK2 cDNA (TK2). AAV-TK2 was administered to Tk2KI , which were serially assessed for weight, motor functions, and survival as well as biochemical functions in tissues. AAV-TK2 treated mice were further treated with deoxynucleosides. Results AAV9 delivery of human TK2 cDNA to Tk2KI mice efficiently rescued Tk2 activity in all the tissues tested except kidney, delayed disease onset, and increased lifespan. Sequential treatment of Tk2KI 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 Tk2KI mice dramatically improved mtDNA copy numbers in liver and kidney, animal growth, and lifespan. Interpretation Our data indicate that AAV-TK2 gene therapy as well as combination deoxynucleoside and gene therapies is more effective in Tk2KI mice than pharmacological alone. Thus, combination of gene therapy with substrate enhancement is promising therapeutic approach for TK2 deficiency and potentially other metabolic disorders. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text