Muscle-directed AAV gene therapy rescues the maple syrup urine disease phenotype in a mouse model
| Autor: | Aditya Dandekar, James M. Wilson, Jenny A. Greig, Matthew Jennis, Scott N. Ashley, Hanying Yan, Joanna K. Chorazeczewski, Melanie K. Smith |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism Genetic enhancement medicine.medical_treatment Genetic Vectors Pharmacology Liver transplantation medicine.disease_cause Biochemistry Virus Mice Endocrinology Maple Syrup Urine Disease Genetics Medicine Animals Molecular Biology Gene Mutation business.industry Maple syrup urine disease Metabolic disorder Genetic Therapy Dependovirus medicine.disease Phenotype Disease Models Animal Administration Intravenous Female business Amino Acids Branched-Chain |
| Zdroj: | Molecular genetics and metabolism. 134(1-2) |
| ISSN: | 1096-7206 |
| Popis: | Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder characterized by a dysfunctional mitochondrial enzyme complex, branched-chain alpha-keto acid dehydrogenase (BCKDH), which catabolizes branched-chain amino acids (BCAAs). Without functional BCKDH, BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues. MSUD is currently incurable and treatment is limited to dietary restriction or liver transplantation, meaning there is a great need to develop new treatments for MSUD. We evaluated potential gene therapy applications for MSUD in the intermediate MSUD (iMSUD) mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH. Systemic delivery of an adeno-associated virus (AAV) vector expressing DBT under control of the liver-specific TBG promoter to the liver did not sufficiently ameliorate all aspects of the disease phenotype. These findings necessitated an alternative therapeutic strategy. Muscle makes a larger contribution to BCAA metabolism than liver in humans, but a muscle-specific approach involving a muscle-specific promoter for DBT expression delivered via intramuscular (IM) administration only partially rescued the MSUD phenotype in mice. Combining the muscle-tropic AAV9 capsid with the ubiquitous CB7 promoter via IM or IV injection, however, substantially increased survival across all assessed doses. Additionally, near-normal serum BCAA levels were achieved and maintained in the mid- and high-dose cohorts throughout the study; this approach also protected these mice from a lethal high-protein diet challenge. Therefore, administration of a gene therapy vector that expresses in both muscle and liver may represent a viable approach to treating patients with MSUD. |
| Databáze: | OpenAIRE |
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