Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.

Overview

1. Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
2. Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
3. Tufts University Cummings School of Veterinary Medicine, North Grafton, MA, USA
4. Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA
5. RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
6. Clinic for Special Children, Gordonville, PA, USA
7. Plowshare Therapies, Lancaster, PA, USA

Abstract

Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha−/− mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data and code availability

Datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Raw metabolomic data, summary statistics, and analysis scripts supporting the findings of this study will be provided to qualified researchers for non-commercial research purposes, consistent with institutional and ethical guidelines.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Authors: added Kevin A Strauss (0000-0002-6429-8657); removed Kevin A Strauss

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 5 keywords, 13 MeSH terms, 3 funders, 35 references.

Cite

This paper

Wang, J., Turgeon, C. T., Loken, P. R., Gray-Edwards, H., Gao, G., Tortorelli, S., Wang, D., & Strauss, K. A. (2026). Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice. Molecular therapy : the journal of the American Society of Gene Therapy, 34(8), 4569-4580. https://doi.org/10.1016/j.ymthe.2026.05.008

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