Human gene therapyJul 9, 2026

Gene Therapy Using hBAG3 Improves Symptoms in a Mouse Model of Hereditary Muscle Disease Caused by Valosin Protein

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 10, 2026

Abstract

Overexpression of human BAG3 improved treadmill running distance and reduced TDP-43-positive aggregates in a mouse model of hereditary inclusion body myositis.

Mutations in the VCP gene are linked to hereditary inclusion body myositis, characterized by protein aggregates and mitochondrial abnormalities.
The autophagy-lysosome pathway is essential for degrading misfolded proteins and maintaining mitochondrial function in this condition.
hBAG3 treatment enhanced functional performance in mice, as indicated by improved treadmill running distance and rotarod duration.
Histological analysis showed a reduction in TDP-43-positive aggregates and fewer fibers with mitochondrial enzyme abnormalities after hBAG3 treatment.
Increased levels of mitophagy and mitochondrial biogenesis markers were observed, suggesting enhanced mitochondrial health.
The LC-II/I ratio increased, indicating improved autophagic activity following gene therapy with hBAG3.

Simplified

Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.

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Gene Therapy Using hBAG3 Improves Symptoms in a Mouse Model of Hereditary Muscle Disease Caused by Valosin Protein

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