BAG3 gene therapy emerges as a potential treatment for myofibrillar myopathies

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Myofibrillar myopathies (MFMs) are characterized by the accumulation of protein aggregates in muscle fibers and myofibrillar disintegration, resulting in progressive skeletal muscle weakness and significantly impairing patient quality of life.¹ An autosomal dominant form of MFM called myotilinopathy (MFM3) is caused by mutations in the z-disc protein myotilin that inhibit its degradation and promote aggregate formation.² Current treatments for myotilinopathy and other MFMs focus on symptom management rather than addressing the primary causes of disease. However, an emerging hypothesis in the field proposes that enhancing degradation via autophagy upregulation may clear out the pathological protein aggregates and ameliorate the most detrimental effects of these myopathies.^3,4 As reported in a recent issue of Molecular Therapy Advances, Ozes et al. tested this hypothesis by overexpressing BAG3—a co-chaperone and a key component of the chaperone-assisted selective autophagy pathway—in a mouse model of myotilinopathy.² They found that BAG3 gene therapy does indeed enhance autophagy and reduce aggregate load, thus diminishing the molecular and histological markers of disease. Furthermore, BAG3-treated mice also showed improvements in skeletal muscle function compared to untreated mice. The Ozes et al. study provides the strongest evidence to date that autophagy activation is a viable therapeutic strategy for myotilinopathy. It also showcases the promise of BAG3 gene therapy as a generalizable treatment for other MFMs.

Defective autophagy and increased aggregate abundance in muscle fibers are hallmarks of MFMs.³ Autophagy is an alternative route to the proteasomal system in which misfolded or damaged proteins are delivered to the lysosome via vesicular compartments and subsequently degraded. Autophagy is especially important for sarcomere proteostasis (sarcophagy) because striated muscle is subject to high loads of mechanical and oxidative stress, which increase protein misfolding/damage and can overwhelm the capacity of other degradation pathways. Like the proteosome, autophagy can degrade proteins in a ubiquitin-dependent, selective manner.⁵ However, autophagy is more efficient at handling large protein aggregates. Understandably then, autophagy upregulation as a treatment for MFMs is an active area of investigation. Previous work shows that in vitro induction of autophagy via small molecules can effectively reduce aggregate formation in mammalian myoblasts.^4,6 In vivo, the autophagy-enhancing compound metformin reduces myofibrillar disintegration and improves performance in bag3^−/− zebrafish, a model that recapitulated some aspects of MFMs.⁶ Induction of autophagy using non-pharmacological modalities in MFM models is less studied, but a previous report revealed that autophagy upregulation via PKCα overexpression reduces aggregation of an MFM-causing desmin mutant.⁴ As a reliable enhancer of autophagy,⁷ BAG3 is a strong candidate for addressing autophagic deficiencies.

The potential of BAG3 therapies has been recognized previously, though primarily in the context of cardiac muscle. In humans, loss-of-function mutations in BAG3 can cause dilated cardiomyopathy.⁷ The evidence for BAG3’s cardioprotective role is sufficiently robust that several adeno-associated virus (AAV)-based BAG3 gene therapies are in clinical trials for patients with BAG3-associated dilated cardiomyopathy (Figure 1). In contrast, BAG3’s protective effects in skeletal muscle are not as well characterized, but the studies that do exist are promising. For example, in a mouse model of diabetes, BAG3 overexpression in ischemic gastrocnemius muscle reduced necrosis and enhanced regeneration.⁸ While there are multiple clinical trials for BAG3 gene therapy in cardiomyopathies, there are currently none available for skeletal muscle diseases.

Figure 1.

Overview of recent clinical trials/studies on BAG3 therapeutics and/or gene therapies for myotilinopathy. Created in BioRender. Sherer, L. (2026).

The Ozes et al. study² demonstrates the feasibility of a BAG3-focused approach for treating myotilinopathy and possibly other MFMs. The authors utilized the TgT57I myotilinopathy mouse model and systemically delivered human BAG3-expressing AAVrh74 with expression of the transgene under control of the muscle-specific tMCK (triple-tandem muscle creatine kinase) promoter. Eight months post-injection, they evaluated skeletal muscle function based on rotarod duration, treadmill endurance, grip strength, and in vivo muscle contractility. After sacrificing the mice, they also assessed aggregate accumulation using histology and immunofluorescence imaging, finding a decrease in aggregate density and area in the tibialis anterior and quadriceps muscles. This decline in aggregate burden in response to BAG3 treatment was accompanied by an increase in muscle fiber size and a reduction in insoluble myotilin levels, whereas the treatment did not have a significant effect on soluble myotilin expression. The authors also examined autophagy markers (p62 and LC3 I/II), and as expected, the changes in autophagy markers were consistent with improved autophagy flux. Overall, the study presents compelling evidence for the therapeutic capabilities of BAG3 in MFMs.

The significance of the Ozes et al. report comes from their mammalian model and their integration of functional, molecular, and histological data. The functional readouts are particularly notable due to their relevance for patient quality of life. Yet, Ozes et al. are not the first to develop a therapy for myotilinopathy and observe promising results in a TgT57I mouse model. Another research group treated TgT57I mice with AAVs that expressed myotilin-targeting microRNA (Figure 1) and found that their treatment effectively reduced aggregate abundance and increased muscle strength.⁹ While these results demonstrate the efficacy of myotilin microRNA, a BAG3 gene therapy approach is more likely to be successfully translated into the clinic. A major advantage is its generalizability to other types of MFMs. Instead of knocking down a specific protein like myotilin, which is mutated in only 10% of MFMs,² BAG3 gene therapy targets a process—autophagy—that is broadly defective in these diseases and deeply linked to the apparent root pathological cause (i.e., aggregate accumulation).

While the Ozes et al. data are persuasive, there are a few caveats to consider. First, BAG3 expression in the heart could have influenced some of the study’s outcomes. While the promoter (tMCK) was mostly specific to skeletal muscle, there was low expression of human BAG3 in the heart in 2 out of the 3 mice tested.² This may explain why the BAG3-treated TgT57I had such an exceptional improvement in treadmill endurance, which depends on cardiovascular function more than the other functional metrics do. Another consideration is that BAG3’s non-autophagy roles (e.g., YAP-TAZ signaling and apoptosis suppression)⁷ may contribute to the therapeutic benefits of BAG3. It is also important to note that BAG3 gene therapy did not completely restore skeletal muscle function, possibly indicating additional drivers of pathology beyond defective autophagy. Indeed, one recent study of an MFM-causing desmin mutant paired antioxidants with pharmacological autophagy upregulation, which produced better outcomes than autophagy upregulation alone.⁴ As such, combining BAG3 with other types of therapeutics should be explored in the future. More broadly, AAV vectors can lead to serious adverse events (e.g., thrombotic microangiopathy and hepatoxicity), particularly at high doses.¹⁰ Successful translation of the proposed BAG3 therapy will require more dosage optimization and safety testing in relevant pre-clinical models and possibly capsid engineering to minimize immune responses to the AAV.

Even with these considerations, the Ozes et al. study is significant because it broadens the potential scope of BAG3 therapeutics. While previous work concentrated on cardiac muscle, this study shifts the focus to skeletal muscle. Moreover, the current BAG3 gene therapies in clinical trials are specifically aimed at compensating for loss-of-function, pathogenic BAG3 mutants in dilated cardiomyopathy. In contrast, the Ozes et al. study moves beyond simple gene replacement, demonstrating that BAG3 gene therapy can counteract pathogenic mutants of other downstream proteins. This work highlights the promise of BAG3 as a therapy and will hopefully inspire more research into the benefits of BAG3 in skeletal muscle diseases broadly.

Acknowledgments

This work was supported by the National Institutes of Health (R01HL136737, R01HL172492, and R01HL175964 to J.A.K.) and the American Heart Association (24POST1200285 to L.A.S.).

Declaration of interests

J.A.K. is a paid consultant for Rocket Pharmaceuticals and Affinia Therapeutics, who are pursuing BAG3 gene therapy.