Treatment with MyoSPRY and other Fc-SPRY fusion proteins improved plasma membrane repair and protected against contraction injury-induced force decrement in a mouse model of Duchenne muscular dystrophy.
Do TRIM72/Fc-fusion proteins improve plasma membrane repair and protect against muscle injury in preclinical models of Duchenne muscular dystrophy?
Engineered TRIM72/Fc-fusion proteins improve plasma membrane repair and protect against muscle injury in preclinical models of Duchenne muscular dystrophy, offering a potential therapeutic approach with improved pharmacokinetics.
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from physiological levels of muscle contraction. Defective sarcolemma repair can cause or exacerbate cardiovascular and muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophies. The tripartite motif family protein 72 (TRIM72), also called mitsugumin 53 (MG53), is essential for membrane repair by facilitating vesicle fusion at injury sites while binding the phospholipid phosphatidylserine (PS). Our laboratory and others have shown that treatment with recombinant TRIM72 protein (rhTRIM72) ameliorates muscle disease pathology in preclinical models. However, the therapeutic potential of rhTRIM72 in muscle diseases was limited by off-target effects on systemic metabolism, poor pharmacokinetics, and manufacturing challenges. To address these issues, we created improved therapeutic proteins by fusing the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. We hypothesized that this approach would increase protein serum half-life through endogenous antibody recycling machinery, simplify manufacturing using existing biologic drug purification methods, and decrease off-target effects by truncating TRIM72. Multiple TRIM72/Fc-fusion proteins display effective PS binding activity in biochemical pulldown experiments. Laser confocal microscopy ablation and dye exclusion assays in myoblast cells revealed that TRIM72/Fc-fusion proteins improved plasma membrane repair upon intracellular overexpression or exogenous application. These experiments found that one of the fusion proteins we call MyoSPRY, comprised of the Fc fused to the SPRY domain of TRIM72, could increase membrane repair. Exogenous treatment with MyoSPRY and other Fc-SPRY proteins improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy (DMD) mouse model. Subcutaneous injection experiments show that Fc-fusion proteins exhibit extended half-lives in vivo and protect muscle against acute eccentric contraction injury-induced force decrement in a mouse model of DMD. Together, these results indicate that our novel Fc-fusion proteins address barriers impeding the clinical development of rhTRIM72 and represent a possible therapeutic approach for diseases driven by altered membrane integrity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Giarrano et al. (Fri,) conducted a other in Duchenne muscular dystrophy and muscle diseases. TRIM72/Fc-fusion proteins (MyoSPRY) was evaluated on Plasma membrane repair and protection against acute eccentric contraction injury-induced force decrement. Treatment with MyoSPRY and other Fc-SPRY fusion proteins improved plasma membrane repair and protected against contraction injury-induced force decrement in a mouse model of Duchenne muscular dystrophy.