Recombinant GDF11 Promotes Recovery in a Rat Permanent Ischemia Model of Subacute Stroke.

Abstract

Stroke remains a leading cause of death and disability, underscoring the urgent need for treatments that enhance recovery. GDF11 (growth differentiation factor 11), a member of the TGF-β (transforming growth factor-β) superfamily, is a circulating protein involved in cellular development and tissue repair. GDF11 has gained attention for its potential regenerative properties in aging and disease contexts, making it a candidate for stroke recovery therapies. The therapeutic benefits of rGDF11 (recombinant GDF11) were evaluated using a rat ischemic stroke model, in which focal cerebral infarcts were induced in 8- to 10-week-old young adult male Sprague-Dawley rats by permanently occluding the proximal right middle cerebral artery. Rats received single or multiple doses of rGDF11 (0.1-4 mg/kg) or vehicle from 24 to 72 hours post-injury. Sensorimotor functions were evaluated, and brain and serum samples were examined to determine the mechanisms of action and identify biomarkers, using immunofluorescence, target-specific ELISAs, and an aptamer-based proteomics platform. We confirmed rGDF11 activity in vitro and in established in vivo mouse models of cardiac hypertrophy and glucose metabolism and assessed the efficacy of rGDF11 treatment in 6 preclinical stroke studies using independent Contract Research Organizations, with all study animals and treatment groups blinded. All 6 studies revealed consistent improvement in sensorimotor outcomes with rGDF11. rGDF11-treated rats showed increased cortical vascularization and radial glia in the ventricular zone. Serum analysis revealed that rGDF11 caused dose-dependent decreases in CRP (C-reactive protein) and identified novel pharmacodynamic biomarkers and pathways associated with potential mechanisms of action of rGDF11. These results demonstrate that systemically delivered rGDF11 enhances neovascularization, reduces inflammation, promotes neurogenesis, and improves sensorimotor function post-injury in a rat model of ischemic stroke. More importantly, these data define an optimized and clinically feasible rGDF11 dosing regimen for therapeutic development in ischemic stroke and identify a panel of candidate pharmacodynamic and mechanistic biomarkers to support clinical translation.