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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.