In the 1950’s, the discovery of growth factors (GFs) held great promise for tissue regeneration. Nevertheless, the translation of GFs into clinical therapies is far from having fulfilled the expectations, and is currently facing important limitations related to safety and cost-effectiveness. In fact, significant improvement of tissue healing is achieved by repeated delivery of high doses of GFs to the impaired tissue, which also dramatically increase the cancer risk of patients, as has been warned by the U.S. Food and Drug Administration. Interestingly, in physiological conditions, GFs are highly effective at very low doses, thanks to their optimal delivery by the local extracellular matrix (ECM). Thus, we reasoned that GFs with high affinity for ECM proteins would induce better tissue morphogenesis because of their longer-term release from the ECM and their subsequent prolonged receptor activation. We recently characterized the interactions between 25 GFs and 6 key ECM molecules, and discovered a peptidic domain from the Placental Growth Factor-2 (PlGF-2123-144) that displays a super-affinity for ECM proteins. We used rational protein engineering to incoporate PlGF-2123-144 into GFs that bear clinical translation limitations, particularly VEGF-A, PDGF-BB and BMP-2. We successfully showed that engineered GFs-PlGF-2123-144 display super-affinity for ECM proteins and heparan sulfate proteoglycans, which allow them to be strongly retained into fibrin clots and endogenous ECMs. Furthermore, we demonstrated that the delivery of low doses of GF-PlGF-2123-144 drastically enhance tissue healing in models of skin chronic wound in db/db mice and critical-size bone defect in rats, in comparison to wild-type GFs. Impressively, this acceleration in tissue healing has been observed when GF-PlGF-2123-144 were delivered with fibrin matrices or by simple topical applications on the wounds. In conclusion, the super-affinity of GF-PlGF-2123-144 for the ECM allows a precise spatio-temporal delivery and release of these engineered factors into wounds, what permits to significantly reduce their therapeutic doses and side effects. This broadly applicable growth factors engineering approach may overcome some of the important and current limitations of growth factor-based therapies in the clinic.

Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing

249th National Meeting (2015)

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