RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients

Abstract

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is highlighted by numerous pathologies and situations of acute and chronic injury associated with dysregulation or destruction of ECM components. Heparan sulfate (HS) is a key component of the ECM, where it fulfils important functions associated with tissue homeostasis. Its degradation following tissue injury disrupts this delicate equilibrium and may impair the wound healing process. ReGeneraTing Agents (RGTA^®s) are polysaccharides specifically designed to replace degraded HS in injured tissues. The unique properties of RGTA^® (resistance to degradation, binding and protection of ECM structural and signaling proteins, like HS) permit the reconstruction of the ECM, restoring both structural and biochemical functions to this essential substrate, and facilitating the processes of tissue repair and regeneration. Here, we review 25 years of research surrounding this HS mimic, supporting the mode of action, pre-clinical studies and therapeutic efficacy of RGTA^® in the clinic, and discuss the potential of RGTA^® in new branches of regenerative medicine.

Keywords: Extracellular scaffold; Heparan sulfate mimics; RGTA®; Regeneration.

Fig. 1

Mode of Action of ReGeneraTing Agent (RGTA^®) Following Extensive Tissue Damage. 1. The Extracellular Matrix (ECM) organization in healthy tissue (left panel). Blue dots correspond to communication peptides, stored and protected by glycosaminoglycans. Heparan sulfate (HS) (light pink helices) links the matrix proteins (white fibers) to form a scaffold around cells. 2. Following extensive tissue damage, HS is degraded by glycanase (yellow figurines), the ECM scaffold structure is destroyed and proteases (yellow figurines) may enter, destroying matrix proteins and stored growth factors. 3. A rapid repair response is triggered resulting in scars or fibroses. 4. If the cause of the lesion is not resolved, wounds remain in an inflammatory phase, leading to a cycle of repair and destruction. 5. RGTA^® (green helices) replaces degraded HS, allowing reconstruction of the ECM scaffold and restoring the cellular microenvironment. This facilitates tissue regeneration and restoration of tissue to a state similar to that of healthy tissue. 6. Excess RGTA^® may hinder the healing process by drawing growth factors and communication peptides away from the wound site. In this situation, the bioavailability of growth factors required for efficient wound healing is reduced, emphasizing the need to optimize the RGTA^® treatment protocol (dose and timing) in accordance with the tissue specific matrix turnover

Fig. 2

Filling of craniotomy defects. A. Operative view of the defect. X-ray of defects treated with a collagen plaster soaked in 30 ul of B. saline, C. RGTA^® solution (25 μg/ml) D. RGTA^® solution (100 μg/ml) and E. RGTA^® solution (400 ug/ml), after 4 weeks. F. Full macroscopic view of the skull defect with top arrows showing both sides of the defect and bottom arrows indicating new bone formation. Note the convex shape of the new bone structure, matching with expected original bone. v at the center indicates the saggital vein. G. Enlargement showing the lamellar organization of the flat bone as expected from a skull. H. alkaline phosphatase positive osteoblastic cells