World’s First Clinical Case of Gene-Activated Bone Substitute Application

Abstract

Treatment of patients with large bone defects is a complex clinical problem. We have initiated the first clinical study of a gene-activated bone substitute composed of the collagen-hydroxyapatite scaffold and plasmid DNA encoding vascular endothelial growth factor. The first patient with two nonunions of previously reconstructed mandible was enrolled into the study. Scar tissues were excised; bone defects (5–14 mm) between the mandibular fragments and nonvascularized rib-bone autograft were filled in with the gene-activated bone substitute. No adverse events were observed during 12 months of follow-up. In 3 months, the average density of newly formed tissues within the implantation zone was 402.21 ± 84.40 and 447.68 ± 106.75 HU in the frontal and distal regions, respectively, which correlated with the density of spongy bone. Complete distal bone defect repair with vestibular and lingual cortical plates formation was observed in 6 and 12 months after surgery; thereby the posterior nonunion was successfully eliminated. However, there was partial resorption of the proximal edge of the autograft entailed to relapse of the anterior nonunion. Thus, the first clinical data on the safety and efficacy of the gene-activated bone substitute were obtained. Given a high complexity of the clinical situation the treatment, results might be considered as promising. NCT02293031.

3D Printed Gene-activated Octacalcium Phosphate Implants for Large Bone Defects Engineering

“…Based on our previous results in OCP studies[ 27 ], 3D printing of OCP-based implants[ 11 ] and standardized gene-activated materials[ 23 , 28 ], we have started the development of a personalized gene-activated bone substitute based on the OCP and plasmid DNA that delivers VEGFA gene, applicable for large bone defects substitution and guided bone regeneration. We expected the increased level of VEGFA to promote angiogenesis and reparative osteogenesis.…”

“…Moreover, a direct stimulating effects of VEGF on proliferation and differentiation of bone cells[ 29 ] and non-canonic intracrine effects specific for a VEGF gene transfer[ 30 ] were described. Additional prerequisites to use this gene construct in the study were our previously obtained clinical data on a successful treatment of a patient with mandibular non-unions with the use of a gene-activated material, delivering VEGFA [ 28 ].…”

The Few Who Made It: Commercially and Clinically Successful Innovative Bone Grafts

“…A sophisticated new approach able to circumvent this limitation is based on the exogenous delivery of plasmid DNAs from gene-activated matrices to the host cells in the site of bone defects, to induce the endogenous production of reparative growth factors. In a recent clinical trial, a combination product based on a collagen-hydroxyapatite medical device and a plasmid DNA encoding for vascular endothelial growth factor-A (VEGF-A), showed to promote bone ingrowth in maxillofacial bone defects without causing adverse effects ( Bozo et al, 2016 ). Similarly, Histograft (Russia) has developed an octacalcium phosphate scaffold carrying VEGF-A coding plasmid that has completed a clinical trial (NCT03076138).…”

Scaffold‐Based Delivery of Nucleic Acid Therapeutics for Enhanced Bone and Cartilage Repair

“…Additionally, the announcement by the FDA Commissioner Scott Gottlieb, M.D, in July 2018, on the new framework for the development, review and approval of gene therapies, holds great promise in shaping the future of medicine. This “fast‐tracking” of gene therapies by regulatory bodies, along with the recent approval of several gene therapies and the first clinical case of scaffold‐based gene delivery, will only further enhance the ongoing drive among researchers for the creation and clinical approval of novel therapeutic strategies such as those described throughout this review.…”