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Results of Clinical Trials of the World’s First Gene-Activated Material Published

Clinical trials of the world’s first gene-activated material for bone tissue regeneration used before dental implants and for the treatment of patients with bone defects have been completed. The gene-activated bone substitute simplifies the implementation of bone grafting, minimizes the use of the patient’s own bone tissue and takes the treatment results to a qualitatively new level.

The innovative medical device was developed by Histograft LLC, a Russian biotech company, the Skolkovo resident, in collaboration with the Human Stem Cells Institute (HSCI) and A. A. Baikov Institute of Metallurgy and Materials Science, Russian Academy of Sciences (IMET RAS).
The results of experimental and clinical studies supported by the Russian Science Foundation (RSF) have been published in the Frontiers in Bioengineering and Biotechnology journal.

Gene-activated material is a substance (matrix) compatible with the body with constructs from the genes of those compounds (factors) that lead to bone growth. Such constructs can be introduced into the implant material (in vivo gene therapy) or into multipotent mesenchymal stromal cells, which are then implanted on matrices (ex vivo gene therapy). Among gene-activated materials there are also tissue-engineered products containing cells, where constructs with therapeutic genes have been introduced.

The gene-activated bone substitute, marketed as “Histograft”, is based on octacalcium phosphate (OCP) granules and naked plasmid DNA carrying the vascular endothelial growth factor gene (pDNA-VEGF), a signaling protein produced by cells to stimulate the growth of blood vessels. OCP is one of the calcium phosphates that the authors of the article previously identified as a possible precursor of bone mineral components, capable of facilitating the specialization of young bone cells, and as an effective scaffold for cell delivery (https://pubs.acs.org/doi/abs/10.1021/am502583p). The granules serve as a matrix for bone tissue formation, and the DNA increases blood supply and bone tissue regeneration in the surgical area. The novel material simplifies bone grafting, minimizes the use of the patient’s own bone tissue and brings the results of treatment to a qualitatively new level.

In 2019, the Russian healthcare regulator (Roszdravnadzor) issued a registration certificate (marketing authorization) for this gene-activated bone substitute (OCP/pDNA-VEGF) to Histograft LLC. In April 2020, the company began its production and introduction into clinical practice in Russia. In April 2020, the company began manufacturing and introducing the medicinal product into clinical practice. It is intended for bone augmentation prior to the placement of dental implants and for the treatment of patients with bone defects.

At first, the scientists confirmed the mechanism of action of the material they created in the laboratory, and then conducted a clinical study on 20 patients. It has shown safety and high efficiency of the material in jaw bone grafting. Monitoring the patients for about a year, the researchers studied bone sections under a microscope and revealed a relatively rapid formation of own (native) bone tissue.

Ilya Bozo, Director of Histograft LLC and a practicing maxillofacial surgeon, said: “Publication of an article in a journal of such level indicates not only the compliance of the research with international standards, but also the significance of the results, both for the scientific community and for patients. The unique translational research has spanned over 10 years of joint work of several research teams. Various stages of the research were supported by grants from the Russian Science Foundation, the Fund for the Promotion of Innovations, investments by Artur Isaev and HSCI. An important milestone has passed, but there is still a lot of work and new variants of gene-activated materials that we are developing. Today, Histograft, in cooperation with HSCI and IMET RAS, continues to develop innovative gene-activated matrices containing plasmid DNA encoding therapeutic genes (VEGF, etc.) and plans to introduce into clinical practice the products as gel, membrane and personalized (3D-printed) implants. Prototypes have been developed, preclinical studies have been performed, 3D printing technology is undergoing an optimization stage based on the results of experimental studies on large laboratory animals.”

Vladimir Komlev, head of work, Doctor of Technical Sciences, Corresponding Member of the Russian Academy of Sciences, Director of IMET RAS, commented: “The comprehensive nature of this work — from fundamental research to product creation — is an outstanding example of effective coordination of efforts of the state, business and science in a priority area, namely, improving the quality of human life, and is fully consistent with the tasks set by the President of the Russian Federation within the framework of the Meeting of the Council for Science and education and programmes for the development of genetic technologies. The successful completion of the project was founded upon the use of appropriate set of instruments made available by the State — the Russian Science Foundation, the Fund for the Promotion of Innovations, and private investments.”

Figure 1. Critically sized bone defect repair in rabbits. (A) Full-defect histological images; (B) histological images from the central part of the defects at higher magnification: 1 – remaining fragments of implanted materials, 2 – newly formed bone tissue, 3 – fibrous tissue, H&E staining, scale bar: 300 μm; (C) quantitative evaluation of angiogenesis and bone formation; bone tissue rate is defined as the percentage of newly formed bone tissue in the total square of the defect (normal rate for the rabbit parietal bone measured with this method – 53 ± 3.5%). Bone defects were mostly filled by fibrous tissue in the empty defect group confirming the model to be critical-sized. The asterisks above the lines connecting the groups indicate statistically significant differences (p < 0.05). Source: Ilia Y. Bozo et al. / Front. Bioeng. Biotechnol., 2021

Figure 2. Bone grafting results in patients with unilateral alveolar ridge atrophy (A) and bone defect caused by radicular cyst (B). On the left – CT scans, on the right – histological images of the trephine biopsies: 1 – gene-activated bone substitute fragments, 2 – newly formed bone tissue, 3 – fibrous tissue, Mallory trichrome staining. Source: Ilia Y. Bozo et al. / Front. Bioeng. Biotechnol., 2021

Figure 3. Bone grafting results in patients with bilateral alveolar ridge atrophy. (A) The patient completed the clinical trial, on the left – CT scans: upper image – coronal view, bottom images – sagittal view, on the right – histological images of the trephine biopsy; (B) another patient completed the clinical trial, on the left – CT scans: upper image – coronal view, 6 months after surgery, bottom images – coronal view, 10 months after surgery and 4 months after dental implant placement; on the right – histological images of the trephine biopsy. 1 – gene-activated bone substitute fragments, 2 – newly formed bone tissue. H&E staining. Source: Ilia Y. Bozo et al. / Front. Bioeng. Biotechnol., 2021