Human Stem Cells Institute

Moscow, Russia

Human Stem Cells Institute

Moscow, Russia
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Zorin V.,Human Stem Cells Institute | Zorina A.,Human Stem Cells Institute | Kopnin P.,Blokhin Cancer Research Center | Leonov S.,Moscow Institute of Physics and Technology | And 3 more authors.
Aging | Year: 2017

Development of personalized skin treatment in medicine and skin care may benefit from simple and accurate evaluation of the fraction of senescent skin fibroblasts that lost their proliferative capacity. We examined whether enriched analysis of colonies formed by primary human skin fibroblasts, a simple and widely available cellular assay, could reveal correlations with the fraction of senescent cells in heterogenic cell population. We measured fractions of senescence associated β-galactosidase (SA-βgal) positive cells in either mass cultures or colonies of various morphological types (dense, mixed and diffuse) formed by skin fibroblasts from 10 human donors. Although the donors were chosen to be within the same age group (33-54 years), the colony forming efficiency of their fibroblasts (ECO-f) and the percentage of dense, mixed and diffuse colonies varied greatly among the donors. We showed, for the first time, that the SA-βgal positive fraction was the largest in diffuse colonies, confirming that they originated from cells with the least proliferative capacity. The percentage of diffuse colonies was also found to correlate with the SA-βgal positive cells in mass culture. Using Ki67 as a cell proliferation marker, we further demonstrated a strong inverse correlation (r=-0.85, p=0.02) between the percentage of diffuse colonies and the fraction of Ki67+ cells. Moreover, a significant inverse correlation (r=-0.94, p=0.0001) between the percentage of diffuse colonies and ECO-f was found. Our data indicate that quantification of a fraction of diffuse colonies may provide a simple and useful method to evaluate the extent of cellular senescence in human skin fibroblasts. © Zorin et al.

PubMed | Moscow State University, Ryazan State Medical University and Human Stem Cells Institute
Type: | Journal: Case reports in dentistry | Year: 2016

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 (5-14mm) 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.

Grigorian A.S.,Human Stem Cells Institute | Schevchenko K.G.,Human Stem Cells Institute
Cellular Transplantation and Tissue Engineering | Year: 2011

Gene therapeutic approaches to the restoration of the ischemic tissue perfusion are considered very promising, but to this time the molecular mechanisms which allow the therapeutic gene encoding plasmid to transfect the target cell and underlie the positive clinical effects remain unknown. In this review the possible molecular mechanisms of the angiogenic factor VEGF encoding plasmid penetration into the cytoplasm and the nucleus of the target cell are discussed, and also the methods for better transfection and the gene of interest expression are proposed.

Zorin V.L.,Human Stem Cells Institute | Komlev V.S.,RAS Institute of Metallurgy | Zorina A.I.,Human Stem Cells Institute | Khromova N.V.,Nn Blokhin Russian Cancer Research Center | And 4 more authors.
Biomedical Materials (Bristol) | Year: 2014

Biocompatible ceramic fillers are capable of sustaining bone formation in the proper environment. The major drawback of these scaffolding materials is the absence of osteoinductivity. To overcome this limitation, bioengineered scaffolds combine osteoconductive components (biomaterials) with osteogenic features such as cells and growth factors. The bone marrow mesenchymal stromal cells (BMMSCs) and the β-tricalcium phosphate (β-TCP) are well-known and characterized in this regard. The present study was conducted to compare the properties of novel octacalcium phosphate ceramic (OCP) granules with β-TCP (Cerasorb®), gingiva-derived mesenchymal stromal cells (GMSCs) properties with the BMMSCs and osteogenic and angiogenic properties of a bioengineered composite based on OCP granules and the GMSCs. This study demonstrates that GMSCs and BMMSCs have a similar osteogenic capacity. The usage of OCP ceramic granules in combination with BMMSCs/GMSCs significantly affects the osteo- and angiogenesis in bone grafts of ectopic models. © 2014 IOP Publishing Ltd.

Chogovadze A.G.,Human Stem Cells Institute
Cellular Transplantation and Tissue Engineering | Year: 2012

Advances in methods of molecular genetic diagnosis have made it possible to determine whether a child will be born with a certain genetic disorder. And the use of assisted reproductive technologies make it possible to screen for genetic conditions at an earlier embryonic stage, before implanting the embryo in the mothers uterus. However, such diagnostic technologies can potentially be used for non-medical purposes, i.e., for sex selection. This contradicts to modern concepts of bioethics, so most countries have introduced legislative restrictions on the conduction of such genetic testing.

PubMed | Moscow State University, Kazan Federal University and Human Stem Cells Institute
Type: | Journal: BioMed research international | Year: 2015

Bone grafts are medical devices that are in high demand in clinical practice for substitution of bone defects and recovery of atrophic bone regions. Based on the analysis of the modern groups of bone grafts, the particularities of their composition, the mechanisms of their biological effects, and their therapeutic indications, applicable classification was proposed that separates the bone substitutes into ordinary and activated. The main differential criterion is the presence of biologically active components in the material that are standardized by qualitative and quantitative parameters: growth factors, cells, or gene constructions encoding growth factors. The pronounced osteoinductive and (or) osteogenic properties of activated osteoplastic materials allow drawing upon their efficacy in the substitution of large bone defects.

PubMed | Human Stem Cells Institute
Type: | Journal: American journal of cardiovascular drugs : drugs, devices, and other interventions | Year: 2017

The effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. pl-VEGF165, a gene therapy drug, was approved in Russia for the treatment of atherosclerotic peripheral arterial disease (PAD) after clinical studies in 2011. The study drug is an original gene construction in which pl-VEGF165 1.2mg is the active substance.This postmarketing surveillance study was undertaken to evaluate the safety (identification of uncommon side effects) and efficacy of gene therapy in patients in routine clinical practice.In total, 210 patients with stage II-III chronic limb ischemia (according to the Fontaine classification modified by AV Pokrovsky) in 33 healthcare facilities in Russia and the Ukraine were enrolled in the study. The control group (n=60) received conservative therapy without prostaglandins and prostacyclins, and the treatment group (n=150) received treatment with pl-VEGF165 as two intramuscular injections for a total dose of 2.4mg. Pain-free walking distance (PWD) (the primary efficacy criterion for Fontaine stages II-III), blood flow linear velocity (BFLV), and ankle-brachial index (ABI) were monitored for 6months. The safety of pl-VEGF165 gene transfer in terms of the trial protocol was initially evaluated 6months after the start of the study; adverse events (AEs) and serious adverse events (SAEs) were recorded during both routine visits and unscheduled requests for medical care.Overall, PWD increased by 177%, from 100.36.9 to 277.116.2m (p=0.0001), in the treatment group, whereas the mean value was unchanged in the control group (p=0.218). Both BFLV and ABI values increased by 24% (p=0.0001) in the treatment group but decreased in the control group. The greatest therapeutic effect was observed for stage III disease: PWD increased by 683% (p=0.0001). No angiogenic therapy-related AEs or side effects were recorded, and target limb salvage was 96 and 97% in the treatment and control groups, respectively. The results obtained in this study are not significantly different from those observed in the phase IIb/III registration clinical study completed in intramuscular gene transfer is an effective treatment for moderate to severe claudication due to chronic lower limb ischemia in routine clinical practice. identifier: NCT02369809.

PubMed | Human Stem Cells Institute and Yaroslavl State University
Type: Journal Article | Journal: Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery | Year: 2016

The authors share their experience in comprehensive conservative treatment of patients presenting with chronic lower limb ischaemia (CLLI) associated with atherosclerosis of peripheral arteries by means of the first Russian registered gene therapeutic agent Neovasculgen (plasmid with the vegf165 gene), analysing the long-term outcomes of treating a total of 45 patients with stage II and III CLLI according to the classification of Pokrovsky-Fontain. The patients were followed up for 5 years. Efficacy of treatment was assessed by registering the dynamics of the pain-free walking distance (PFWD), linear blood velocity (LBV), ankle-brachial index (ABI), as well as the limb salvage rate and survival of patients. All patients showed good tolerance of treatment, with neither side effects nor complications noted. Clinical improvement in stage IIB CLLI was observed in 91% of patients with complete stabilization of the clinical course during 5 years. The limb salvage rate in this group amounted to 95%, with the survival rate equalling 82%. In patients with stage III CLLI, improvement was noted in 78% of cases, manifesting itself by a decrease of its degree to stage IIB (44.4%) and to stage IIA (33.3%). Progression of CLLI followed by amputation was registered in 22% of cases, with the survival rate of 78%. Hence, the use of a single course of combined treatment including the gene therapeutic agent Neovasculgen in patients with stage II and III CLLI resulted in a persistent positive effect in a considerable majority of patients in the remote period of not less than 5 years.

PubMed | Human Stem Cells Institute and Yaroslavl State University
Type: Comparative Study | Journal: Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery | Year: 2016

Presented herein are comparative remote results of combined surgical treatment of 121 patients with stage IIB-III lower limb chronic ischaemia (LLCI) by means of indirect revascularization (lumbar sympathectomy--LSE and revascularizing osteotrepanation of the tibial bone--ROT) and gene therapy using the first registered Russian gene therapeutic agent Neovasculgen. Depending on the LLCI degree and the method of treatment, during 3 years we assessed such parameters as the limb salvage rate, pain-free walk distance (PFWD), ankle-brachial index (ABI) and linear blood velocity (LBV). An increase in the PFWD in patients with initial stage IIB LLCI in the group of gene therapy was considerably higher than in other types of treatment (p=0.0001-0.0004). Using indirect methods of revascularization was accompanied and followed by less positive alterations in the PFWD values which by the end of the third year of follow up were observed to decrease. The values of PFWD after ROT at 2 and 3 years were higher than after LSE (p=0.006). During the first year of follow up the highest increment of the ABI was observed after ROT. At two years, the ABI values after ROT and gene therapy became equal. The worst result during 3 years as compared with other methods of treatment was demonstrated by LSE (p=0.006). Changes in ABI after gene therapy were statistically significant at all terms of follow up (p=0.008-0.02). There were no limb amputations in the remote period of follow up in patients with the initial stage IIB of the disease. Patients with initial stage III LLCI also showed a considerably better result by the increment of increased PFWD after gene-therapeutic treatment (p=0.001-0.0005). A small increment of the PFWD after LSE maintained during 1 year and after LSE during 2 years. The ABI values in all periods of follow up were higher after gene therapy (p=0.01-0.003). During the 2- and 3-year period the increment of this parameter after ROT was more significant than after LSE (p=0.046-0.05). Changes in the ABI after gene therapy at all terms also turned out to be more substantial (p=0.03-0.008). An increase in the LBV during the first and second years after ROT turned out more significant as compared to LSE (p=0.05). The limb salvage rate in patients with initial stage III LLCI during the whole period after gene therapy amounted to 78%, after ROT being 54% and after LSE equalling 45%.

News Article | November 29, 2016

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