Pilot study of the safety and efficacy of angiogenic therapy in diabetic foot syndrome

BACKGROUND: The syndrome of diabetic foot remains the main cause of non-traumatic amputation of the lower extremity in the world. Even with the provision of comprehensive medical care in the conditions of a specialized center, 10-15% of patients do not succeed in healing the ulcerative defect due to the ischemic component. AIMS: The objective of this study is evaluation of safety and efficacy of pl-VEGF165 transfer in patients with neuroischemic type of diabetic foot syndrome. METHODS: The pilot study included 35 diabetic patients with neuroischemic foot ulcers (Wagner stage 1-2) who were not candidates for revascularization procedures (NCT02538705). The patients were closely monitored after repeated pl-VEGF165 intramuscular gene transfer (2,4 mg) at 1, 3, and 6 months after treatment. The primary efficacy endpoint was the surface area of the ulcers (sq.cm), the secondary endpoints were transcutaneous oxygen tension (Tcp02), ankle-brachial index (ABI), neuropathy disability score (NDS), neuropathy symptoms score (NSS), and Michigan neuropathy screening instrument (MNSI). Adverse events were monitored throughout the study. RESULTS: The use of pl-VEGF165 as part of complex treatment allowed to achieve wound healing in 65,7% of patients with chronic ulcerative defects, the safety of the target limb was 84%. Carrying out therapeutic angiogenesis as a part of the combined therapy ensured a reduction in the average area of the resistant to treatment defects from 3.6 [1.0; 7.05] cm2 to 0.0 [0.0;2.0] cm2 (p=0,001), which correlated with an increase in the TcPo2 index by 15% from 35 [29.5; 40.5] to 40.5 [36.0; 46.5] mm Hg (p= p=0,005) and in the ABI by 16% from 0.96 [0.82;1.08] to 1.11 [0.85; 1.24] (p=0,062). The decrease in the signs of diabetic neuropathy was determined - the scores of NSS scales and VAT decreased from 6,5 [5.75; 8.0) to 6.0 [5.25; 7.0] (p=0,004) and from 9.0 [8.0; 13.5] to 8.0 [7.0; 12.7] (p=0,001), respectively. No adverse effects associated with the use of pl-VEGF165 were recorded. CONCLUSIONS: Thus, preliminary results of the pilot study show that the use of pl-VEGF165 gene transfer in combination therapy allows for complete healing of neuroischemic diabetic foot ulcers in the majority of patients

Design and Immunological Properties of the Novel Subunit Virus-like Vaccine against SARS-CoV-2

The COVID-19 pandemic is ongoing, and the need for safe and effective vaccines to prevent infection and to control spread of the virus remains urgent. Here, we report the development of a SARS-CoV-2 subunit vaccine candidate (Betuvax-CoV-2) based on RBD and SD1 domains of the spike (S) protein fused to a human IgG1 Fc fragment. The antigen is adsorbed on betulin adjuvant, forming spherical particles with a size of 100–180 nm, mimicking the size of viral particles. Here we confirm the potent immunostimulatory activity of betulin adjuvant, and demonstrate that two immunizations of mice with Betuvax-CoV-2 elicited high titers of RBD-specific antibodies. The candidate vaccine was also effective in stimulating a neutralizing antibody response and T cell immunity. The results indicate that Betuvax-CoV-2 has good potential for further development as an effective vaccine against SARS-CoV-2

Glu20Ter Variant in PLEC 1f Isoform Causes Limb-Girdle Muscle Dystrophy with Lung Injury

Plectinopathies are orphan diseases caused by PLEC gene mutations. PLEC is encoding the protein plectin, playing a role in linking cytoskeleton components in various tissues. In this study, we describe the clinical case of a 26-year-old patient with an early onset plectinopathy variant “limb-girdle muscle dystrophy type 2Q,” report histopathological and ultrastructural findings in m. vastus lateralis biopsy and a novel homozygous likely pathogenic variant (NM_201378.3:c.58G>T, NP_958780.1:p.Glu20Ter) in isoform 1f of the gene PLEC. The patient had an early childhood onset with retarded physical development, moderate weakness in pelvic girdle muscles, progressive weakening of limb-girdle muscles after the age of 21, pronounced atrophy of axial muscles, and hypertrophy of the gastrocnemius, deltoid, and triceps muscles, intermittent dyspnea, and no skin involvement. Findings included: non-infectious bronchiolitis and atelectasis signs, biopsy revealed myodystrophal pattern without macrophage infiltration, muscle fiber cytoskeleton disorganization resulted from the plectin loss, incomplete reparative rhabdomyogenesis, and moderate endomysial fibrosis. We have determined a novel likely pathogenic variant in PLEC 1f isoform that causes limb-girdle muscle dystrophy type 2Q and described the third case concerning an isolated myodystrophic phenotype of LGMD2Q with the likely pathogenic variant in PLEC 1f isoform. In addition, we have demonstrated the presence of severe lung injury in a patient and his siblings with the same myodystrophic phenotype and discussed the possible role of plectin deficiency in its pathogenesis

SARS-CoV-2 Subunit Virus-like Vaccine Demonstrates High Safety Profile and Protective Efficacy: Preclinical Study

Public health threat coming from a rapidly developing COVID-19 pandemic calls for developing safe and effective vaccines with innovative designs. This paper presents preclinical trial results of “Betuvax-CoV-2”, a vaccine developed as a subunit vaccine containing a recombinant RBD-Fc fusion protein and betulin-based spherical virus-like nanoparticles as an adjuvant (“Betuspheres”). The study aimed to demonstrate vaccine safety in mice, rats, and Chinchilla rabbits through acute, subchronic, and reproductive toxicity studies. Along with safety, the vaccine demonstrated protective efficacy through SARS-CoV-2-neutralizing antibody production in mice, rats, hamsters, rabbits, and primates (rhesus macaque), and lung damage and infection protection in hamsters and rhesus macaque model. Eventually, “Betuvax-CoV-2” was proved to confer superior efficacy and protection against the SARS-CoV-2 in preclinical studies. Based on the above results, the vaccine was enabled to enter clinical trials that are currently underway

Safety and Immunogenicity of Betuvax-CoV-2, an RBD-Fc-Based SARS-CoV-2 Recombinant Vaccine: Preliminary Results of the First-in-Human, Randomized, Double-Blind, Placebo-Controlled Phase I/II Clinical Trial

COVID-19, being a life-threatening infection that evolves rapidly, remains a major public health concern calling for the development of vaccines with broad protection against different pathogenic strains and high immunogenicity. Aside from this, other concerns in mass immunization settings are also the scalability of production and relative affordability of the technology. In that regard, adjuvanted protein vaccines with particles mimicking the virus stand out among known vaccine technologies. The “Betuvax-CoV-2” vaccine, developed on the basis of a recombinant protein and an adjuvant, has already been tested in preclinical studies and has advanced to clinical evaluation. Open, double-blinded, placebo-controlled, randomized phase I/II clinical trial of the “Betuvax-CoV-2,” recombinant protein subunit vaccine based on the S-protein RBD fused with the Fc-fragment of IgG, was conducted to evaluate safety and immunogenicity in response to the vaccination. Methods: In the phase I/II clinical trial, 116 healthy adult men and women, ages 18–58, were enrolled: 20 in Stage I, and 96 in Stage II. In Stage I, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 1) or 20 µg (group 2) on day 30. In Stage II, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 3) or 20 µg (group 4) on day 30. In group 5, both injections were replaced with placebo. The primary outcome measures were safety (number of participants with adverse events throughout the study) and antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA and CMIA). Antigen-specific cell-mediated immunity and changes in neutralizing antibodies (detected with a SARS-CoV-2 neutralization assay) were measured as a secondary outcome. The trial is registered with ClinicalTrials.gov (Study Identifier: NCT05270954). Findings: Both vaccine formulations (20 µg + 5 µg and 20 µg + 20 µg) were safe and well tolerated. Most adverse events were mild, and no serious adverse events were detected. On day 51,anti-SARS-CoV-2 total and IgG antibody titers and anti-SARS-CoV-2 neutralizing antibodies were significantly higher in the vaccine groups (both formulations) than in the placebo. A more pronounced CD4+-mediated immune response was observed in the group of volunteers administered with the 20 + 20 μg vaccine formulation. Interpretations: RBD-Fc-based COVID-19 “Betuvax-CoV-2” vaccine in doses (20 + 5 µg and 20 + 20 µg) demonstrated an excellent safety profile and induced a strong humoral response. Further research on the protective effectiveness of the “Betuvax-CoV-2” vaccine for the prevention of COVID-19 is on its way