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Functionality of a bicistronic construction containing HEXA and HEXB genes encoding β-hexosaminidase A for cell-mediated therapy of GM2 gangliosidoses

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Neural Regeneration Research 2022年第1期17卷 122-129页

作者： Alisa A.Shaimardanova Daria S.Chulpanova Valeriya V.Solovyeva Aleksandr M.Aimaletdinov Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia

Tay-Sachs disease and Sandhoff disease are severe hereditary neurodegenerative disorders caused by a deficiency ofβ-hexosaminidase A(HexA)enzyme,which results in the accumulation of GM2 gangliosides in the nervous system cells.In this work,we analyzed the efficacy and safety of cell-mediated gene therapy for Sandhoff disease and Sandhoff disease using a bicistronic lentiviral vector encoding cDNA of HexAα-andβ-subunit genes separated by the nucleotide sequence of a P2A peptide(HEXA-HEXB).The functionality of the bicistronic construct containing the HEXA-HEXB genetic cassette was analyzed in a culture of HEK293T cells and human umbilical cord blood mononuclear cells(hUCBMCs).Our results showed that the enzymatic activity of HexA in the conditioned medium harvested from genetically modified HEK293T-HEXA-HEXB and hUCBMCs-HEXA-HEXB was increased by 23 and 8 times,respectively,compared with the conditioned medium of native cells.Western blot analysis showed that hUCBMCs-HEXA-HEXB secreted both completely separated HEXA and HEXB proteins,and an uncleaved protein containing HEXA+HEXB linked by the P2A peptide.Intravenous injection of genetically modified hUCBMCs-HEXA-HEXB to laboratory Wistar rats was carried out,and the HexA enzymatic activity in the blood plasma of experimental animals,as well as the number of live cells of immune system organs(spleen,thymus,bone marrow,lymph nodes)were determined.A significant increase in the enzymatic activity of HexA in the blood plasma of laboratory rats on days 6 and 9(by 2.5 and 3 times,respectively)after the administration of hUCBMCsHEXA-HEXB was shown.At the same time,the number of live cells in the studied organs remained unchanged.Thus,the functionality of the bicistronic genetic construct encoding cDNA of the HEXA and HEXB genes separated by the nucleotide sequence of the P2A peptide was shown in vitro and in vivo.We hypothesize that due to the natural ability of hUCBMCs to overcome biological barriers,such a strategy can restore the activity of the missing enzyme in the ce

关键词： bicistronic vector cell-mediated gene therapy GM2 gangliosidosis P2A peptide Sandhoff disease Tay-Sachs disease umbilical cord blood mononuclear cells β-hexosaminidase

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Mesenchymal stem cells and the neuronal microenvironment in the area of spinal cord injury

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Neural Regeneration Research 2019年第2期14卷 227-237页

作者： Yana O.Mukhamedshina Olga A.Gracheva Dina M.Mukhutdinova Yurii A.Chelyshev Albert A.Rizvanov OpenLab Gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region)Federal University Department of Histology Cytology and Embryology Kazan State Medical University Department of Therapy and Clinical Diagnostics with radiology Faculty of Veterinary Medicine Bauman Kazan State Academy of Veterinary Medicine OpenLab Gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region) Federal University

Cell-based technologies are used as a therapeutic strategy in spinal cord injury(SCI). Mesenchymal stem cells(MSCs), which secrete various neurotrophic factors and cytokines, have immunomodulatory, anti-apoptotic and anti-inflammatory effects, modulate reactivity/phenotype of astrocytes and the microglia, thereby promoting neuroregeneration seem to be the most promising. The therapeutic effect of MSCs is due to a paracrine mechanism of their action, therefore the survival of MSCs and their secretory phenotype is of particular importance. Nevertheless, these data are not always reported in efficacy studies of MSC therapy in SCI. Here, we provide a review with summaries of preclinical trials data evaluating the efficacy of MSCs in animal models of SCI. Based on the data collected, we have tried(1) to establish the behavior of MSCs after transplantation in SCI with an evaluation of cell survival, migration potential, distribution in the area of injured and intact tissue and possible differentiation;(2) to determine the effects MSCs on neuronal microenvironment and correlate them with the efficacy of functional recovery in SCI;(3) to ascertain the conditions under which MSCs demonstrate their best survival and greatest efficacy.

关键词： spinal cord injury mesenchymal stem cells survival migration Rho/ROCK/PTEN astrocytes microglia myelin-forming cells axon growth tissue integrity

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Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

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Neural Regeneration Research 2020年第4期15卷 586-596页

作者： Alisa A.Shaimardanova Valeriya V.Solovyeva Daria S.Chulpanova Victoria James Kristina V.Kitaeva Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry The Russian Academy of SciencesMoscowRussia School of Veterinary Medicine and Science University of NottinghamSutton Bonington CampusLeicestershireUK

Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.

关键词： biomarkers cell-mediated therapy central nervous system diseases diagnosis exosomes extracellular RNAs extracellular vesicles microRNAs microvesicles neurodegenerative diseases

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Increasingβ-hexosaminidase A activity using genetically modified mesenchymal stem cells

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Neural Regeneration Research 2024年第1期19卷 212-219页

作者： Alisa A.Shaimardanova Daria S.Chulpanova Valeriya V.Solovуeva Shaza S.Issa Aysilu I.Mullagulova Angelina A.Titova Yana O.Mukhamedshina Anna V.Timofeeva Alexander M.Aimaletdinov Islam R.Nigmetzyanov Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Department of Histology Cytology and EmbryologyKazan State Medical UniversityKazanRussia

GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorde rs.These diseases result from a deficiency of lysosomal enzymeβ-hexosaminidase A(HexA),which is responsible for GM2 ganglioside degradation.HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells,leading to severe progressive neurodegeneration and neuroinflammation.To date,there is no treatment for these diseases.Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses.This study aimed to evaluate the ability of genetically modified mesenchymal stem cells(MSCs-HEXA-HEXB)to restore HexA deficiency in Tay-Sachs disease patient cells,as well as to analyze the functionality and biodistribution of MSCs in vivo.The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon intera ction with MSCs-HEXA-HEXB.The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme,detectable in vivo,and intravenous injection of the cells does not cause an immune response in animals.These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses.

关键词： adeno-associated viral vectors cell therapy cell-mediated gene therapy gene therapy GM2 gangliosidosis Sandhoff disease Tay-Sachs disease β-hexosaminidase

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Gene-modified leucoconcentrate for personalized ex vivo gene therapy in a mini pig model of moderate spinal cord injury

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Neural Regeneration Research 2021年第2期16卷 357-361页

作者： Rustem R.Islamov Farid V.Bashirov Mikhail E.Sokolov Andrei A.Izmailov Filip O.Fadeev Vage A.Markosyan Maria A.Davleeva Olga V.Zubkova Maxim M.Smarov Denis Yu.Logunov Boris S.Naroditskyi Ilnur I.Salafutdinov Albert A.Rizvanov Ramil G.Turaev Kazan State Medical University KazanRussia Gamaleya Research Institute of Epidemiology and Microbiology MoscowRussia Kazan Federal University KazanRussia The Republican Blood Center of the Ministry of Health of the Republic of Tatarstan KazanRussia

We previously demonstrated that gene-modified umbilical cord blood mononuclear cells overexpressing a combination of recombinant neurotrophic factors are a promising therapeutic approach for cell-mediated gene therapy for neurodegenerative diseases,neurotrauma,and stroke.In this study,using a mini pig model of spinal cord injury,we proposed for the first time the use of gene-modified leucoconcentrate prepared from peripheral blood in the plastic blood bag for personalized ex vivo gene therapy.Leucoconcentrate obtained from mini pig peripheral blood was transduced with a chimeric adenoviral vector(Ad5/35 F)that carried an enhanced green fluorescent protein(EGFP)reporter gene in the plastic blood bag.The day after blood donation,the mini pigs were subjected to moderate SCI and four hours post-surgery they were intravenously autoinfused with gene-modified leucoconcentrate.A week after gene-modified leucoconcentrate therapy,fluorescent microscopy revealed EGFP-expressing leucocytes in spinal cord at the site of contusion injury.In the spleen the groups of EGFP-positive cells located in the lymphoid follicles were observed.In vitro flow cytometry and fluorescent microscopy studies of the gene-modified leucoconcentrate samples also confirmed the production of EGFP by leucocytes.Thus,the efficacy of leucocytes transduction in the plastic blood bag and their migratory potential suggest their use for temporary production of recombinant biologically active molecules to correct certain pathological conditions.This paper presents a proof-of-concept of simple,safe and effective approach for personalized ex vivo gene therapy based on gene-modified leucoconcentrate autoinfusion.The animal protocols were approved by the Kazan State Medical University Animal Care and Use Committee(approval No.5)on May 27,2014.

关键词： chimeric Ad5/35F virus enhanced green fluorescent protein gene-modified leucoconcentrate mini pig peripheral blood personalized ex vivo gene therapy plastic blood bag spinal cord injury

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Genetically modified human umbilical cord blood cells as a promising strategy for treatment of spinal cord injury

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Neural Regeneration Research 2016年第9期11卷 1420-1421页

作者： Yana O. Mukhamedshina albert A. rizvanov Kazan (Volga Region) Federal University Kazan Russia

Spinal cord injury （SCI） continues to be a pressing health and social problem. The injury leads to neuronal and glial cell death accompanied by degeneration of nerve fibers. There are currently no particularly effective treatments. SCI causes profound disabil- ity of people affected and has attracted increased attention in the international field of neuroregeneration. For the past two decades, much hope has been placed in cell therapies for the restoration of both structure and function of the injured spinal cord. Embryonic and neural stem cells, olfactory ensheathing cells, microglia-like cells, Schwann cells, mesenchymal stem cells.

关键词： gene cell VEGF GDNF Genetically modified human umbilical cord blood cells as a promising strategy for treatment of spinal cord injury SCI

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Application of neurotrophic and proangiogenic factors as therapy after peripheral nervous system injury

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Neural Regeneration Research 2022年第6期17卷 1240-1247页

作者： Kamilla Faritovna Idrisova Alina Kazymovna Zeinalova Galina Andreevna Masgutova Alexey Andreevich Bogov Jr. Cinzia Allegrucci Valeriia Yurievna Syromiatnikova Ilnur Ildusovich Salafutdinov Ekaterna Evgenievna Garanina Dina Ivanovna Andreeva Adilet Abdullaatovich Kadyrov albert Anatolevich rizvanov Ruslan Faridovich Masgutov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Republican Clinical Hospital KazanRussia Biodiscovery Institute School of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK Department of Traumatology and Orthopedics Kazan State Medical AcademyKazanRussia

The intrinsic ability of peripheral nerves to regenerate after injury is extremely limited,especially in case of severe injury.This often leads to poor motor function and permanent disability.Existing approaches for the treatment of injured nerves do not provide appropriate conditions to support survival and growth of nerve cells.This drawback can be compensated by the use of gene therapy and cell therapy-based drugs that locally provide an increase in the key regulators of nerve growth,including neurotrophic factors and extracellular matrix proteins.Each growth factor plays its own specific angiotrophic or neurotrophic role.Currently,growth factors are widely studied as accelerators of nerve regeneration.Particularly noteworthy is synergy between various growth factors,that is essential for both angiogenesis and neurogenesis.Fibroblast growth factor 2 and vascular endothelial growth factor are widely known for their proangiogenic effects.At the same time,fibroblast growth factor 2 and vascular endothelial growth factor stimulate neural cell growth and play an important role in neurodegenerative diseases of the peripheral nervous system.Taken together,their neurotrophic and angiogenic properties have positive effect on the regeneration process.In this review we provide an in-depth overview of the role of fibroblast growth factor 2 and vascular endothelial growth factor in the regeneration of peripheral nerves,thus demonstrating their neurotherapeutic efficacy in improving neuron survival in the peripheral nervous system.

关键词： fibroblast growth factor 2 growth factors nerve growth factor peripheral nerve injury peripheral nervous system vascular endothelial growth factor

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Angiogenesis and nerve regeneration induced by local administration of plasmid pBud-coVEGF165-coFGF2 into the intact rat sciatic nerve

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Neural Regeneration Research 2021年第9期16卷 1882-1889页

作者： Ruslan Masgutov Alina Zeinalova Alexey Bogov Galina Masgutova Ilnur Salafutdinov Ekaterina Garanina Valeriia Syromiatnikova Kamilla Idrisova Adelya Mullakhmetova Dina Andreeva Liliya Mukhametova Adilet Kadyrov Igor Pankov albert rizvanov OpenLab“Gene and Cell Technologies” Institute of Fundamental Medicine and BiologyKazan Federal UniversityKazanRussia Republican Clinical Hospital KazanRussia Department of Traumatology and Orthopedics Kazan State Medical AcademyKazanRussia

Vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present study, we elucidated the local and systemic effects of plasmid construct рBud-coVEGF165-coFGF2 injected into the epineurium of intact rat sciatic nerve. Results of histological examination of sciatic nerve and multiplex immunoassays of serum showed the absence of immunogenicity and biosafety of plasmid рBud-coVEGF165-coFGF2. Moreover, local administration of plasmid DNA construct resulted in significantly decreased levels of pro-inflammatory cytokines in the peripheral blood, including tumor necrosis factor α(TNFα) and interleukin-12, and significantly increased levels of cytokines and chemokines including Regulated upon Activation, Normal T Cell Expressed and Presumably Secrete(RANTES), epidermal growth factor, interleukin-2, and monocyte chemoattractant protein 1. These changes in the peripheral blood on day 7 after injection of plasmid construct рBud-coVEGF165-coFGF2 show that the plasmid construct has systemic effects and may modulate immune response. At the same time, reverse transcriptionpolymerase chain reaction revealed transient expression of coFGF2, coVEGF165, ratFGF2 and ratVEGFA with direct transport of transcripts from distal part to proximal part of the sciatic nerve. Immunohistochemical staining revealed prolonged presence of VEGFA in sciatic nerve till 14 days post-injection. These findings suggest that local administration of plasmid construct рBud-coVEGF165-coFGF2 at a concentration of 30 ng/μL results in the formation of pro-angiogenic stimuli and, and the plasmid construct, used as a drug for gene therapy, might potentially facilitate regeneration of the sciatic nerve. The study was approved by the Animal Ethics Committee of Kazan Federal University, procedures were approved by the Local Ethics Committee(approval No. 5) on May 27, 2014.

关键词： chemokines cytokines fibroblast growth factor gene therapy growth factors peripheral nerve system sciatic nerve regeneration vascular endothelial growth factor

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Combination of epidural electrical stimulation with ex vivo triple gene therapy for spinal cord injury:a proof of principle study

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Neural Regeneration Research 2021年第3期16卷 550-560页

作者： Filip Olegovich Fadeev Farid Vagizovich Bashirov Vahe Arshaluysovich Markosyan Andrey Alexandrovich Izmailov Tatyana Vyacheslavovna Povysheva Mikhail Evgenyevich Sokolov Maxim Sergeevich Kuznetsov Anton Alexandrovich Eremeev Ilnur Ildusovich Salafutdinov albert Anatolyevich rizvanov Hyun Joon Lee Rustem Robertovich Islamov Department of Medical Biology and Genetics Kazan State Medical UniversityKazanRussia Federal University KazanRussia Department of Neurology University of Mississippi Medical CenterJacksonMSUSA Research Service G.V.(Sonny)Montgomery VA Medical CenterJacksonMSUSA

Despite emerging contemporary biotechnological methods such as gene-and stem cell-based therapy,there are no clinically established therapeutic strategies for neural regeneration after spinal cord injury.Our previous studies have demonstrated that transplantation of genetically engineered human umbilical cord blood mononuclear cells producing three recombinant therapeutic molecules,including vascular endothelial growth factor(VEGF),glial cell-line derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)can improve morpho-functional recovery of injured spinal cord in rats and mini-pigs.To investigate the efficacy of human umbilical cord blood mononuclear cells-mediated triple-gene therapy combined with epidural electrical stimulation in the treatment of spinal cord injury,in this study,rats with moderate spinal cord contusion injury were intrathecally infused with human umbilical cord blood mononuclear cells expressing recombinant genes VEGF165,GDNF,NCAM1 at 4 hours after spinal cord injury.Three days after injury,epidural stimulations were given simultaneously above the lesion site at C5(to stimulate the cervical network related to forelimb functions)and below the lesion site at L2(to activate the central pattern generators)every other day for 4 weeks.Rats subjected to the combined treatment showed a limited functional improvement of the knee joint,high preservation of muscle fiber area in tibialis anterior muscle and increased H/M ratio in gastrocnemius muscle 30 days after spinal cord injury.However,beneficial cellular outcomes such as reduced apoptosis and increased sparing of the gray and white matters,and enhanced expression of heat shock and synaptic proteins were found in rats with spinal cord injury subjected to the combined epidural electrical stimulation with gene therapy.This study presents the first proof of principle study of combination of the multisite epidural electrical stimulation with ex vivo triple gene therapy(VEGF,GDNF and NCAM)for treatment of spinal cord injury in rat mode

关键词： adenoviral vector epidural electrical stimulation gene therapy glial cell-line derived neurotrophic factor human umbilical cord blood mononuclear cell neural cell adhesion molecule spinal cord injury vascular endothelial growth factor

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