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Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model

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Neural Regeneration Research 2023年第7期18卷 1505-1511页

作者： Maria Aleksandrovna Davleeva Ravil Rasimovich Garifulin farid vagizovich bashirov Andrei Aleksandrovich Izmailov Leniz Faritovich Nurullin Ilnur Ildusovich Salafutdinov Dilara Zilbarovna Gatina Dmitrij Nikolaevich Shcherbinin Andrei Aleksandrovich Lysenko Irina Leonidovna Tutykhina Maksim Mikhailovich Shmarov Rustem Robertovich Islamov Department of Histology Cytology and EmbryologyKazan State Medical UniversityKazanRussia Кazan Institute of Biochemistry and Biophysics Federal Research Center of Kazan Scientific Center of Russian Academy of SciencesKazanRussia Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia The National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F.Gamaleya of the Ministry of Health of the Russian Federation MoscowRussia

Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligo

关键词： autologous genetically-enriched leucoconcentrate chimeric adenoviral vector gene therapy glial cell line-derived neurotrophic factor mini-pig neural cell adhesion molecule spinal cord contusion injury 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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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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