Symptomatic Improvement, Increased Life-Span and Sustained Cell Homing in Amyotrophic Lateral Sclerosis After Transplantation of Human Umbilical Cord Blood Cells Genetically Modified with Adeno-Viral Vectors Expressing a Neuro-Protective Factor and a Neural Cell Adhesion Molecule

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable, chronic, fatal neuro-degenerative disease characterized by progressive loss of moto-neurons and paralysis of skeletal muscles. Reactivating dysfunctional areas is under earnest investigation utilizing various approaches. Here we present an innovative gene-cell construct aimed at reviving inert structure and function. Human umbilical cord blood cells (hUCBCs) transduced with adeno-viral vectors encoding human VEGF, GDNF and/or NCAM genes were transplanted into transgenic ALS mice models. Significant improvement in behavioral performance (open-field and grip-strength tests), as well as increased life-span was observed in rodents treated with NCAM-VEGF or NCAM-GDNF co-transfected cells. Active trans-gene expression was found in the spinal cord of ALS mice 10 weeks after delivering genetically modified hUCBCs, and cells were detectable even 5 months following transplantation. Our gene-cell therapy model yielded prominent symptomatic control and prolonged life-time in ALS. Incredible survivability of xeno-transpanted cells was also observed without any immune-suppression. These results suggest that engineered hUCBCs may offer effective gene-cell therapy in ALS.

Electrophysiological, Morphological, and Ultrastructural Features of the Injured Spinal Cord Tissue after Transplantation of Human Umbilical Cord Blood Mononuclear Cells Genetically Modified with the VEGF and GDNF Genes

“…Evidence for grafted cells in the endothelium of capillaries has been shown previously [26], but the data did not indicate that these cells had transmigrated through the vessel wall and differentiated into endothelial cells. Our data indicates differentiation of progenitors in hUCB-MC population into endothelial cells.…”

“…For these cells, alternative pathways of differentiation could include formation of microglial cells or macrophages. Previously our group reported that hUCB-MCs may differentiate into microglia-like (Iba1 + ) cells in spinal cord after transplantation in ALS mice [26]. Elucidation of the differentiation pathways requires further studies including immunocytochemical typing.…”

Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

“…[16][17][18] In previous studies on amyotrophic lateral sclerosis treatment, we developed UCB-MCs transfected with a pBudCE4.1 dual-expression-cassette plasmid vector encoding vascular endothelial growth factor and cell adhesion molecule (VEGF-L1CAM) and VEGF-FGF2 19,20 and UCB-MCs transduced concurrently with adenoviral vectors encoding VEGF and GDNF, VEGF and neural cell adhesion molecule (NCAM), or GDNF and NCAM. 21 The main positive action of the UCB-MCs was that they facilitated targeted delivery of the recombinant therapeutic molecules to motor neurons and thereby prolonged the survival of the neurons.…”

Experimental validation of gene therapy for ischemic stroke

“…Заготовку крови пуповины про-изводили по инструкции банка стволовых клеток Казанского государственного меди-цинского университета. Выделение МККП проводили в градиенте плотности фиколла по стандартной методике [6].…”