A Biosafety Study of Human Umbilical Cord Blood Mononuclear Cells Transduced with Adenoviral Vector Carrying Human Vascular Endothelial Growth Factor cDNA In Vitro.

The biosafety of gene therapy remains a crucial issue for both the direct and cell-mediated delivery of recombinant cDNA encoding biologically active molecules for the pathogenetic correction of congenital or acquired disorders. The diversity of vector systems and cell carriers for the delivery of therapeutic genes revealed the difficulty of developing and implementing a safe and effective drug containing artificial genetic material for the treatment of human diseases in practical medicine. Therefore, in this study we assessed changes in the transcriptome and secretome of umbilical cord blood mononuclear cells (UCB-MCs) genetically modified using adenoviral vector (Ad5) carrying cDNA encoding human vascular endothelial growth factor (VEGF165) or reporter green fluorescent protein (GFP). A preliminary analysis of UCB-MCs transduced with Ad5-VEGF165 and Ad5-GFP with MOI of 10 showed efficient transgene expression in gene-modified UCB-MCs at mRNA and protein levels. The whole transcriptome sequencing of native UCB-MCs, UCB-MC+Ad5-VEGF165, and UCB-MC+Ad5-GFP demonstrated individual sample variability rather than the effect of Ad5 or the expression of recombinant vegf165 on UCB-MC transcriptomes. A multiplex secretome analysis indicated that neither the transduction of UCB-MCs with Ad5-GFP nor with Ad5-VEGF165 affects the secretion of the studied cytokines, chemokines, and growth factors by gene-modified cells. Here, we show that UCB-MCs transduced with Ad5 carrying cDNA encoding human VEGF165 efficiently express transgenes and preserve transcriptome and secretome patterns. This data demonstrates the biosafety of using UCB-MCs as cell carriers of therapeutic genes.

Evaluation of New Potential Inflammatory Markers in Patients with Nonvalvular Atrial Fibrillation.

Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter.

Role of Oxysterols in the Activation of the NLRP3 Inflammasome as a Potential Pharmacological Approach in Alzheimer's Disease.

Alzheimer's disease (AD), the most prevalent form of dementia, is a complex clinical condition with multifactorial origin posing a major burden to health care systems across the world. Even though the pathophysiological mechanisms underlying the disease are still unclear, both central and peripheral inflammation has been implicated in the process. Piling evidence shows that the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in AD. As dyslipidemia is a risk factor for dementia, and cholesterol can also activate the inflammasome, a possible link between lipid levels and the NLRP3 inflammasome has been proposed in Alzheimer's. It is also speculated that not only cholesterol but also its metabolites, the oxysterols, may be involved in AD pathology. In this context, mounting data suggest that NLRP3 inflammasome activity can be modulated by different peripheral nuclear receptors, including liver-X receptors, which present oxysterols as endogenous ligands. In light of this, the current review explores whether the activation of NLRP3 by nuclear receptors, mediated by oxysterols, may also be involved in AD and could serve as a potential pharmacological avenue in dementia.

A Potential Role for the Ketogenic Diet in Alzheimer's Disease Treatment: Exploring Pre-Clinical and Clinical Evidence.

Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (NDs). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer's disease (AD) is regarded as an ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interactions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of ß-amyloid peptide (Aß), the hyperphosphorylation of tau protein, neurotoxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. The KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing metabolic ketosis whereby the main source of energy becomes ketone bodies instead of glucose. Thus, under these dietary conditions, neuronal death via lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve via the slowing down of symptoms and delaying of the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between the KD and the improvement of AD indicators, drawing insights from both preclinical and clinical investigations. Via a comprehensive examination of the studies detailed in this review, it is evident that the KD emerges as a promising alternative for managing AD. Moreover, its efficacy is notably enhanced when dietary composition is modified, thereby opening up innovative avenues for decreasing the progression of AD.

Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain.

BACKGROUND: Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice. METHODS: Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1ß, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels. RESULTS: CBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals. CONCLUSIONS: Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior.

Obesity is a multifactorial disease, which in turn contributes to the onset of comorbidities, such as diabetes and atherosclerosis. Moreover, there are only few options available for treating obesity, and most current pharmacotherapy causes severe adverse effects, while offering minimal weight loss. Literature shows that metabotropic glutamate receptor 5 (mGluR5) modulates central reward pathways. Herein, we evaluated the effect of VU0409106, a negative allosteric modulator (NAM) of mGluR5 in regulating feeding and obesity parameters. Diet-induced obese C57BL/6 mice were treated for 14 days with VU0409106, and food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in mice treated with high-fat diet (HFD) after chronic treatment with VU0409106. Furthermore, a negative modulation of mGluR5 also reduces binge-like eating, the most common type of eating disorder. Altogether, our results pointed out mGluR5 as a potential target for treating obesity, as well as related disorders.

Comparison of Inflammatory Mediators in Patients With Atrial Fibrillation Using Warfarin or Rivaroxaban.

Background: Atrial fibrillation (AF) is the most common arrhythmia associated with high risk of venous thromboembolism. Inflammatory mechanisms may be involved in the pathophysiology of AF and in the AF-related thrombogenesis, and patients with AF might benefit from the use of anticoagulants with anti-inflammatory properties. However, the evidence is still scarce, and it points out the need of trials seeking to investigate the levels of inflammatory mediators in patients with AF under different anticoagulant therapies. Therefore, this study was designed to define whether patients with AF treated either with an activated coagulation factor X (FXa) inhibitor (rivaroxaban) or with a vitamin K inhibitor (warfarin) present changes in peripheral levels of inflammatory mediators, mainly cytokines and chemokines. Methods: A total of 127 subjects were included in this study, divided into three groups: patients with non-valvular atrial fibrillation (NVAF) using warfarin (N = 42), patients with NVAF using rivaroxaban (N = 29), and controls (N = 56). Plasma levels of inflammatory mediators were quantified by immunoassays. Results: Patients with AF (both warfarin and rivaroxaban groups) presented increased levels of inflammatory cytokines in comparison with controls. The use of rivaroxaban was associated with decreased levels of inflammatory cytokines in comparison with warfarin. On the other hand, patients with AF using rivaroxaban presented increased levels of the chemokines (MCP-1 in comparison with warfarin users; MIG and IP-10 in comparison with controls). Conclusions: AF is associated with an inflammatory profile that was less pronounced in patients on rivaroxaban in comparison with warfarin users. Further studies are necessary to assess the clinical implications of our results and whether patients with AF would benefit from rivaroxaban anti-inflammatory effects.

Physical Inactivity is Liable to the Increased Cardiovascular Risk and Impaired Cognitive Profile.

BACKGROUND: Sedentary life-style is a significant public health issue. It increases the incidence of type-2 diabetes mellitus (DM2) and systemic arterial hypertension (SAH), which in turn may impair physical and mental health. In fact, disrupted glucose metabolism is characteristic of Alzheimer's dementia, and it is often dubbed as type-3 diabetes. OBJECTIVE: The purpose of this study was to assess the level of activity, body composition, cardiovascular risk and cognitive profile of patients with DM2 and/or SAH. The study was cross-sectional design. METHOD: The sample consisted of 120 individuals which 35% men and 65% women, with an average of 64±9 years old and 60±11 years old, respectively. Various parameters were evaluated such as anthropometric variables, pedometer recordings and brief cognitive screening battery (BCSB), which assesses the immediate memory, verbal fluency, learning, late memory and recognition. Chi-square and Fisher's exact test were applied to observe possible differences between men and women. In addition to Kruskall-Wallis, in the comparison between patients with SAH; DM2 and SAH + DM2. RESULTS: A high rate of physical inactivity was found among those enrolled in this project. Females were characterized by increased body fat, whereas men displayed visceral fat excess. BCSB demonstrated reduced verbal fluency, late memory and recognition, with women presenting significantly worse results. CONCLUSION: Low level of daily physical activity is apparently correlated with obesity, elevated cardiovascular risk, and cognitive dysfunction.

Inflammatory and Infectious Processes Serve as Links between Atrial Fibrillation and Alzheimer's Disease.

Atrial fibrillation (AF) is one of the most prevalent forms of arrhythmia that carries an increased risk of stroke which, in turn, is strongly associated with cognitive decline. The majority of dementia cases are caused by Alzheimer's disease (AD) with obscure pathogenesis. While the exact mechanisms are unknown, the role of inflammatory processes and infectious agents have recently been implicated in both AD and AF, suggesting a common link between these maladies. Here, we present the main shared pathways underlying arrhythmia and memory loss. The overlapping predictive biomarkers and emerging joint pharmacological approaches are also discussed.

Cognitive Disposition to Wine Consumption: How the Brain Is Wired to Select the Perfect Bottle With a Novel Musical Twist.

Taste is not a veridical perception: it is modifiable by cognitive and affective processes, as well as by expectations. Even though molecular composition determines the savor, various other factors such as external characteristics and basic assumptions have a sway over perceived pleasantness of food and drink. The rituals associated with wine tastings especially underscore the importance of these subjective ramifications. While auditory stimuli are known to influence drinking experience, the impact of melody on the product itself and on corollary consumer preference is unknown. As routine judgments are also influenced by informational cues, here we evaluated whether description of a unique technological innovation (i.e., serenaded grapes and barrels) as cogent suggestion of quality improves willingness to buy. This project unveils that the belief about music-fed wines, which might be construed as a motivational bias, can alter purchasing decisions; however, further neuro-marketing studies are warranted with this respect.

Stable Co-Cultivation of the Moss Physcomitrella patens with Human Cells in vitro as a New Approach to Support Metabolism of Diseased Alzheimer Cells.

Alzheimer's disease (AD) is a devastating slowly progressive neurodegenerative disorder with no cure. While there are many hypotheses, the exact mechanism causing this pathology is still unknown. Among many other features, AD is characterized by brain hypometabolism and decreased sugar availability, to which neurons eventually succumb. In light of this aspect of the disease, we hypothesized that boosting fuel supply to neurons may help them survive or at least alleviate some of the symptoms. Here we demonstrate that live moss Physcomitrella patens cells can be safely co-cultured with human fibroblasts in vitro and thus have a potential for providing human cells with energy and other vital biomolecules. These data may form the foundation for the development of novel approaches to metabolic bioengineering and treatment of diseased cells based on live plants. In addition, by providing alternative energy sources to human tissues, the biotechnological potential of this interkingdom setup could also serve as a springboard to foster innovative dietary processes addressing current challenges of mankind such as famine or supporting long-haul space flight.

Oxidative stress markers in cognitively intact patients with diabetic neuropathy.

Various forms of vascular injury are frequently associated with type-2 diabetes mellitus (DM2). Macro-angiopathy has alarming signs and symptoms such as those seen with stroke or heart attack, however the presentation of small vessel disease is generally more subtle and therefore usually unnoticed for a long period of time. While it may affect any organ, complications involving the nervous system such as diabetic poly-neuropathy (DPN) are especially debilitating, and it may also be a risk factor for other brain disorders such as dementia. The underlying mechanisms are likely to be multi-faceted, but piling evidence indicates oxidative stress as one of the crucial factors. Here we evaluate the oxidative profile of patients with DM2. The total anti-oxidant capacity appears to be reduced in DM2 with or without complications. Of the specific bio-markers studied, the levels of tissue-damage indicator malon-dialdehyde (MDA) were significantly lower in the DM2 + DPN population only. These results suggest that diabetic patients present with wavering oxidative status, and the low MDA concentrations in patients with complications such as DPN may represent either an exhausted anti-oxidative defense system or a response to anti-inflammatory medications. The findings may also support the use of anti-oxidants such as vitamins A and E.

Influence of pharmacological and epigenetic factors to suppress neurotrophic factors and enhance neural plasticity in stress and mood disorders.

Stress-induced major depression and mood disorders are characterized by behavioural abnormalities and psychiatric illness, leading to disability and immature mortality worldwide. Neurobiological mechanisms of stress and mood disorders are discussed considering recent findings, and challenges to enhance pharmacological effects of antidepressant, and mood stabilizers. Pharmacological enhancement of ketamine and scopolamine regulates depression at the molecular level, increasing synaptic plasticity in prefrontal regions. Blood-derived neurotrophic factors facilitate mood-deficit symptoms. Epigenetic factors maintain stress-resilience in hippocampal region. Regulation of neurotrophic factors blockades stress, and enhances neuronal survival though it paralyzes limbic regions. Molecular agents and neurotrophic factors also control behavioral and synaptic plasticity in addiction and stress disorders. Future research on neuronal dynamics and cellular actions can be directed to obtain the etiology of synaptic dysregulation in mood disorder and stress. For the first time, the current review contributes to the literature of synaptic plasticity representing the role of epigenetic mechanisms and glucocorticoid receptors to predict depression and anxiety in clinical conditions.

Effects of Transplanted Umbilical Cord Blood Mononuclear Cells Overexpressing GDNF on Spatial Memory and Hippocampal Synaptic Proteins in a Mouse Model of Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is a progressive incurable neurodegenerative disorder. Glial cell line-derived neurotrophic factor (GDNF) is a prominent regulator of brain tissue and has an impressive potential for use in AD therapy. While its metabolism is still not fully understood, delivering neuropeptides such as GDNF via umbilical cord blood mononuclear cells (UCBMCs) to the sites of neurodegeneration is a promising approach in the development of innovative therapeutic avenues. METHODS: UCBMCs were transduced with adenoviral vectors expressing GDNF and injected into AD transgenic mice. Various parameters including homing and survival of transplanted cells, expression of GDNF and synaptic proteins, as well as spatial memory were evaluated. RESULTS: UCBMCs were observed in the hippocampus and cortex several weeks after transplantation, and their long-term presence was associated with improved spatial memory. Post-synaptic density protein 95 (PSD-95) and synaptophysin levels in the hippocampus were also effectively restored following the procedure in AD mice. CONCLUSIONS: Our data indicate that gene-cell therapy with GDNF-overexpressing UCBMCs may produce long-lasting neuroprotection and stimulation of synaptogenesis. Such adenoviral constructs could potentially possess a high therapeutic potential for the treatment of AD.

Evaluating the effects of exercise on cognitive function in hypertensive and diabetic patients using the mental test and training system.

OBJECTIVES: Systemic arterial hypertension (SAH) and diabetes mellitus (DM) are important risk factors for developing cognitive impairment. General life-style changes including physical training are known to reduce elevated blood pressure and sugar levels, as well as improve mental health. The objective of this study was to evaluate whether supervised physical exercise enhances the cognitive status of patients with chronic diseases. METHODS: Volunteers with SAH, DM or SAH + DM participated in either aerobic or resistance training during a period of 12 weeks. Several domains of cognitive functions were evaluated using the mental test and training system before and after the 3 months. RESULTS: Participants with either of these chronic diseases demonstrated significantly improved attention and concentration, but not reaction time, following the supervised exercise. CONCLUSIONS: Structured physical training promotes several aspects of cognitive functions in diabetic and hypertensive patients.

Single-nucleotide polymorphisms in a cohort of significantly obese women without cardiometabolic diseases.

BACKGROUND/OBJECTIVES: Obesity is an important risk factor for the development of diseases such as diabetes mellitus, hypertension, and dyslipidemia; however, a small number of individuals with long-standing obesity do not present with these cardiometabolic diseases. Such individuals are referred to as metabolically healthy obese (MHO) and potentially represent a subgroup of the general population with a protective genetic predisposition to obesity-related diseases. We hypothesized that individuals who were metabolically healthy, but significantly obese (BMI ≥ 35 kg/m2) would represent a highly homogenous subgroup, with which to investigate potential genetic associations to obesity. We further hypothesized that such a cohort may lend itself well to investigate potential genotypes that are protective with respect to the development of cardiometabolic disease. SUBJECTS/METHODS: In the present study, we implemented this novel selection strategy by screening 892 individuals diagnosed as Class 2 or Class 3 obese and identified 38 who presented no manifestations of cardiometabolic disease. We then assessed these subjects for single-nucleotide polymorphisms (SNPs) that associated with this phenotype. RESULTS: Our analysis identified 89 SNPs that reach statistical significance (p < 1 × 10-5), some of which are associated with genes of biological pathways that influences dietary behavior; others are associated with genes previously linked to obesity and cardiometabolic disease as well as neuroimmune disease. This study, to the best of our knowledge, represents the first genetic screening of a cardiometabolically healthy, but significantly obese population.

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease.

The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.

Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats.

Natural brain repair after stroke is extremely limited, and current therapeutic options are even more scarce with no clinical break-through in sight. Despite restricted regeneration in the central nervous system, we have previously proved that human umbilical cord blood mono-nuclear cells (UCB-MC) transduced with adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) successfully rescued neurons in amyotrophic lateral sclerosis and spinal cord injury. This proof-of-principle project was aimed at evaluating the beneficial effects of the same triple-gene approach in stroke. Rats subjected to distal occlusion of the middle cerebral artery were treated intrathecally with a combination of these genes either directly or using our cell-based (UCB-MC) approach. Various techniques and markers were employed to evaluate brain injury and subsequent recovery after treatment. Brain repair was most prominent when therapeutic genes were delivered via adenoviral vector- or UCB-MC-mediated approach. Remodeling of brain cortex in the stroke area was confirmed by reduction of infarct volume and attenuated neural cell death, depletion of astrocytes and microglial cells, and increase in the number of oligodendroglial cells and synaptic proteins expression. These results imply that intrathecal injection of genetically engineered UCB-MC over-expressing therapeutic molecules (VEGF, GDNF, and NCAM) following cerebral blood vessel occlusion might represent a novel avenue for future research into treating stroke.

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity.

Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo. Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.

Evaluation of direct and cell-mediated triple-gene therapy in spinal cord injury in rats.

Current treatment options for spinal cord injury (SCI) are scarce. One of the most promising innovative approaches include gene-therapy, however no single gene has so far been shown to be of clinical relevance. This study investigates the efficacy of various combinations of vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), angiogenin (ANG) and neuronal cell adhesion molecule (NCAM) in rats. Multiple therapeutic genes were administered intrathecally either via adenoviral vectors or by using genetically modified human umbilical cord blood mononuclear cells (hUCBMCs). Following the induction of SCI, serial assessment of cord regeneration was performed, including morphometric analysis of gray and white matters, electrophysiology and behavioral test. The therapeutic gene combinations VEGF+GDNF+NCAM and VEGF+ANG+NCAM had positive outcomes on spinal cord regeneration, with enhanced recovery seen by the cell-based approach when compared to direct gene therapy. The efficacy of the genes and the delivery methods are discussed in this paper, recommending their potential use in SCI.