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Find video protocols related to scientific articles indexed in Pubmed.
Accuracy and precision of targeting using frameless stereotactic system in deep brain stimulator implantation surgery.
Neurol India
PUBLISHED: 11-13-2014
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To assess the accuracy of targeting using NexFrame frameless targeting system during deep brain stimulation (DBS) surgery.
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Deep brain stimulation for chronic pain: intracranial targets, clinical outcomes, and trial design considerations.
Neurosurg. Clin. N. Am.
PUBLISHED: 09-22-2014
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For over half a century, neurosurgeons have attempted to treat pain from a diversity of causes using acute and chronic intracranial stimulation. Targets of stimulation have included the sensory thalamus, periventricular and periaqueductal gray, the septum, the internal capsule, the motor cortex, posterior hypothalamus, and more recently, the anterior cingulate cortex. The current work focuses on presenting and evaluating the evidence for the efficacy of these targets in a historical context while also highlighting the major challenges to having a double-blind placebo-controlled clinical trial. Considerations for pain research in general and use of intracranial targets specifically are included.
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Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes.
Neurosurgery
PUBLISHED: 09-05-2014
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The first US Food and Drug Administration approved clinical trial for a stem cell-based treatment of amyotrophic lateral sclerosis has now been completed.
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Vesicle associated membrane protein 8 (VAMP8)-mediated zymogen granule exocytosis is dependent on endosomal trafficking via the constitutive-like secretory pathway.
J. Biol. Chem.
PUBLISHED: 08-19-2014
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Acinar cell zymogen granules (ZG) express 2 isoforms of the vesicle-associated membrane protein family (VAMP2 and -8) thought to regulate exocytosis. Expression of tetanus toxin to cleave VAMP2 in VAMP8 knock-out (-/-) acini confirmed that VAMP2 and -8 are the primary VAMPs for regulated exocytosis, each contributing ?50% of the response. Analysis of VAMP8(-/-) acini indicated that although stimulated secretion was significantly reduced, a compensatory increase in constitutive secretion maintained total secretion equivalent to wild type (WT). Using a perifusion system to follow secretion over time revealed VAMP2 mediates an early rapid phase peaking and falling within 2-3 min, whereas VAMP8 controls a second prolonged phase that peaks at 4 min and slowly declines over 20 min to support the protracted secretory response. VAMP8(-/-) acini show increased expression of the endosomal proteins Ti-VAMP7 (2-fold) and Rab11a (4-fold) and their redistribution from endosomes to ZGs. Expression of GDP-trapped Rab11a-S25N inhibited secretion exclusively from the VAMP8 but not the VAMP2 pathway. VAMP8(-/-) acini also showed a >90% decrease in the early endosomal proteins Rab5/D52/EEA1, which control anterograde trafficking in the constitutive-like secretory pathway. In WT acini, short term (14-16 h) culture also results in a >90% decrease in Rab5/D52/EEA1 and a complete loss of the VAMP8 pathway, whereas VAMP2-secretion remains intact. Remarkably, rescue of Rab5/D52/EEA1 expression restored the VAMP8 pathway. Expressed D52 shows extensive colocalization with Rab11a and VAMP8 and partially copurifies with ZG fractions. These results indicate that robust trafficking within the constitutive-like secretory pathway is required for VAMP8- but not VAMP2-mediated ZG exocytosis.
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Introduction to neuropathic pain syndromes.
Neurosurg. Clin. N. Am.
PUBLISHED: 08-05-2014
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Chronic pain impairs the quality of life for millions of individuals and therefore presents a serious ongoing challenge to clinicians and researchers. Debilitating chronic pain syndromes cost the US economy more than $600 billion per year. This article provides an overview of the epidemiology, clinical presentation, and treatment outcomes for craniofacial, spinal, and peripheral neurologic pain syndromes. Although the authors recognize that the diagnosis and treatment of the chronic forms of neuropathic pain syndromes represent a clinical challenge, there is an urgent need for standardized classification systems, improved epidemiologic data, and reliable treatment outcomes data.
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Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy.
Hum. Gene Ther.
PUBLISHED: 04-28-2014
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Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). Previously, we showed that central nervous system (CNS) delivery of an adeno-associated viral (AAV) vector encoding SMN1 produced significant improvements in survival in a mouse model of SMA. Here, we performed a dose-response study in SMA mice to determine the levels of SMN in the spinal cord necessary for efficacy, and measured the efficiency of motor neuron transduction in the spinal cord after intrathecal delivery in pigs and nonhuman primates (NHPs). CNS injections of 5e10, 1e10, and 1e9 genome copies (gc) of self-complementary AAV9 (scAAV9)-hSMN1 into SMA mice extended their survival from 17 to 153, 70, and 18 days, respectively. Spinal cords treated with 5e10, 1e10, and 1e9 gc showed that 70-170%, 30-100%, and 10-20% of wild-type levels of SMN were attained, respectively. Furthermore, detectable SMN expression in a minimum of 30% motor neurons correlated with efficacy. A comprehensive analysis showed that intrathecal delivery of 2.5e13 gc of scAAV9-GFP transduced 25-75% of the spinal cord motor neurons in NHPs. Thus, the extent of gene expression in motor neurons necessary to confer efficacy in SMA mice could be obtained in large-animal models, justifying the continual development of gene therapy for SMA.
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Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes.
Ann. Neurol.
PUBLISHED: 01-17-2014
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The US Food and Drug Administration-approved trial, "A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1," is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.
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Cellular therapeutics delivery to the spinal cord: technical considerations for clinical application.
Ther Deliv
PUBLISHED: 11-16-2013
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Current literature demonstrates the efficacy of cell-based therapeutics in small animal models of varied spinal cord diseases. However, logistic challenges remain towards development of an optimized delivery approach to the human spinal cord. Clinical trials utilize a variety of methods to achieve this aim. In this article, the authors review currently employed delivery methods, compare the merits of alternate delivery paradigms, introduce their implementation in completed and ongoing clinical trials, and discuss promising near-term advances in image-guided delivery and in vivo graft tracking.
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Gene and protein therapies utilizing VEGF for ALS.
Pharmacol. Ther.
PUBLISHED: 10-04-2013
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.
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Use of intrathecal baclofen for treatment of severe spasticity in selected patients with motor neuron disease.
Neurorehabil Neural Repair
PUBLISHED: 07-24-2013
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To assess the safety and efficacy of intrathecal baclofen (ITB) therapy for severe spasticity in patients with upper-motor neuron predominant motor neuron disease (U-MND).
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Progress in gene therapy for neurological disorders.
Nat Rev Neurol
PUBLISHED: 04-23-2013
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Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.
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Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients.
Neurology
PUBLISHED: 04-10-2013
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In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).
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Regulated neuronal neuromodulation via spinal cord expression of the gene for the inwardly rectifying potassium channel 2.1 (Kir2.1).
Neurosurgery
PUBLISHED: 01-02-2013
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Neuromodulation is used to restore neural function in disorders that stem from an imbalance in the activity of specific neural networks when they prove refractory to pharmacological therapy. The Kir2.1 gene contributes to stabilizing the resting potential below the threshold of activation of voltage-gated sodium channels and action potentials. Therefore, the delivery of the Kir2.1 gene to neuronal cells could reduce the probability of action potential generation, inhibiting excessive neural activity.
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Translational stem cell therapy for amyotrophic lateral sclerosis.
Nat Rev Neurol
PUBLISHED: 12-13-2011
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Effective treatments are urgently needed for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of motor neurons. In 2009, the FDA approved the first phase I safety trial of direct intraspinal transplantation of neural stem cells into patients with ALS, which is currently in progress. Stem cell technologies represent a promising approach for treating ALS, but several issues must be addressed when translating promising experimental ALS therapies to patients. This article highlights the key research that supports the use of stem cells as a therapy for ALS, and discusses the rationale behind and approach to the phase I trial. Completion of the trial could pave the way for continued advances in stem cell therapy for ALS and other neurodegenerative diseases.
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Characterization of a murine model of SMA.
Neurobiol. Dis.
PUBLISHED: 10-14-2011
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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, which is the leading genetic cause of mortality in children. To date no effective treatment exists for SMA. The genetic basis for SMA has been well documented as a mutation in the gene for survival of motor neuron (SMN). Because there is an understanding of which gene needs to be replaced (SMN) and where it needs to be replaced (spinal motor systems), SMA is an ideal target for gene replacement via gene therapy. While a variety of animal models for SMA exist, they are either too fulminant to realistically test most gene delivery strategies, or too mild to provide a robust read out of the therapeutic effect. The field, therefore, requires a robust model with a slower symptomatic progression. A conditional knockout of SMN in neuronal cell types, giving a phenotype of functional motor defects, weight loss and reduced life expectancy partially satisfies this need (Frugier, Tiziano et al. 2000). This Cre/LoxP mediated neuron specific model presents an attractive alternative. In the present manuscript, we characterize the functional motor deficits of the model. We observed a decline in locomotor ability, as assessed by open field testing. The finer functions of motor skills such as righting reflex and grip strength were also observed to degenerate in the SMA mice. The decline in motor function that we observed here correlates with the anatomical decline in motor neurons and motor axons presented in the literature (Ferri, Melki et al. 2004). This work adds to our understanding and knowledge base of this Cre/LoxP model and provides a basis from which functional recovery, following interventions can be assessed.
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Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats.
Amyotroph Lateral Scler
PUBLISHED: 08-24-2011
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Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.
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Treatment of Harlequin syndrome by costotransversectomy and sympathectomy: case report.
Neurosurgery
PUBLISHED: 07-29-2011
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Harlequin syndrome is a rare neurological condition involving various degrees of unilateral hyperhidrosis and erythema of the head and neck. We present a clinical presentation and description of curative therapy in a patient with a sudden onset of Harlequin syndrome following a thoracotomy.
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Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery.
Hum. Gene Ther.
PUBLISHED: 07-25-2011
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Gene therapy for motor neuron diseases requires efficient gene delivery to motor neurons (MNs) throughout the spinal cord and brainstem. The present study compared adeno-associated viral (AAV) vector serotypes 1, 6, 8, and 9 for spinal cord delivery in adult mice, by the intraparenchymal or intrathecal route of administration. Whereas intraparenchymal injections resulted in local transduction of the lumbar segment of the spinal cord, intrathecal injections led to a broader distribution, transducing cells along the sacral, lumbar, and lower thoracic spinal cord. Overall, AAV6 and AAV9 performed better than the other serotypes. Dramatic differences in cell-specific expression patterns could be observed when constructs bearing the chicken ?-actin (Cba) versus cytomegalovirus (CMV) promoter were compared. In summary, intrathecal delivery of AAV6 or AAV9 vectors containing the CMV promoter yielded the strongest levels of biodistribution and MN transduction in the spinal cord.
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Gene therapy for amyotrophic lateral sclerosis.
Neurobiol. Dis.
PUBLISHED: 06-02-2011
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Gene therapy continues to be a potential option for amyotrophic lateral sclerosis (ALS). This chapter will inform the reader about promising therapeutic transgenes and proof-of-principle studies in transgenic rodent models of ALS. Challenges regarding the disease targets and time for therapeutic intervention will be also discussed. Finally, restorative therapy for ALS, as well as gene therapy for other motor neuron diseases will be briefly reviewed.
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Platform and cannula design improvements for spinal cord therapeutics delivery.
Neurosurgery
PUBLISHED: 04-08-2011
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Only recently have data been published attempting to validate a technology and technique suitable for targeted delivery of biological payloads to the human spinal cord.
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Assessment of hippocampal adeno-associated viral vector gene delivery via frameless stereotaxis in a nonhuman primate.
Stereotact Funct Neurosurg
PUBLISHED: 04-07-2011
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Expression of the neuropeptide galanin in hippocampal neurons reduces seizures in the kainic acid rodent model of epilepsy. In order to translate these findings into a human clinical trial, the safety and feasibility of hippocampal adeno-associated viral (AAV) vector expression must be demonstrated in a nonhuman primate model.
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Stem cell technology for the study and treatment of motor neuron diseases.
Regen Med
PUBLISHED: 03-12-2011
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Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.
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Pain in amyotrophic lateral sclerosis: a neglected aspect of disease.
Neurol Res Int
PUBLISHED: 03-06-2011
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons, muscle wasting, and respiratory dysfunction. With disease progression, secondary symptoms arise creating new problematic conditions for ALS patients. Amongst these is pain. Although not a primary consequence of disease, pain occurs in a substantial number of individuals. Yet, studies investigating its pathomechanistic properties in the ALS patient are lacking. Therefore, more exploratory efforts into its scope, severity, impact, and treatment should be initiated. Several studies investigating the use of Clostridial neurotoxins for the reduction of pain in ALS patients suggest the potential for a neural specific approach involving focal drug delivery. Gene therapy represents a way to accomplish this. Therefore, the use of viral vectors to express transgenes that modulate the nociceptive cascade could prove to be an effective way to achieve meaningful benefit in conditions of pain in ALS.
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Clinical problem solving: monster on the hook--case problems in neurosurgery.
Neurosurgery
PUBLISHED: 02-12-2011
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Nonfunctioning and functioning pituitary tumors can present in numerous ways. They may be difficult to diagnose correctly and, even with proper treatment, may lead to complications.
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Clinical problem-solving: aneurysm or spinal arteriovenous fistula-bait and switch.
Neurosurgery
PUBLISHED: 02-12-2011
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The authors use an instructive case to review the challenges of diagnosis in subarachnoid hemorrhage (SAH) and to reinforce the nuances of clinical management.
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Gene therapy: a potential approach for cancer pain.
Pain Res Treat
PUBLISHED: 01-21-2011
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Chronic pain is experienced by as many as 90% of cancer patients at some point during the disease. This pain can be directly cancer related or arise from a sensory neuropathy related to chemotherapy. Major pharmacological agents used to treat cancer pain often lack anatomical specificity and can have off-target effects that create new sources of suffering. These concerns establish a need for improved cancer pain management. Gene therapy is emerging as an exciting prospect. This paper discusses the potential for viral vector-based treatment of cancer pain. It describes studies involving vector delivery of transgenes to laboratory pain models to modulate the nociceptive cascade. It also discusses clinical investigations aimed at regulating pain in cancer patients. Considering the prevalence of pain among cancer patients and the growing potential of gene therapy, these studies could set the stage for a new class of medicines that selectively disrupt nociceptive signaling with limited off-target effects.
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Gene delivery of AAV2-neurturin for Parkinsons disease: a double-blind, randomised, controlled trial.
Lancet Neurol
PUBLISHED: 10-20-2010
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In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinsons disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial.
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To glue or not to glue? That is the question!!!
Neurosurgery
PUBLISHED: 08-31-2010
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The purpose of Clinical Problem Solving manuscripts is to present management challenges in an attempt to give practicing neurosurgeons insight into how field leaders address these dilemmas. This illustration is accompanied by a brief review of the literature on the topic. We describe the case of a patient who presented with recurrent headaches resulting from a nondominant hemisphere parietal arteriovenous malformation. Challenges in prognosis, treatment, and complication management are discussed.
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Full scope of options.
Neurosurgery
PUBLISHED: 06-19-2010
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The purpose of Clinical Problem Solving articles is to present management challenges to give practicing neurosurgeons insight into how field leaders address these dilemmas. This illustration is accompanied by a brief review of the literature on the topic.
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Viral vector-mediated gene transfer for CNS disease.
Expert Opin Biol Ther
PUBLISHED: 02-06-2010
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Gene therapy is a promising strategy for the treatment of many neurological disorders that currently lack effective treatment. Recent improvements in vectorology and vector engineering have improved overall safety and delivery of viral vectors.
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Preclinical safety validation of a stabilized viral vector direct injection approach to the cervical spinal cord.
Clin Transl Sci
PUBLISHED: 12-09-2009
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The current lack of a validated intraspinal delivery approach precludes translation of promising cell or viral-based therapeutics for treatment of varied spinal cord afflictions. We have developed a stabilized cervical microinjection platform with the intent of precise delivery to intraspinal sites of interest. Nine 30-40 kg female swine underwent coordinate-based microinjection AAV2-GFP at three injected volumes (10, 25, and 50 microL (n= 3/group)) and matched infusion rates (1.0, 2.5, and 5.0 microL/min) over a period (t= 10 minutes). Preliminary validation is provided by behavioral and targeting data demonstrating safe delivery of a viral vector carrying a fluorescent reporter gene to the cervical spinal cord ventral horn.
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Invited review: festschrift edition of neurosurgery peripheral nervous system as a conduit for delivering therapies for diabetic neuropathy, amyotrophic lateral sclerosis, and nerve regeneration.
Neurosurgery
PUBLISHED: 11-21-2009
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In this review, we describe how therapies that promote axonal regeneration and neuronal protection can complement surgery for a successful functional restoration in peripheral nerve disorders. We discuss the advantages of peripheral drug delivery and the role of the neurosurgeon in the precise delivery of molecular therapies to surgically inaccessible structures. Strategies for enhancing uptake and retrograde transport of therapeutics, including gene therapy, are emphasized as conduits for delivery of therapeutics. Finally, candidate therapeutic proteins and genes are discussed in the context of application to degenerative disorders of the nervous system, including nerve injury, peripheral neuropathy, and amyotrophic lateral sclerosis.
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Cervical spinal cord therapeutics delivery: preclinical safety validation of a stabilized microinjection platform.
Neurosurgery
PUBLISHED: 10-17-2009
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The current series represents a preclinical safety validation study for direct parenchymal microinjection of cellular grafts into the ventral horn of the porcine cervical spinal cord.
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A conditioning lesion provides selective protection in a rat model of Amyotrophic Lateral Sclerosis.
PLoS ONE
PUBLISHED: 05-07-2009
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Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. The death of motoneuron is preceded by the failure of neuromuscular junctions (NMJs) and axonal retraction. Thus, to develop an effective ALS therapy you must simultaneously preserve motoneuron somas, motor axons and NMJs. A conditioning lesion has the potential to accomplish this since it has been shown to enhance neuronal survival and recovery from trauma in a variety of contexts.
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Optogenetic neuromodulation.
Neurosurgery
PUBLISHED: 05-01-2009
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Modulation of the nervous system by electrical or chemical means (neuromodulation) is becoming increasingly sophisticated, with application to a growing number of neurological diseases. However, both chemical and electrical neuromodulation are limited in their specificity. Electrical stimulation, for example, indiscriminately activates different neuronal populations within the electrical field, leading to side effects that can limit efficacy. The delivery of genes that encode proteins capable of conveying light sensitivity to neurons has provided a tool that may overcome some of the limitations of traditional neuromodulation techniques. Activation or inhibition of specific neuronal populations with different wavelengths of light opens up possibilities for modulating neural circuits with previously unimagined levels of precision. We briefly review this new technology, illustrating its advantages and potential applications.
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Modern treatment of cerebral metastases: Integrated Medical Learning(SM) at CNS 2007.
J. Neurooncol.
PUBLISHED: 02-23-2009
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Cerebral metastases are a common problem and pose complex treatment decisions, with reference to local control of treated lesions, prevention of new brain metastases, and toxicity of available treatments. At the 2007 Congress of Neurological Surgeons (CNS) Annual Meeting, a novel active learning process, called Integrated Medical Learning(SM), was used to better understand contemporary practice patterns and to monitor the success of education about these critical treatment decisions.
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Comparative analysis of HIV-1-based lentiviral vectors bearing lyssavirus glycoproteins for neuronal gene transfer.
Genet Vaccines Ther
PUBLISHED: 01-13-2009
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The delivery of therapeutic genes to the central nervous system (CNS) using viral vectors represents an appealing strategy for the treatment of nerve injury and disorders of the CNS. Important factors determining CNS targeting include tropism of the viral vectors and retrograde transport of the vector particles. Retrograde transport of equine anemia virus (EIAV)-based lentiviral vectors pseudotyped with the glycoprotein derived from the Rabies virus RabERA strain from peripheral muscle to spinal motor neurons (MNs) was previously reported. Despite therapeutic effects achieved in mouse models of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), the efficiency of this approach needs to be improved for clinical translation. To date there has not been a quantitative assessment of pseudotyped HIV-1-based lentiviral vectors to transduce MNs. Here, we describe quantitative tests to analyze the retrograde transport capacity of HIV-1 vectors pseudotyped with the G glycoprotein derived from Rabies and Rabies-related viruses (Lyssaviruses).
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Intraspinal cord delivery of IGF-I mediated by adeno-associated virus 2 is neuroprotective in a rat model of familial ALS.
Neurobiol. Dis.
PUBLISHED: 01-13-2009
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Amyotrophic lateral sclerosis (ALS) is a devastating disease that is characterized by the progressive loss of motor neurons. Patients with ALS usually die from respiratory failure due to respiratory muscle paralysis. Consequently, therapies aimed at preserving segmental function of the respiratory motor neurons could extend life for these patients. Insulin-like growth factor-I (IGF-I) is known to be a potent survival factor for motor neurons. In this study we induced high levels of IGF-I expression in the cervical spinal cord of hSOD1(G93A) rats with intraspinal cord (ISC) injections of an adeno-associated virus serotype 2 vector (CERE-130). This approach reduced the extent of motor neuron loss in the treated segments of the spinal cord. However, a corresponding preservation of motor function was observed in male, but not female, hSOD1(G93A) rats. We conclude that ISC injection of CERE-130 has the potential to protect motor neurons and preserve neuromuscular function in ALS.
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Surgical technique for spinal cord delivery of therapies: demonstration of procedure in gottingen minipigs.
J Vis Exp
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This is a compact visual description of a combination of surgical technique and device for the delivery of (gene and cell) therapies into the spinal cord. While the technique is demonstrated in the animal, the procedure is FDA-approved and currently being used for stem cell transplantation into the spinal cords of patients with ALS. While the FDA has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for validating the combination of a surgical procedure, a device, and the safety of a final therapy for human use. The size, anatomy, and general vulnerability of the spine and spinal cord of the swine are recognized to better model the human. Moreover, the surgical process of exposing and manipulating the spinal cord as well as closing the wound in the pig is virtually indistinguishable from the human. We believe that the healthy pig model represents a critical first step in the study of procedural safety.
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Update on gene and stem cell therapy approaches for spinal muscular atrophy.
Expert Opin Biol Ther
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Spinal muscular atrophy (SMA) is the leading genetic cause of pediatric death to which at present there is no effective therapeutic. The genetic defect is well characterized as a mutation in exon 7 of the survival of motor neuron (SMN) gene. The current gene therapy approach focuses on two main methodologies, the replacement of SMN1 or augmentation of SMN2 readthrough. The most promising of the current work focuses on the delivery of SMN via AAV9 vectors via intravenous delivery.
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Stem cell therapy for the spinal cord.
Stem Cell Res Ther
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ABSTRACT: Injury and disease of the spinal cord are generally met with a poor prognosis. This poor prognosis is due not only to the characteristics of the diseases but also to our poor ability to deliver therapeutics to the spinal cord. The spinal cord is extremely sensitive to direct manipulation, and delivery of therapeutics has proven a challenge for both scientists and physicians. Recent advances in stem cell technologies have opened up a new avenue for the treatment of spinal cord disease and injury. Stem cells have proven beneficial in rodent models of spinal cord disease and injury. In these animal models, stem cells have been shown to produce their effect by the dual action of cell replacement and the trophic support of the factors secreted by these cells. In this review we look at the main clinical trials involving stem cell transplant into the spinal cord, focusing on motor neuron diseases and spinal cord injury. We will also discuss the major hurdles in optimizing stem cell delivery methods into the spinal cord. We shall examine current techniques such as functional magnetic resonance imaging guidance and cell labeling and will look at the current research striving to improve these techniques. With all caveats and future research taken into account, this is a very exciting time for stem cell transplant into the spinal cord. We are only beginning to realize the huge potential of stem cells in a central nervous system setting to provide cell replacement and trophic support. Many more trials will need to be undertaken before we can fully exploit the attributes of stem cells.
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Cellular and molecular approaches to motor neuron therapy in amyotrophic lateral sclerosis and spinal muscular atrophy.
Neurosci. Lett.
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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive fatal neurodegenerative diseases. They differ in their disease development but have in common a loss of motor neuron as they progress. Research is ongoing to further understand the origin of these diseases but this common thread of motor neuron loss has provided a target for the development of therapies for both ALS and SMA. It is the linked fields of gene and cell therapy that are providing some of the most interesting therapeutic possibilities.
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Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes.
Neurosurgery
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No United States-based clinical trials have attempted delivery of biological therapies directly to the spinal cord for treatment of amyotrophic lateral sclerosis (ALS) because of the lack of a meaningful US Food and Drug Administration-authorized cell candidate and a validated delivery approach.
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Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients.
Stem Cells
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Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase I trial of intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS). This is a first-in-human clinical trial with the goal of assessing the safety and tolerability of the surgical procedure, the introduction of stem cells into the spinal cord, and the use of immunosuppressant drugs in this patient population. Twelve patients received either five unilateral or five bilateral (10 total) injections into the lumbar spinal cord at a dose of 100,000 cells per injection. All patients tolerated the treatment without any long-term complications related to either the surgical procedure or the implantation of stem cells. Clinical assessments ranging from 6 to 18 months after transplantation demonstrated no evidence of acceleration of disease progression due to the intervention. One patient has shown improvement in his clinical status, although these data must be interpreted with caution since this trial was neither designed nor powered to measure treatment efficacy. These results allow us to report success in achieving the phase I goal of demonstrating safety of this therapeutic approach. Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord, with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.