Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic sideeffects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non- GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."

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.

We report on the diagnostic capability of magnetic resonance imaging (MRI)-based tracking of ferumoxytol-labeled human neural progenitor cells (hNPCs) transplanted into the porcine spinal cord. hNPCs prelabeled with two doses of ferumoxytol nanoparticles (hNPC-F Low and hNPC-F High ) were injected into the ventral horn of the spinal cord in healthy minipigs. Ferumoxytol-labeled grafts were tracked in vivo up to 105 days after transplantation with MRI. Injection accuracy was assessed in vivo at day 14 and was predictive of “on” or “off” target cell graft location assessed by histology. No difference in long-term cell survival, assessed by quantitative stereology, was observed among hNPCF Low , hNPC-F High , or control grafts. Histological iron colocalized with MRI signal and engrafted human nuclei. Furthermore, the ferumoxytol-labeled cells retained nanoparticles and function in vivo. This approach represents an important leap forward toward facilitating translation of cell-tracking technologies to clinical trials by providing a method of assessing transplantation accuracy, delivered dose, and potentially cell survival.

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 μL (n = 3/group)) and matched infusion rates (1.0, 2.5, and 5.0 μL/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.

Objective Neurosurgeons have taken on the role of innovators, continuing to move the field forward over the centuries. More recently, innovation has taken the form of new technological devices and therapeutics, which require patenting. The aim of this study is to identify major areas of innovation in the field of neurosurgery by evaluating patent records. Methods This study quantifies the number of patents the American Association of Neurological Surgeons (AANS) neurosurgeons hold across different subspecialties. The United States Patent and Trademark Office (USPTO) patent database was queried using the names of 7,293 AANS members who filed patents between 1976 and 2019. Results A total of 346 (4.7%) AANS neurosurgeons hold a total of 1,025 patents. The number of patents held by each neurosurgeon ranged from one to 109. The areas that patents were filed under include cellular and genetic science (40), drug delivery (45), image guidance (82), neuromodulation (52), pain (7), peripheral nerve stimulation (24), spine (398), surgical devices (148), trauma (16), tumor (78), vascular (67), and other (68). No patents were filed under pediatrics (0). The fields with the greatest number of filed patents are spine, instruments/devices, and image guidance. Conclusion Given the technical nature of the field of neurosurgery, instruments and devices that improve localization, visualization, targeting, and spinal reconstruction are often in demand. Furthermore, since the rates of spinal procedures and implants continue to increase, higher patenting may be motivated by the opportunity to develop new products that can result in royalty payments to neurosurgeons. The advent of new technologies undoubtedly continues to push the field of neurosurgery forward.

The promise of stem cell regeneration has been the hope of many neurologic patients with permanent damage to the central nervous system. There are hundreds of stem cell trials worldwide intending to test the regenerative capacity of stem cells in various neurological conditions from Parkinson׳s disease to multiple sclerosis. Although no stem cell therapy is clinically approved for use in any human disease indication, patients are seeking out trials and asking clinicians for guidance. This review summarizes the current state of regenerative stem cell transplantation divided into seven conditions for which trials are currently active: demyelinating diseases/spinal cord injury, amyotrophic lateral sclerosis, stroke, Parkinson׳s disease, Huntington׳s disease, macular degeneration and peripheral nerve diseases.

Objective The first US Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis (ALS) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells (HSSCs) transplanted into the spinal cord in patients with ALS. Methods Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real-time PCR methods (qPCR). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. Results Genomic DNA from donor HSSCs was identified in all cases, comprising 0.67–5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were XY-positive by FISH, confirming donor origin. A subset of XY-positive cells labeled for the neuronal marker NeuN and stem cell marker SOX2. Interpretation This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSCs survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.

Objective 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. Methods Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures. Results The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials. Interpretation This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.

Seeding nerve guidance conduits with Schwann cells can improve the outcome of peripheral nerve injury repair. Bone marrow stem cells (BMSCs) represent a good choice of cell source as they can differentiate into Schwann cells under appropriate conditions. In this work, we systematically investigated the differentiation of BMSCs into Schwann cells on scaffolds comprising electrospun fibers. We changed the alignment, diameter, and surface properties of the fibers to optimize the differentiation efficiency. The uniaxial alignment of fibers not only promoted the differentiation of BMSCs into Schwann cells but also dictated the morphology and alignment of the derived cells. Coating the surface of aligned fibers with laminin further enhanced the differentiation and thus increased the secretion of neurotrophins. When co-cultured with PC12 cells or chick dorsal root ganglion, the as-derived Schwann cells were able to promote the outgrowth of neurites from cell bodies and direct their extension along the fibers, demonstrating the positive impacts of both the neurotrophic effect and the morphological contact guidance. This work offers a promising strategy for integrating fiber guidance with stem cell therapy to augment peripheral nerve injury repair.

Background: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer. Methods: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range. Results: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals. Conclusions: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs.