The Impact of combination biologics on treadmill quadrupedal locomotion after spinal cord hemi-contusion in non-human primates

Non-human primates can be trained to ambulate on a treadmill. Cervical contusions lead to both upper and lower extremity functional deficits. These can be analyzed in a coupled manner using kinematic tracking of forelimb and hindlimb joint cycles. We tested the following hypotheses. 1) Kinematic analysis has sufficient sensitivity to detect differences in injury severity after C3/4 hemi-contusion. 2) The impact of locally delivered experimental therapeutics including autologous Schwann cells (aSC) and lentivirus expressing chondroitinase ABC (LV-ChABC) on gait is evident on limb-coupled kinematic analysis. 3) This analysis adds relevant data not evident in hand dexterity testing.
Five monkeys (M. fascicularis) were pre-trained. Following a right sided hemi-contusion the animals were randomized into A) No treatment controls (n= 1); B) LV-ChABC injected perilesionally 2 hours post spinal cord injury (n=2); C) LV-ChABC injection and transplant of aSC 14 days post-injury (n=2). Treadmill activity occurred weekly. Quadrupedal locomotion analysis was performed pre-injury, 3 and 6 months post-injury. Joints in the left and right sides were marked with ultraviolet ink and data was captured using black lights and a Vicon Motus tracking system. The variables assessed were joint track consistency and distance, stride length, and height.
All animals, except those receiving LV-ChABC, had notable deficits in quadrupedal locomotion at 3 months post-injury (step height, length). The wrist and ankle joint cycles were inconsistent possibly due to impaired strength, proprioception, and balance. By six months post-injury the joint cycles of groups A and B were more consistent and approached baseline. Animals in group C (aSC) showed persistent gait impairments. Analysis of contusion parameters including force delivered and ultrasound quantitative assessment of injury volume do not account for the behavioral differences.
Kinematic quadrupedal locomotor assessment is useful to quantify recovery, adding to assessments of hand dexterity. The animals continue to survive. Final MRI, histology, and CST tracing will be correlated to the quadrupedal kinematic analysis.

1The Miami Project to Cure Paralysis, 2Pedriatic Critical Care, 3Neurolog. Surgery, Univ. of Miami, Miller Sch. of Med., Miami, FL; 4The Wolfson Ctr. for Age-Related Dis., King’s Col. London, London, United Kingdom; 5Dept. of Mol. and Cell. Neurobio., Vrije Univ. Amsterdam, Ctr. for Neurogenomics and Cognition research, Amsterdan, Netherlands; 6Lab. for Neuroregeneration, Netherlands Inst. for Neurosci., Amsterdam, Netherlands
R. De Negri: None. A.J. Santamaria: None. F.D. Benavides: None. A.Y. Flores: None. N. James: None. Y. Nunez: None. J.P. Solano: None. J. Verhaagen: None. E.J. Bradbury: None. J.D. Guest: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Rehabilitation, Spinal Research | 1 Comment

Breakthrough Regenerative Therapeutics Company Establishes Scientific Advisory Board

Fortuna Fix Inc. (“Fortuna”), a private, clinical-stage biotech company, is aiming to be the first to eliminate the need for embryonic and fetal stem cells by using direct reprogramming of autologous cells to treat neurodegenerative diseases. Fortuna announced today the launch of its Scientific Advisory Board (“SAB”) with Professor Michael Fehlings, MD, PhD; Father Kevin FitzGerald, S.J., PhD; Col. (R) Dallas Hack, MD, MPH; and Professor James Giordano, PhD.

“We are excited and honored to have these world-leading experts join our SAB,” says CEO Jan-Eric Ahlfors. “We look forward to working with them to bring our novel regenerative medicine solutions to patients suffering from neurotrauma and neurodegeneration.”

Jan-Eric Ahlfors CEO and Chief Scientific Officer

Fortuna’s two flagship technologies — autologous directly reprogrammed neural precursor cells (“drNPC”) and Regeneration Matrix (“RMx™”) — are poised to lead a revolution in neuro-regeneration.

For the first time, patients suffering from neurotrauma or neurodegeneration will be able to get treated with autologous neural stem cells produced by direct reprogramming (i.e. starting with and only using the patient’s own cells, bypassing use of pluripotent stem cells and avoiding harvesting and use of human embryos or fetuses). The method of direct reprogramming developed by Fortuna relies on an ethical, rapid, high throughput, low cost and fully automated manufacturing process. As drNPC do not involve any genetic engineering, pluripotent stem cells, or use of immune-suppression, it provides patients with personalized stem cells that are also expected to have a greater safety profile. In addition, drNPC are expected to replace dead neural cells, something that no other current technology can do effectively.

RMx™ is a unique and highly efficient bio-scaffold for the promotion of neural tissue regrowth.

“Our testing of drNPC at the Krembil Neuroscience Centre of the University Health Network in various Spinal Cord Injury (“SCI”) animal models to characterize their regenerative capacity and safety profile indicates that drNPC are a promising source of therapeutic stem cells with potential for tissue preservation and functional improvement after SCI. I am highly encouraged by the reprogramming efficiency of drNPC and look forward to leading the clinical development of drNPC for SCI,” says Professor Fehlings, after working on the drNPC in his lab for two years.

Dr. Hack further remarks: “Fortuna’s autologous drNPC represent a major advance in cell therapy for treatment of CNS injury and degeneration. For the first time, neurons, astrocytes and oligodendrocytes — the three type of cells of the brain and spinal cord — can be repaired and replaced where these cells have died or been destroyed due to trauma or neurodegenerative disease. Fortuna’s proprietary automated manufacturing addresses a key hurdle of personalized cell therapy, making drNPC commercially viable both at small and large scale”

“Stem cell therapeutics have been plagued with controversy and hype, raising ethical and political issues that have resulted in a relatively hostile funding environment for research and development in the field. I am excited to work alongside Fortuna to help advance development of their ethical and commercially viable platform for cell therapeutics to benefit patients, their families, and our entire society,” says Father FitzGerald.

The SAB members encompass unique expertise in key areas of importance for the company:

About Fortuna Fix Inc.

Fortuna is a private, clinical-stage biotech company with a patented direct cell reprogramming technology platform together with a patented bio-scaffolding technology for treatment of neurodegenerative diseases and neurotrauma. The company is focused on clinical development of its platforms for a range of neurodegenerative diseases including SCI, Parkinson’s disease, stroke, TBI, and ALS. The company has developed a proprietary fully automated GMP manufacturing system for production of drNPC, initially to be used in clinical trials in Parkinson’s disease and Spinal Cord Injury.

Read the Full NewsWire Press Release: 

Fortuna Fix Website Link:

LINK: Working 2 Walk 2015 Presentations  Part 1.(Science Time): First-in man Clinical Trials on Directly Re-programmed Autologous Neural Stem Cells

LINK: Working 2 Walk 2015 Presentations Part 2. Jan-Eric Ahlfors Human Clinical Studies

Posted in Biomaterials, Chronic Spinal Cord Injury Research, Regenerative Medicine, Rehabilitation, Spinal Research, Stem Cell Research, Unite 2 Fight Paralysis | Tagged , , , , | 2 Comments

Oxygen improves blood flow, restores more function in spinal cord injuries

Karim Fouad and post-doctoral fellows Yaqing Li (center) and Ana M. Lucas-Osma (right) and their team made a new discovery that could alter how we view spinal cord function and rehabilitation after spinal cord injuries.
Credit: Laurie Wang, University of Alberta

A new discovery at the University of Alberta will fundamentally alter how we view spinal cord function and rehabilitation after spinal cord injuries. Neuroscientists found that spinal blood flow in rats was unexpectedly compromised long after a spinal cord injury (chronically ischemia), and that improving blood flow or simply inhaling more oxygen produces lasting improvements in cord oxygenation and motor functions, such as walking.

Previous work had shown that while blood flow was temporarily disrupted at the injury site, it resumed rapidly, and it was more or less assumed that the blood flow was normal below the injury. This turns out to be wrong.

The Edmonton Journal with David Bennett Video

See the Full News Article at Science Daily HERE

Journal Reference:
Yaqing Li, Ana M Lucas-Osma, Sophie Black, Mischa V Bandet, Marilee J Stephens, Romana Vavrek, Leo Sanelli, Keith K Fenrich, Antonio F Di Narzo, Stella Dracheva, Ian R Winship, Karim Fouad, David J Bennett. Pericytes impair capillary blood flow and motor function after chronic spinal cord injury. Nature Medicine, 2017; DOI: 10.1038/nm.4331

Karim Fouad Links

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Rehabilitation, Spinal Research | Tagged , , , , , , , , , , , ,

Discovery Offers New Hope to Repair Spinal Cord Injuries

By Dana G. Smith, PhD / Gladstone News / April 24, 2017

Todd McDevitt (right), Jessica Butts (center) and Dylan McCreedy (left) created a special type of neuron from human stem cells that could potentially repair spinal cord injuries. [Photo: Chris Goodfellow, Gladstone Institutes]

Scientists at the Gladstone Institutes created a special type of neuron from human stem cells that could potentially repair spinal cord injuries. These cells, called V2a interneurons, transmit signals in the spinal cord to help control movement. When the researchers transplanted the cells into mouse spinal cords, the interneurons sprouted and integrated with existing cells.

V2a interneurons relay signals from the brain to the spinal cord, where they ultimately connect with motor neurons that project out to the arms and legs. The interneurons cover long distances, projecting up and down the spinal cord to initiate and coordinate muscle movement, as well as breathing. Damage to V2a interneurons can sever connections between the brain and the limbs, which contributes to paralysis following spinal cord injuries.

“Interneurons can reroute after spinal cord injuries, which makes them a promising therapeutic target,” said senior author Todd McDevitt, PhD, a senior investigator at Gladstone and a professor in the Department of Bioengineering and Therapeutic Sciences at UCSF. “Our goal is to rewire the impaired circuitry by replacing damaged interneurons to create new pathways for signal transmission around the site of the injury.”

Several clinical trials are testing cell replacement therapies to treat spinal cord injuries. Most of these trials involve stem cell–derived neural progenitor cells, which can turn into several different types of brain or spinal cord cells, or oligodendrocyte progenitor cells, which create the myelin sheaths that insulate and protect nerve cells. However, these approaches either do not attempt or cannot reliably produce the specific types of adult spinal cord neurons, such as V2a interneurons, that project long distances and rebuild the spinal cord.

Read the FULL News Article at the Gladstone Institute LINK

PNAS Abstract LINK


Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , , , | 2 Comments

Robotic platform maximizing gravity-dependent gait interactions to train standing and walking after neurological disorders

Jean Baptiste Mignardot (G. Courtine Lab)

Gait recovery after neurological disorders requires re-mastering the interplay between body mechanics and gravitational forces. Despite the importance of gravity-dependent gait interactions for promoting this learning, this essential aspect of gait rehabilitation have received little attention. Here, we introduce a robotic interface that assists trunk movements in order to maximize gravity-dependent gait interactions during highly participative locomotion within a large and safe environment. We elaborated an algorithm that automatically configures multidirectional forces applied to the trunk based on patient-specific needs. This robotic assistance enabled walking in non-ambulatory individuals with spinal cord injury and stroke, and allowed less impaired individuals to execute skilled locomotion that they could not perform without robotic assistance. The robotic interface improved locomotor performance after a single gait training session, whereas the same amount of training restricted to vertical support on a treadmill did not ameliorate gait. These results establish a new rehabilitation framework to augment motor recovery after neurological disorders.

Abstract Authors: *J.B. MIGNARDOT1,2, C. G. LE GOFF1,2, R. VAN DEN BRAND1,2, N. FUMEAUX1, S. CARDA4,2, J. VON ZITZEWITZ1, J. BLOCH2,3, G. COURTINE1,2; 1EPFL, Lausanne, Switzerland; 2Clin. Neurosciences, 3Neurosurg., Univ. Hosp. of Vaud, Lausanne, Switzerland; 4Neurorehabilitation, Univ. Hosp. of Vaud, Lausanne, Switzerland

Disclosures: J. Mignardot: None. C.G. Le Goff: None. R. van den Brand: None. N. Fumeaux: None. S. Carda: None. J. von Zitzewitz: None. J. Bloch: None. G. Courtine: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research | Tagged ,

Mayo pushes forward with Neuromodulation Discoveries for SCI

Peter J. Grahn, PhD

Drs. Peter Grahn, Kendall Lee, Igor Lavrov, and Kristin Zhao, from Mayo Clinic in Rochester, MN, review the results of their study appearing in the April 2017 issue of Mayo Clinic Proceedings showing volitional movement, standing, and step-like actions via spinal cord neuromodulation in a patient with chronic paralysis due to spinal cord injury.

Read the Full Publication Text Here: Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Tagged , ,

Gait rehabilitation enabled by epidural electrical stimulation of lumbar segments in a person with a chronic incomplete SCI

Various studies in animal models showed that robot-assisted gait rehabilitation enabled by epidural electrical stimulation of the lumbar spinal cord improves the recovery of leg motor control after spinal cord injury. Recent studies showed that this stimulation is also capable of activating lumbar spinal circuits in paraplegic people. Here, we conducted a preliminary study to evaluate the therapeutic impact of a gait rehabilitation program enabled by an overground robotic bodyweight support and continuous epidural electrical stimulation in a non-ambulatory person with a chronic incomplete spinal cord injury. The participant suffered a herniated disc collapse at the cervical level, which led to severe deficits on the left leg and moderate impairments on the right leg (AIS-C). After following a conventional rehabilitation program for more than one year after injury, she was not able to walk overground, even with assistive devices. She had previously been implanted with an epidural electrode array over lumbar spinal cord segments to alleviate neuropathic pain in the legs. We searched the electrode configurations in this array that targeted the muscles that the participant could not access voluntarily. Continuous stimulation through these electrode configurations improved a number of relevant gait parameters during locomotion. The participant then underwent a gait rehabilitation program that was conducted overground using a multidirectional robotic support system, and facilitated with the personalized stimulation protocols. After completion of the gait rehabilitation program, the participant was able to use a walker to progress overground without robotic assistance and without stimulation. Her WISCI-II score had thus increased from zero to thirteen, while her AIS score converted from C to D. Urodynamic examination revealed the disappearance of uninhibited bladder contractions and detrusor sphincter dyssynergia. This study provides preliminary evidence that robot-assisted gait rehabilitation enabled by epidural electrical stimulation may promote clinically relevant neurological improvements that persist without stimulation.

Abstract Authors
1Brain Mind Institute, Ctr. for Neuroprosthetics, 2Ctr. for Neuroprosthetics, Inst. of Bioengineering, Ecole Polytechnique Federale De Lausanne, Lausanne, Switzerland; 3Clin. Neurosci., 4Neurorehabilitation, 5Neuro-urology, 6Neurosurg., Univ. Hosp. of Vaud (CHUV), Lausanne, Switzerland
C.G. Le Goff: None. J. Mignardot: None. R. van den Brand: None. M. Capogrosso: None. I. Fodor: None. G. Eberle: None. B. Schurch: None. S. Carda: None. J. von Zitzewitz: None. J. Bloch: None. G. Courtine: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research

Stretching the boundaries of neural implants

Rubbery, multifunctional fibers could be used to study spinal cord neurons and potentially restore function.
David L. Chandler | MIT News Office

Image: Chi (Alice) Lu and Seongjun Park Credit: MIT

Implantable fibers have been an enormous boon to brain research, allowing scientists to stimulate specific targets in the brain and monitor electrical responses. But similar studies in the nerves of the spinal cord, which might ultimately lead to treatments to alleviate spinal cord injuries, have been more difficult to carry out. That’s because the spine flexes and stretches as the body moves, and the relatively stiff, brittle fibers used today could damage the delicate spinal cord tissue.

Now, researchers have developed a rubber-like fiber that can flex and stretch while simultaneously delivering both optical impulses, for optoelectronic stimulation, and electrical connections, for stimulation and monitoring. The new fibers are described in a paper in the journal Science Advances, by MIT graduate students Chi (Alice) Lu and Seongjun Park, Professor Polina Anikeeva, and eight others at MIT, the University of Washington, and Oxford University.

Read the Full Article Here:

Read the Full Paper at Science Advances HERE:

Engineering a spinal cord repair kit at MIT – Science Nation (Professor Polina Anikeeva) Posted Earlier

Posted in Biomaterials, Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research

Rerouting cortical drive through residual spinal tissue mediates motor function recovery after severe SCI

A severe contusion of thoracic segments disrupts the motor-circuit communication matrix linking the brain and the spinal cord. Electrochemical stimulation applied over lumbar segments restored this communication, which enabled volitional control of leg movements in rodents and humans with motor complete paralysis. However, the circuit-level mechanisms through which the cortical drive regains functional access to the spinal circuits controlling leg movements during electrochemical stimulation remain poorly understood. Using mice expressing light-sensitive channels in cortical projection neurons, we first showed that electrochemical stimulation enabled the hindlimb motor cortex to regain a graded control over hindlimb locomotor movements in otherwise paralyzed animals. Using virus-mediated tract tracing and circuit-specific inactivation techniques, we found that after injury the cortical drive is rerouted through glutamatergic reticular neurons with residual projections below the injury. Robot-assisted gait training enabled by electrochemical stimulation promoted an extensive reorganization of these pathways. We found a robust growth of motor cortex projections into the reticular formation, and a substantial sprouting of residual reticulospinal axons into specific regions of the spinal cord below the injury. We established causal relationships between this anatomical reorganization and the recovery of voluntary leg motor control in response to gait rehabilitation. These results illustrate the remarkable capability of neural pathways to reorganize in order to mediate motor recovery, even after the most severe types of spinal cord injury.

Abstract Authors
Swiss Federal Inst. of Technol., Lausanne, Switzerland
L. Asboth: None. Q. Barraud: None. L. Friedli: None. J. Beauparlant: None. C. Martinez-Gonzalez: None. S. Anil: None. G. Pidpruzhnykova: None. E. Rey: None. L. Baud: None. J. Kreider: None. M. Anderson: None. J. von Zitzewitz: None. G. Courtine: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research | 1 Comment

Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

Kathren L. Fink, Francesc López-Giráldez, In-Jung Kim, Stephen M. Strittmatter, William B.J. Cafferty Open Access

•Mechanisms driving functional plasticity of intact CNS circuits are unknown
•Retrograde spinal tracing reveals CST neurons undergoing functional plasticity
•Transcriptional profiling of these neurons reveals pro-axon growth targets
•Molecular modulation of the identified LPA-LPPR1 axis enhances plasticity post-SCI

Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

See the Full Article at

Posted in Chronic Spinal Cord Injury Research, Spinal Research