Miracle chemical ‘cocktail’ could cure spinal cord damage

By Stephen Beech, SWNS

A chemical “cocktail” could restore movement for people crippled after suffering spinal cord injuries, suggests new research.

Scientists say the mixture of three molecules could potentially be given therapeutically to patients to aid in their recovery after serious injury.

After spinal cord injury or stroke, axons originating in the brain’s cortex and along the spinal cord become damaged, disrupting motor skills.

Now, according to findings published in the journal Neuron, a team of scientists at Boston Children’s Hospital in the United States has developed a method to promote axon regrowth after injury.

They administered the therapeutic cocktail of molecules to mice with either a spinal cord injury or stroke and observed that the mice were able to recover fine motor skills.

Study senior author Doctor Zhigang He, of Boston Children’s Hospital and Harvard Medical School, said: “In our lab, for the first time we have a treatment that allowed the spinal cord injury and the stroke model to regain functional recovery.”

His team designed the mixture by building on earlier work from Dr. Joshua Sanes’ group at Harvard who focused on optical nerve injuries. Sanes observed that the combination of insulin-like growth factor 1 (IGF1) and a protein called osteopontin (OPN) promoted nerve regrowth and vision improvement in optically-injured mice.

Studying a mouse model of stroke, He’s team made a surprising observation.

He said: “We saw what we expected, axon sprouting in the spinal cord.”

“But we also found something unexpected, increased axon sprouting in the subcortical area.”

By genetic manipulation He’s team ablated the sprouted axons of the CST and found that the improvement diminished. That means the functional recovery was not particularly dependent on sprouting in subcortical regions but on those in the spinal cord.

He added: “The functional outcomes of such subcortical sprouting remain to be tested.”

He said that his team are now in talks with rehab centers to determine the prerequisites of ultimately taking their work forward to clinical trials.

See the full article at this New York Post LINK

Posted in Chronic Spinal Cord Injury Research, Gene Therapy, Regenerative Medicine, Spinal Research | Tagged , , , | Leave a comment

Combined expression of pro-regenerative transcription factors and transplanted stem cells to promote corticospinal tract regeneration.

Naveen Jayaprakash

The failure of axon regeneration in the injured spinal cord results in partial or complete loss of function distal to the injury. To restore the function, severed axons must regrow and functionally reconnect to appropriate targets below the injury site. We have shown previously that forced overexpression of pro-regenerative transcription factors including Sox11 and KLF7 promotes axon growth in corticospinal tracts (CST) neurons. Moreover, using optogenetic stimulation to specifically stimulate CST axon terminals, we have shown that newly sprouted, genetically stimulated axons are able to form functional synaptic connections with spinal neurons. However, these experiments were performed in models of partial spinal injury, and growing CST axons were observed mainly in trajectories that circumvented injuries, taking advantage of spared tissue. Here we tested the ability of Sox11 or KLF7-stimulated axons to regenerate through more complete spinal injuries. Adult mice were subjected to complete thoracic crush injuries or severe cervical injuries in which 1mm of tissue was unilaterally removed. Cortical neurons were treated with AAV-Sox11 or AAV-VP16-KLF7 along with AAV-EGFP tracer. CST axons were not observed to traverse these sites of injury. Combined, these data suggest that KLF7- and Sox11-based interventions enhance innate growth ability while maintaining the capacity for synaptic integration, but do not confer the ability to extend into sites of spinal injury. Recent reports indicate that transplanted stem cells can serve as a substrate for CST growth in the injured spinal cord. Accordingly, in current experiments we are combining transcriptional manipulation of injured cortical neurons with transplantation of embryonic and induced pluripotent stem cells into C5 unilateral injury sites. Preliminary data confirm integration of the transplanted cells and fiber outgrowth into host tissue. Ongoing assessment of CST growth into and beyond the grafts will assess the utility of combined stem cells treatment and gene therapy to re-establish lost synaptic connection following spinal cord injury.

Authors
*N. JAYAPRAKASH, Z. WANG, N. KRUEGER, A. KRAMER, M. BLACKMORE;
Marquette Univ., Milwaukee, WI
Disclosures
N. Jayaprakash: None. Z. Wang: None. N. Krueger: None. A. Kramer: None. M. Blackmore: None.

LINK: Session 323 – Spinal Cord Injury Models and Mechanisms

Posted in Chronic Spinal Cord Injury Research, Gene Therapy, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , , | Leave a comment

Structural and Functional Substitution of Deleted Primary Sensory Neurons by New Growth from Intrinsic Spinal Cord Nerve Cells: An Alternative Concept in Reconstruction of Spinal Cord Circuits

In a recent clinical report, return of the tendon stretch reflex was demonstrated after spinal cord surgery in a case of total traumatic brachial plexus avulsion injury. Peripheral nerve grafts had been implanted into the spinal cord to reconnect to the peripheral nerves for motor and sensory function. The dorsal root ganglia (DRG) containing the primary sensory nerve cells had been surgically removed in order for secondary or spinal cord sensory neurons to extend into the periphery and replace the deleted DRG neurons. The present experimental study uses a rat injury model first to corroborate the clinical finding of a re-established spinal reflex arch, and second, to elucidate some of the potential mechanisms underlying these findings by means of morphological, immunohistochemical, and electrophysiological assessments. Our findings indicate that, after spinal cord surgery, the central nervous system sensory system could replace the traumatically detached original peripheral sensory connections through new neurite growth from dendrites.

Full Article LINK at Frontiers in Neurology Journal 

News.com.au Article LINK

Science Alert Article LINK

News Medical Life Sciences Article LINK

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research | Tagged | Leave a comment

U2FP SCI CureCast now includes the 8th episode!

Join Matthew Rodreick, Kate Willette, and guests for our weekly podcast talking about everything related to finding a cure or therapies for paralysis after spinal cord injury.  Why should we care about the science and the whole process of bringing therapies to the clinic? Because that knowledge is fundamental to gaining a voice in decision-making.

Podcast Episode 8:
Kate and Matthew talk with Lee Thibeault about the process of participating in clinical trials. Lee was one of the first individuals from the SCI community to participate in the early clinical trials of Stem Cell Inc. He talks candidly about his experience, its effects and the importance of participating in clinical trials to further the science to cure paralysis.
LINK

Podcast Episodes 1-7 LINK:

Posted in Advocacy, Rehabilitation, Spinal Research, Unite 2 Fight Paralysis | 1 Comment

Chronic SCI: ReNetX Bio Launched to Advance Innovative Neuro-Regenerative Technology Developed at Yale University

NEW HAVEN, Conn., July 24, 2017 (GLOBE NEWSWIRE) — ReNetX Bio, a company developing first-in-class therapeutics to treat injury to the central nervous system, today announced its launch as a new company with the appointment of Erika Smith as Chief Executive Officer. The company also announced the initiation of a Series A financing round to fund its first clinical trial of its lead therapeutic candidate, Nogo Trap, in patients with chronic spinal cord injury.

ReNetX licensed the rights of the innovative neuro-restorative Nogo Receptor platform technology discovered by Stephen Strittmatter, M.D., Ph.D., at Yale University and founder and scientific advisor to ReNetX. The central nervous system contains major extracellular factors that limit regrowth of neurons. The company has developed a decoy receptor, called Nogo Trap, that binds the growth inhibitors allowing the body to grow nerve fibers naturally and directly targeting restoration across all facets of growth: axonal regeneration (long distance), axonal sprouting (medium distance) and synaptic plasticity.

ReNetX, formerly known as Axerion Therapeutics, currently receives development support for the Nogo Trap chronic SCI program from the National Institutes of Health and the National Center for Advancing Translational Sciences. The company is now actively seeking financing for a Series A financing round to provide the capital needed to initiate and complete a Phase 1/2 clinical trial of Nogo Trap in patients with chronic spinal cord injury.

“Spinal cord injury has been a condition so far resistant to treatment by a variety of therapeutic approaches,” said Dr. Strittmatter. “However, based on the research in my laboratory, we believe that we may have an approach that could benefit these patients. Nogo Trap has demonstrated improved neurologic function following central nervous system damage in several animal models. Based on these promising results, we now believe that Nogo Trap should be evaluated in chronic spinal cord injury patients.”

ReNetX appointed Ms. Smith as part of the recapitalization of the company. She has more than 25 years of experience as an investor and entrepreneur in life sciences. Most recently, she was director of the Blavatnik Fund for Innovation at Yale University.

“Spinal cord injury is one of the most significant unmet medical needs with an annual cost of more than $5 billion per year,” said Ms. Smith. “A treatment that could mitigate even only a part of the condition could both improve quality of life of these patients. When the funding is in place, we anticipate swift patient recruitment for our chronic spinal cord injury clinical trial. In the long-term, conditions beyond spinal cord injury including glaucoma and stroke.”

Article LINK:

Stephen Strittmatter PhD MD Lab Link:

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research | Tagged , | 3 Comments

Overexpression of KLF6 in corticospinal tract neurons promotes axon growth after spinal injury

Zimei Wang PhD MD Marquette University

Axonal regeneration in the central nervous system is limited in part by a developmental decline in the intrinsic regenerative capacity of central nervous system (CNS) neurons. Changes in gene expression are likely involved, and thus transcription factors that orchestrate gene expression are attractive targets to understand and overcome intrinsic limits to axon growth in adult neurons. We have shown previously that forced expression of pro-regenerative transcription factors, including Sox11 and a transcriptionally activated form of Krüppel-like factor 7 (VP16-KLF7), can enhance the regenerative ability of injured corticospinal tract (CST) neurons. Here we assessed the ability of KLF6, a transcription factor closely related to KLF7, to promote CST regeneration. KLF6 was delivered to cortical neurons by injection of AAV-KLF6 along with AAV-EGFP tracer, and animals were subjected to pyramidotomy or unilateral cervical hemisection. KLF6 expression promoted a robust increase in midline crossing by transduced (EGFP+) CST axons in the pyramidotomy model, and extensive CST growth in the spinal injury model that extended up to 3mm from the injury site. Immunohistochemistry confirmed viral-mediated upregulation of KLF6 protein, but also revealed endogenous expression of KLF6 in cortical neurons that appeared largely unaffected by spinal axotomy. Intriguingly, forced expression of KLF6 had more modest effects in sensory neurons confronted with spinal injury, causing a decrease in net retraction but not sprouting or regeneration beyond the injury site. To identify potential functional interactions with other pro-regenerative transcription factors, either Sox11 or Myc were co-expressed with KLF6 in cortical neurons challenged with spinal injury. Neither combinatorial treatment resulted in significant increases in CST axon growth above the level of KLF6 alone. Ongoing experiments are testing co-expression of KLF6 with additional pro-regenerative factors including Jun and DCLK. In addition, using CRISPR-mediated knockdown in a Cas9-expressing transgenic mouse, we are currently testing combined KLF6 overexpression and knockdown of PTEN. Finally, RNAseq experiments are underway to identify KLF6 target genes. Overall, these data identify KLF6 as a potent transcriptional promoter of axon regeneration in the injured CST.

Abstract Authors
*Z. WANG, I. VENKATESH, N. KRUEGER, D. NOWAK, B. CALLIF, B. MAUNZE, M. G. BLACKMORE;
Dept. of Biomed. Sci., Marquette Univ., Milwaukee, WI
Disclosures
Z. Wang: None. I. Venkatesh: None. N. Krueger: None. D. Nowak: None. B. Callif: None. B. Maunze: None. M.G. Blackmore: None.

LINK: Session 323 – Spinal Cord Injury Models and Mechanisms

NIH RePorter Link: The Report Expenditures and Results tool allows users to search a repository of NIH-funded research projects and access publications and patents resulting from NIH funding
Project Number: 5R01NS083983-05 Former Number: 5R01NS083983-04
Contact PI / Project Leader: BLACKMORE, MURRAY G
Title: FUNCTIONAL TESTING OF KLF7 IN SPINAL CORD INJURY: AN OPTOGENETIC APPROACH
Awardee Organization: MARQUETTE UNIVERSITY

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

A potent anti-spastic effect after intrathecal NK1 antisense oligonucleotide or subpial AAV9-NK1-ShRNA delivery in rats with chronic spinal transection-induced muscle spasticity

Mariana Bravo Hernandez

BACKGROUND: The spinal NK1 receptor system has been demonstrated to play an important role in the development and maintenance of chronic pain states after peripheral nerve injury. In contrast, its role in the development of spinal hyper-reflexia and muscle spasticity resulting from spinal traumatic injury is not well defined. The goal of the present study was to assess the treatment effect of: i) spinal intrathecal (IT) delivery of NK1 antisense oligonucleotide (NK1-ASO), and ii) subpial (SP) delivery of AAV9-NK1-shRNA in rats with chronic spinal cord transection-induced muscle spasticity. METHODS: Adult Sprague-Dawley (SD) rats (female, 200-300 g) had the Th9 spinal segment transected to induce muscle spasticity. The presence of spasticity was defined as exacerbated EMG response recorded from the gastrocnemius muscle after applying progressively increased paw pressures using von Frey filaments (0.6-26 grams). After baseline spasticity measurement, animals received: i) a single lumbar intrathecal bolus of NK-1-ASO or control antisense oligonucleotide (Cont-ASO), or ii) subpial (SP) AAV9-NK1-shRNA or control AAV9-GFP. Before and after treatment, the presence of spasticity response was measured in 1-week intervals for up to 12 weeks. The effect of each treatment on spinal NK1 expression was evaluated by immunofluorescence and confocal microscopy or by qPCR. RESULTS:In spastic animals receiving IT injection of NK1-ASO, a progressive decrease in measured surface EMG activity after paw tactile stimulation was seen with the maximum effect measured at 2 weeks after injection (p<0.05). A significant anti-spastic affect was still present at 10 weeks after treatment. No changes in spasticity response were measured in animals receiving control ASO. In animals injected SP with AAV9-NK1-shRNA, a comparable anti-spasticity effect was seen at 2 weeks after treatment. Histological and qPCR analysis of the lumbar spinal cord showed a 75-85% reduction in NK1 signal with no change in substance P expression. CONCLUSIONS: These data show that NK1-ASO or AAV9-NK1-shRNA-mediated suppression of spinal NK1 receptor expression may represent a novel therapeutic approach for modulation of chronic spinal injury-induced muscle spasticity and hyper-reflexia.

Abstract Authors
*M. BRAVO HERNANDEZ1, T. YOSHIOZUMI1, M. R. NAVARRO1, K. KAMIZATO1, T. TADOKORO1, O. PLATOSHYN1, S. MARSALA1, J. D. CIACCI2, C. MAZUR3, M. MARSALA1;
1Anesthesiol., 2Neursurgery, Univ. of California San Diego, LA Jolla, CA; 3Ionis Pharmaceuticals, Carlsbad, CA
Disclosures
M. Bravo Hernandez: None. T. Yoshiozumi: None. M.R. Navarro: None. K. Kamizato: None. T. Tadokoro: None. O. Platoshyn: None. S. Marsala: None. J.D. Ciacci: None. C. Mazur: None. M. Marsala: None.

LINK: Session 320 – Injury Responses after Spinal Cord Injury

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

Non-Invasive Paired Stimulation and Anklebot Robot to Improve Lower Extremity Motor Recovery in Chronic Spinal Cord Injury

The Human Spinal Cord Injury Repair laboratory at Burke Medical Research Institute is currently looking for participants with some degree of motor dysfunction in the lower extremity after spinal cord injury for a clinical research study.

The aim of the study is to use robotic kinematics and neurophysiology as possible outcome markers to predict improvement in motor recovery.

Anklebot Clinical Trial for Chronic Incomplete SCI

This project has two objectives:
To investigate the quality of movement in the lower extremity using a robotic device, the Anklebot.
To strength the spared connections between the brain and the muscle after spinal cord injury pairing transcranial magnetic stimulation (TMS) and electrical stimulation. The two stimuli will target the soleus muscle in the lower extremity.

We are expecting to:
Objectively characterized the motor dysfunction using lower limb robotics.
Improve the voluntary motor output using the paired stimulation protocol.

Mar Cortes MD

Mar Cortes, M.D.
Lab Director
Human Spinal Cord Injury Repair Laboratory
Assistant Professor
Weill Cornell Medicine
Role: Principal Investigator

See the Full Article for Addition Enrollment and Eligibility Criteria

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

Spinal cord injury: Using cortical targets to improve motor function

A main goal of rehabilitation strategies in humans with SCI is to strengthen transmission in spared neural networks. Although neuromodulatory strategies have targeted different sites within the central nervous system to restore motor function following SCI, the role of cortical targets remains poorly understood.

“I am excited to see that electrophysiology can be successfully used to guide interventions for recovery of function after spinal cord injury,” says Dr. Perez.

In this study, Drs. Perez, Jinyi Long, Ph.D., and Paolo Federico, Ph.D. used 180 pairs of noninvasive transcranial magnetic stimulation for 30 minutes over the hand representation of the primary motor cortex at an interstimulus interval mimicking the rhythmicity of descending late indirect (I) waves in corticospinal neurons (4.3 ms; late I-wave protocol) or at an interstimulus interval in-between I-waves (3.5 ms; control protocol) on separate days in a randomized order.

Late I-waves are thought to arise from trans-synaptic cortical inputs and have a crucial role in the recruitment of spinal motor neurons following SCI. The researchers found that the excitability of corticospinal projections to intrinsic finger muscles increased in SCI and uninjured participants after the late I-wave but not the control protocol for 30 to 60 minutes after the stimulation. Importantly, individuals with SCI were able to exert more force and electromyographic activity with finger muscles after the stimulation showing an enhanced ability to grasp small objects with their hands.

Full Article at University of Miami Miller School of Medicine

See the FULL Article LINK Science Daily News:

University of Miami Miller School of Medicine
Jinyi Long, Paolo Federico, Monica A. Perez.
A novel cortical target to enhance hand motor output in humans with spinal cord injury. Brain, 2017; 140 (6): 1619 DOI: 10.1093/brain/awx102

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

43 Disability Protesters outside of Senate Mitch McConnell’s office arrested over proposed severe Medicaid cuts.

LINK: The Senate Puts Medicaid on the Chopping Block

A draft version of the AHCA released Thursday shows even deeper cuts to the program than the House version.

Senate Health Care Protest

Many disabled people in wheelchairs were arrested outside of Senate Majority Leaders Office.

The new AHCA is a lot like the old AHCA.

After weeks of secret gestation in back rooms, the Senate released a discussion draft of the chamber’s version of the American Health Care Act. Like the version passed through the House to cheers in May, it is likely to make health care less affordable for low-income, sick, and near-elderly people; it makes Obamacare tax credits for exchange coverage less generous; it restricts and slashes Medicaid funding deeply over the next decade; and it attempts to smooth euphemistically-named “market disruptions” from all those reforms by injecting billions into state funds and reinsurance.

There are some substantial changes in the specifics, though. For starters, the Senate bill would tweak the House bill’s tax subsidy for private insurance purchased on the exchanges. The final version of the House bill provided a tax credit to people making up to 400 percent of the federal poverty line that would be less generous than the existing ACA credits. It would also reduce the amount of expenses covered as recipients get older and have more expenses.

The Senate’s version would cut the eligibility for premium tax credits to those earning up to 350 percent of the poverty line. It would be slightly more generous for poor and near-poor people, although credit percentages would taper off more sharply as recipients grow older, and they would be severely restricted for people as their income approaches that 350 percent threshold. Unlike the House plan, however, the Senate plan would fund Obamacare exchange cost-sharing subsidies through 2019, which would soften some of the immediate impacts of a less generous tax credit.

See the Full Article at The Atlantic by VANN R. NEWKIRK II

Disability Advocacy Protesters were dragged out of the hallway in front of McConnell’s office after the Senate unveiled its health care bill.

CNN Article

Posted in Advocacy