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How likely are we to cure paralysis?

Image credit: https://pixabay.com/photos/wheelchair-disability-lame-handicap-2489427/

Subash Chapagain
Subash Chapagain Feb 04, 2021
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Could it be possible to cure paralysis?

Paraplegia is one of the spinal cord injuries that are yet to have any definitive therapy/treatment discovered for. The condition is marked by loss or impairment of motor or sensory functions of the lower half of the body, rendering the affected motor organs paralyzed. Usually, the loss of signalling from the central nervous system (brain) to the lower body parts -caused by injury to the spinal canal, or underlying congenital conditions- is the reason for this condition. Though some symptoms and complications can be rectified, till date there is no available treatment for paraplegia.

Naturally, the neurons of the adult mammalian central nervous system (CNS) don’t regenerate injured neurons. This regenerative inadequacy can be linked to various reasons. Glial scars formed upon injury, on top of the inhibitory environment by myelin for axonal growth are attributed to the lack of CNS regeneration, along with the intrinsic developmental decline in the growth capacity of axons.

Among other descending (CNS to peripheral) neuronal pathways the corticospinal tract, (CST), and serotonergic (5-HT-positive) axons of the raphespinal tract (RpST) are of particular importance here since they are critical for controlling voluntary fine movements. Since CST is the most resistant to regeneration post-injury, the attempts at inducing the CST’s axonal growth over the last decades have yielded very low success. Delivery of neurotrophic factors and/or neutralizing inhibitory cues have been tried with little to no effect. Till now, only one approach seemed to work: conditional knockout of the phosphatase and tensin homolog (PTEN-/-) in the cortical motor neurons leading to an activation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT)/mTOR signalling pathway that enables partial regeneration of the CST axons.

However, despite facilitating a significant anatomical regeneration of the CST after a spinal cord crush (SCC), the improvement in the functional motor recovery was almost non-existent, leaving scientists to the square zero of finding a treatment for such injuries. Hence, there is a stark need for improvements in translational research that could upscale lab-based findings to apply in clinical settings. In regard to this, what approaches do we have till date with proof-of-concept that we could take into serious consideration as curative treatments for paralysis? How likely are we to solve the case in near future?

[1]Lu, Y., Belin, S. & He, Z. Signaling regulations of neuronal regenerative ability. Curr. Opin. Neurobiol. 27, 135–142 (2014).

[2]Hiebert, G. W., Khodarahmi, K., McGraw, J., Steeves, J. D. & Tetzlaff, W. Brain-derived neurotrophic factor applied to the motor cortex promotes sprouting of corticospinal fibers but not regeneration into a peripheral nerve transplant. J. Neurosci. Res. 69, 160–168 (2002).

[3]Zheng, B. et al. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc. Natl Acad. Sci. USA 102, 1205–1210 (2005)

[4]Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).

Creative contributions

Targeted electro-chemical neuron stimulation restores motor function in paraplegic patients

Manel Lladó Santaeularia
Manel Lladó Santaeularia Feb 17, 2021
In this contribution I'm going to describe a line of research that I've found fascinating since 2018, when I was lucky enough to attend the Keynote Lecture given by Grégoire Courtine in the opening session of the European Society of Gene and Cell Therapy congress in Lausanne. As you can imagine, the congress attendance was full of experts in the gene therapy and gene editing fields, and thus I was surprised that we were opening the congress with a talk about engineering and electro-stimulation, which has nothing to do with these fields. However, as soon as Dr. Courtine started speaking, our collective minds were blown by the research of his team and the future implications it could have.

The team of Grégoire Courtine has spent the last 10 years developing an electrical stimulation system that can restore motor function in paralyzed limbs. And it works, in humans. Amazing right? Let's get into how that works:

Spinal Cord Injuries (SCI) are disruptions of the communication in the nervous system, leading to the loss of essential neurological functions. Most SCIs are not a severing of the whole spinal chord, but what is known as a spinal chord contusion. In those situations, while there is an important damage that blocks the communication through that area of the spinal chord, some intact nerve fibers may remain. These fibers are not activated but are functionally capable of transmitting an electric stimulus. Research had previously shown that epidural electrical stimulation (EES) enables the brain to exploit spared but functionally silent descending pathways in order to produce movements of paralysed limbs, but also improves the ability of the spinal cord to translate task-specific sensory information into the muscle activity that underlies standing and walking . The group of Dr. Courtine found that EES activates motor neurons by recruiting proprioceptive circuits within the posterior roots of the spinal cord. With this knowledge, they were able to develop EES protocols that target individual posterior roots to access the motor neuron pools located in the spinal cord segment innervated by each root. In order to further improve this stimulation, they needed to engage motor neurons at the appropriate tim. For this, they managed to develop a spatially selective EES train that can be delivered with timing that coincides with the intended movement. Thus, they were able to specifically stimulate the neurons they wanted and exactly when they wanted, in order to generate a neuro-motor signal.

This kind of stimulation was able to recover motor function in animal models trained in a gravity-assist device. Interestingly, the training coupled with stimulation of the affected area of the spinal chord promoted an extensive reorganization of the residual neural fibers, which resulted in an improvement of motor function even when the EES was off. This meant that the animal models, in this case rats, were able to walk when receiving EES, with a movement controlled by their own brain, and regained some movement even without EES.

This seems very cool! But surely they haven't tried that in patients yet, right? Well, yes, they have. And it works! They have proven that their system can help paraplegic people regain motility in their paralyzed limbs. Some patients with leg paralysis even managed to achieve complete leg extension without EES after being trained with the EES system. And all that is necessary is the implantation of an electrode system at the place of the injury and some training in order to reorganize the nerve fibers. Yay plasticity! This video summarizes the whole process really well

So, that works in a lab setting, with a gravity assist, but is it possible to use something like that for every day life? Again, the answer is yes! They have developed a very neat system in which the electrical stimulation is controlled wirelessly. The patient can use a smart watch and personalized voice control in order to activate or inactivate the stimulation, so they can use it whenever they want to walk! Here's the patient showing it off in an event

Ok, that's amazing! But is there any improvement on the future? Of course, Dr. Courtine's group is not satisfied with the amazing feat they have achieved! They are now developing a more complex system which includes an electrode situated in the specific region of the motor cortex that is responsible for the movement of the paralyzed limbs. Since that cortex region should be completely functional, they aim to register the signals generated by it and communicate them in real time, via wire-less signaling, to the EES system implanted at the place of the injury. This has already been tried in non-human primates and shown potential for improving the precision and timing of the signalling, thus further expanding the capabilities of this approach.

Could this kind of stimulation be coupled with systems like the one mentioned in this session in order to further improve the regeneration of the motor neurons? What could we do in situations where the spinal chord is completely severed? Are we close to solving the problem of spinal chord injuries for good?

[1]Barolat G, Myklebust JB, Wenninger W. Enhancement of voluntary motor function following spinal cord stimulation--case study. Appl Neurophysiol. 1986;49(6):307-14. doi: 10.1159/000100160. PMID: 3499118.

[2]Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014 May;137(Pt 5):1394-409. doi: 10.1093/brain/awu038. Epub 2014 Apr 8. Erratum in: Brain. 2015 Feb;138(Pt 2):e330. PMID: 24713270; PMCID: PMC3999714.

[3]Wagner FB, Mignardot JB, Le Goff-Mignardot CG, Demesmaeker R, Komi S, Capogrosso M, Rowald A, Seáñez I, Caban M, Pirondini E, Vat M, McCracken LA, Heimgartner R, Fodor I, Watrin A, Seguin P, Paoles E, Van Den Keybus K, Eberle G, Schurch B, Pralong E, Becce F, Prior J, Buse N, Buschman R, Neufeld E, Kuster N, Carda S, von Zitzewitz J, Delattre V, Denison T, Lambert H, Minassian K, Bloch J, Courtine G. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature. 2018 Nov;563(7729):65-71. doi: 10.1038/s41586-018-0649-2. Epub 2018 Oct 31. PMID: 30382197.

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Darko Savic
Darko Savica year ago
Combine the implant technology with localized epigenetic reprogramming (https://www.biorxiv.org/content/10.1101/710210v1.full) to aid the regeneration of nerves. Then after a while, the implant could be removed, leaving the person as good as new.

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Designer cytokines and hyperinterleukin-6 as a promising treatment for paraplegia

Subash Chapagain
Subash Chapagain Feb 18, 2021
Thanks to the recent research advances in neuroscience and immunotherapeutics that has revealed that specially designed genetically engineered proteins can induce a rigorous neuronal regeneration and recover an individual from spinal cord injury .

Stimulation of neural regeneration by designer cytokine

The findings in this study are built on the premises of previous research by the same (and other) groups on the optic nerve regeneration . The activation of critical controllers like the JAK/STAT3 pathway stimulates the regeneration of CNS axons, as reported in these findings. The regeneration can be achieved, at least in principle, by two ways: either delivering Il-6 type cytokines (CNTF, LIF, IL-6), or genetically depleting the intrinsic SOCS3 (Supressor of Cytokine Signalling 3), the protein that normally inhibits JAK/STAT3 pathway .

The efficiency of the cytokines is limited, however, by the low and restricted expression of the cytokine specific alpha-receptor subunits in the CNS neurons, ultimately compromising the pro-regenerative effects. This exact problem has now been addressed. The gene therapeutic approach developed by Fischer et.al uses designer cytokine hyper-interleukin-6 (hIL-6) which consists of the bioactive part of the Il-6 protein covalently linked to the soluble IL-6 receptor alpha subunit .

The designer cytokine has an edge over the natural counterpart as it can directly bind to the signal-transducing receptor subunit glycoprotein 130 (GP130), casually expressed in most of the neurons. When the virus-assisted gene therapy with hIL-6 was applied even just once post-injury, it was seen that it induced more robust optic nerve regeneration than the pre-injury PTEN knockout (PTEN -/- ). This is why it is among the best approaches till date proven in vivo to actually restore motor function after nerve fibre injury.

What did the team do to make it happen?

Motor-sensory cortical nerve cells were induced to produce the hyper-interleukin-6 themselves in the study. To do so, AAV (Adeno-Associated Virus) vectors were used. The vectors basically were viral particles designed specifically to induce the production of this newly coded IL-6 (the hyper interleukin-6) protein. The viral particles specifically deliver the blueprint for the hIL-6 production in the motoneurons. The motor neuron cells, being linked via axonal branches to other nerve cells important for movement processes such as walking, producing hIL-6 in the motoneurons allowed easier transportation of the produced cytokine to these otherwise inaccessible cells. The team found that the hIL-6 therapy enabled locomotor recovery of both hindlimbs in the mouse models used for the study.
The researchers have suggested that the functional recovery mostly depended on the improved regeneration of serotonergic fibres, based on the observation that PTEN-/- induced CST regeneration failed to enable hindlimb recovery, though some extent of neuronal regeneration was seen. This was supported by another finding- the DHT-mediated selective abolition of serotonergic fibres caused the loss of locomotory recovery in these hIL-6-AAV2 treated mice. Hence, the potential of hIL-6 for both RpST and CST regeneration is established.

If this approach could be upscaled to human treatment, it would be of immense impact, relieving people of their otherwise motion-restricted lives. However, prior to the next phase of trials, in the lab and in human patients, what questions regarding the technique would be worth asking?
What other alternative approaches could we come up with to treat paraplegia?

[1]Leibinger, M., Zeitler, C., Gobrecht, P. et al. Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice. Nat Commun 12, 391 (2021). https://doi.org/10.1038/s41467-020-20112-4


[3]Fischer, D. Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration. Eye (Lond.) 31, 173–178 (2017).

[4]Leibinger, M., Andreadaki, A., Diekmann, H. & Fischer, D. Neuronal STAT3 activation is essential for CNTF- and inflammatory stimulation-induced CNS axon regeneration. Cell Death Dis. 4, e805 (2013).

[5]Muller, A., Hauk, T. G. & Fischer, D. Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain 130, 3308–3320 (2007)

[6]Smith, P. D. et al. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64, 617–623 (2009).

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