20/10/2014 neurorepair | Research Topics on Neural Tissue Repair

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neurorepair
Research Topics on Neural Tissue Repair
13MAY2014
GENE THERAPY: a credible option for spinal-
cord repair?
posted in gene therapy, neuroscience by Nelson I. Contreras
(http://neurorepair.files.wordpress.com/2014/05/jk_2014-
march1.jpg)
- Dr. Jessica C.F. Kwok provides some answers:
University of Cambridge (U.K.) http://is.gd/EeV8m3 (http://is.gd/EeV8m3)

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By : Nelson I. Contreras, Ph.D

CINEMA AND BRAIN STRUCTURE
(http://neurorepair.files.wordpress.com/2014/05/connectome.jpg)
Cinema allows us to instantly view -perhaps even as first row
spectators- biological events that take a long time to occur, like the
growth and blooming of a rosebud, or the hatching of a colorful
butterfly out of its chrysalis. Video sequences will also help us
understand how brain growth and development occurs over the
months and years elapsing from inception to adulthood: by the
succession of slow, complex, infinitely precise events taking place by
the millions, all playing crucial roles as part of a staggering organizational process.
Impressive videos relevant to the subject are becoming increasingly accessible in the
web. Below are some remarkable examples:
Seeing through the brain http://is.gd/tW1DSu (http://is.gd/tW1DSu)
Brain pathway structures: the connectivity http://is.gd/HdwGHz (http://is.gd/HdwGHz)
Human brain white matter tractography http://is.gd/rxFqHg (http://is.gd/rxFqHg)
Rodent CNS 3D-dinamic scan http://is.gd/0MVu11 (http://is.gd/0MVu11 )
Beyond looks, the complex, meticulously timed developments conforming such
architectural prodigies, must occur while ensuring meaning, i.e., integration, coherence,
functional plausibility. A bit like it happens when Beethovens 9th Symphony is performed
alive, fully and brilliantly. Using video streams to envisage nervous system development
will likely help us grasp the staggering complexities involved in the conformation of the
Central Nervous System (CNS) at its multiple structural and organizational levels. Such
visions may, however, also bring about paralyzing fears when considering the chances of
actually being able to repair -even if only partially- the physical and functional damages
often affecting CNS as a result of trauma, stroke or other ailments. Not just since Verne,
though,mankind have proved stubborn at the job of trying, so neural repair research seems
blooming nowdays.
BIOELECTRICAL CIRCUITS: THE STUFF NEURAL TISSUE IS MADE OF: Neurons, the
champion cells of nervous tissue are bio-electric units. Firing electrical pulses is their job.
These pulses travel down lengthy projections called axons, i.e., micro insulated
conductors that emerge from neuronal cell bodies and conduct such pulses all along
themselves down to the many axon synaptic endings. Once these pulses reach synaptic
endings, they cause neurotransmitters to be delivered onto the post-synaptic membrane, i.e.,
dendrites located on their sub-connecting neurons. The neurotransmitters so delivered
can thereby excite or inhibit the subserving neurons, thus conforming often complex
electricity-driven neural networks.
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(http://neurorepair.files.wordpress.com/2014/05/neurons-70.gif)
Yes, you are quite right ! Neural networks are electric networks like those that operate in
computers! You may then imagine what it may be like to repair a brain circuit that somehow
has suffered a physical fracture, certainly not an easy task to accomplish!
SPINAL CORD INJURIES: AN IMPORTANT WORLDWIDE PUBLIC HEALTH PROBLEM:
(http://neurorepair.files.wordpress.com/2014/05/neurorepair.jpeg)Among
CNS injuries those caused by ischaemia and trauma are the most
common, including spinal-cord sectioning or injury frequently resulting
from auto and sports accidents. Worldwide, tens of thousands of spinal-
cord injury episodes occur per year and ten times as many living
survivors suffer sequelae from such lesions. The severity of symptoms
depends on the spine-level and extent of the lesion, but often results in
paralysis and anesthesia of the lower (and /or upper) limbs, and also bladder, bowel, sex,
skin and circulatory disfunction.
BIO-REPAIRING NEURAL TISSUE Based on experimental animal research and successful
clinical experiences of tissue reconstructions, particularly involving bones, cartilage and
ligaments, scientists have unraveled the key components whose presence is required for any
tissue-repair to take place: a) regenerative cells, b ) extracellular modulators of process, c )
supporting scaffolding, d) adequate genomic orchestration. Regenerative cells are essential
both for natural tissue repair and for the corresponding technology-based process, where
such cells are artificially provided. Regenerative cells have the capacity to multiply and
further specialize during the process of tissue reconstruction.
(http://neurorepair.files.wordpress.com/2014/05/scaffold.jpg)
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Reparative cells tend to attach and line on natural or artificially provided
foamyscaffolding materials, guided by chemical messages originating in the injury-
milieu, among them various specific trophic or growth factors. Transduction of such
messages to the cell interior involve the operation of complex intracellular signalling
systems often involving localized changes in concentrations of smaller messenger
molecules (like calcium ions or cyclic nucleotides), all finally leading to specific protein
manufacture, Golgi-processing, and scavenging functions, in a coordinated process
involving entire cellular machineries.
NEURAL TISSUE RECOSNTRUCTION:
With these concepts in mind, neuroscientists are actively testing novel
procedures to repair nerve tissue injuries traditionally considered irreversible,
including brain-stroke or trauma lesions such as spinal sectioning. Such
research target various aspects of the reconstruction process including novel
scaffolding materials, trophic-cocktail composition, sources of reparative cells,
etc. Hours after an injury occurs in the CNS a fibrous scar begins to cordon-
off the damaged tissue as part of a natural tissue-susbstitution repairprocess conducted
by neuroglia. The scar-mesh becomes stiffer with time due to progressive chemical cross-
linking. This inhibits neurite (axon &/or dendrite) growth of surviving -contact seeking-
neurons, and poses obstacles to the development of surrogate neural networks. Overcoming
these hurdles requires a combination of technological strategies involving several factors
participating in tissue repair.
CHONDROITINASE ABC: A novel research approach found to help spinal-cord repair
consists in the local in situ- application the enzyme chondroitinase-ABC (chABC) for the
treatment of spinal-cord injury. chABC is believed to act by degrading extracellular-
chondroitin sulfate proteoglycans (CSPGs) present both in the glial scar after injury and
also as a part of the extracellular matrix called the Peri Neuronal Net (PNN). CSPGs are
powerful inhibitors of regenerative processes potentially arising at the lesion site as a result
of natural or artificially induced therapies.
(http://neurorepair.files.wordpress.com/2014/05/spinal-lesion.gif)
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Such research is being carried out by a multinational group partly coordinated by Professor
James Fawcett from the University of Cambridge, UK. In 2011 researchers from this group
reported an experimental study http://is.gd/8XZAQv (http://is.gd/8XZAQv) which included
daily monitoring of sequelae of spinal cord lesions, such as abnormalities in gait-pattern,
heat-sensitivity, neuromotor-conductivity and chord-tissue content of scar-material (CSPGs).
In the presence of appropriate co-adjuvants (including neurotrophin -NTx- and scaffolding),
locally applied Chondroitinase ABC (chABC) partially prevented injury effects in all
monitored targets. Such research seems to enlighten new venues for future clinical studies
on tissue repair in the CNS aiming at enzymically disentangling extracellular matrix to
facilitate functional neurite growth after injury. Furthermore, more effective ways to deliver
chABC at the site of lesion have been designed by applying chABC genes delivered using
viral vectors. The full potential of this kind of gene-therapy is still being experimentally
tested http://is.gd/peyZKy (http://is.gd/peyZKy) .
(http://neurorepair.files.wordpress.com/2014/05/20131122_133242b.jpg) At the same time
novel research paradigms amenable to chABC therapy are being tested by researchers at the
Cambridge Centre for Brain Repair. The centre occupies a significant part of the ED
Adrian Building, on Robinson Way, Cambridge, In order to learn recent details of the
development of spinal-cord research currently developed at the CCBR we decided to
approach Dr. Jessica C.F. Kwok, Ph.D. a young leading researcher working in this group.
Says Dr. Kwok:. We are looking into possibilities to overcome problems coming together
with the enzymatic nature of chondroitinase ABC, such as the stability and maintenance of
enzyme activity. We hope gene-therapy to deliver synthetic chABC-genes into the lesion site
will provide a more versatile and stable, and yet a less invasive treatment to the spinal cord
injury.
We further question Dr. Kwok:
One can imagine that high-tech research -like you are undertaking- requires not just good
hypothesis and the ability co carry out meticulous experiments, would you like to talk about
what else is needed?
Repairing the central nervous system is an extremely difficult task and international
cooperation is crucially important. Currently, there are only a few funding programmes
which bridge different continents together. In addition, there is a lack public awareness
on the disease condition. To facilitate the advancement of fundamental research which
will ultimately benefit spinal cord injured patients, efforts should start from the bottom.
Communication between scientists and the public should be encouraged, and various
governments, funding sources and charities should consider allocating more fundings
into the area. We know that the task lying in front of us is challenging, however, we
believe every small steps will contribute significantly to the benefit of the patients at the
end.

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How far into their year-spanning life cycle have you been able to monitor behavioural
benefits of ChondroitinaseABC mediated spinal-chord repair therapies in rats? Have such
therapeutic effects lasted?
The behavioral benefits from to the spinal cord repair are long lasting. The behavioral
benefits are usually resulted from a re-connection of the severed network and once these
connections are re-established, the benefits observed will last long. , replies Jessica.
Does enzymatic disassemby of PNNs per se lead to converting lesion-surviving neurons
into progenitor-stage cells, thereby making exogenous progenitor-cell injections
unnecessary?
No, the removal of PNNs per se does not convert spared neurons into progenitor-stage
cells. The disassembly of PNNs opens up opportunity for the surviving neurons to make
novel connections to either take up/replace the jobs which are performed by the lost
neurons. You may consider it as a biological detour, using an alternative path to achieve
the same function(s).
Given the multiplicity of physico-chemical factors non-synchronously involved in
neurorepair, how much need is there for multivariate (perhaps robotics assisted) testing in
order to speed-up success? How feasible does that look now?
My quick answer will be: there is a need for robust, high-throughput screening (such as the
robotic systems) to speed up the screening process; on the other hand, a tedious but yet
thorough mechanistic understanding of individual identified molecules are also important
to finalize the understanding and increase the depth of the basic physiological knowledge.
Are research groups focusing on combined (neurotrophins etc) chondroitinase-ABC
therapies in other CNS-repair paradigms such as in monocular deprivation or embryo-
culture experiments?
This question is hard to answer. It is very much paradigm based. For challenging
conditions such as repairing a injured spinal cord, we probably need a combination of
various strategies to maximise the functional outcome, while in less challenging condition,
chondroitinase application alone may be sufficient.
How soon would you envisage a confluence between bio-wired and wireless research
approaches to spinal cord repair?
As a prototype, it may happen within the next 5 years. However, our understanding on
the neural coding is not enough to make it run as a smooth fully functional system, so a
longer time period will be expected.
Does current spinal-cord repair research at Cambridge include bioelectrical kinds of
stimulationas possibly synergistically coactive players in CNS repair experiments?
Yes, we are also currently working on refining electrical implants in controlling bladder
functions (and possibly other systems) after spinal cord injury. Here is some info:
http://www.ncbi.nlm.nih.gov/pubmed/24197736 (http://www.ncbi.nlm.nih.gov/pubmed/24197736)
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http://www.ncbi.nlm.nih.gov/pubmed/22569953 (http://www.ncbi.nlm.nih.gov/pubmed/22569953)
Besides spinal-cord repair you have also reported studies on embryonic hindbrain to reveal
the role of chondroitin sulphate (CS) in axonal initiation and projection http://is.gd/jcyfxu
(http://is.gd/jcyfxu)What type of neurorepair-relevant questions would be expected to be
answered by such type of experiments that could not be answered by postnatal
experimentation?
The study orientation is very different between embryonic and postnatal experiments.
A study in an embryonic nervous system allows us to understand and manipulate the
nerve growth at the time when the growth is initiated and pathfinding is actively taking
place. In postnatal brain, most of the basic circuitry has already been laid down and
connected although refinement is still taken place, the initiation of growth and factors
affecting long distance path-finding is finished. So, embryonic study will give an
advantage for studies involve in the above mentioned events.
RELEVANT PUBMED REFERENCES: http://is.gd/ESFhCB (http://is.gd/ESFhCB)

cambrige, chondroitinase, gene-therapy, injury, Kwok, neurorepair, spinal-cord, spinal-

injury, spinal-repair, tissue-repair

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