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CSRO
MAGAZINE BACK ISSUES
This past year has been a very positive one for CSRO. Our research
in the areas of gene therapy and enteric neurotransplantation are
progressing well as presented in this issue.
Clinical studies are continuing with 4-AP. Acorda Therapeutics is
the Biotechnology Company that has been licensed to perform these
clinical trials and bring 4-AP to market. They have supplied an article
in this issue to update everyone on their progress.We are in the
process of funding several new projects this year. We will be reporting
these research initiatives to you as they come online throughout
1999.
The Internet has become an exciting and most useful source of research
for current and historic endeavors in the field of spinal cord injuries.
Check our web site frequently for updated information. Your feedback
is appreciated at csro@globalserve.net.
You now have the opportunity to participate in our Affinity Program.
This Affinity Program is an excellent way for you to assist CSRO
to raise much-needed funds for Research and it is easy to do! CSRO
has made agreements with Speedy Muffler King (Nationwide), Therapy
Supplies and Sunrise Medical Ltd. (Ontario only). When you need your
muffler replaced or brakes repaired, go to Speedy. Tell the Service
Manager to refer to Affinity #103. When he enters your bill into
the computer, he will also enter #103. CSRO then receives a percentage
of your payment from Speedy Muffler King. Additionally, when you
are purchasing supplies or a wheelchair from Therapy Supplies or
Sunrise Medical, show them your membership card and they will contribute
a portion of the sale to CSRO.
I take this opportunity, on behalf of the Board of Directors of the
Canadian Spinal Research Organization, to express our sincere appreciation
to all of you for contributing both financially and through volunteering
at our administrative offices and events. Our Chapters throughout
the country continue to dedicate themselves to CSRO. I am very thankful
to each of them for their ongoing commitment.We are very proud of
our progress and this is due to your continuing support and interest
in CSRO. Let’s keep the great work going forward.
Sincerely,
Ray Wickson
President, CSRO
rwickson@csro.com
Dr.Michel
P. Rathbone
Enteric Neuron and Glia Transplantation into Spinal
Cord |
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Fact can be stranger than fiction - fish skin and intestines may
each help in spinal cord injuries. Your mother likely told you that
eating fish was good for your brains - now a group of researchers
at McMaster University funded by the CSRO are finding that it may
be good for injured spinal cords, too. The substances which make
fish skin shiny are called purines (pronounced “pwe-er-eens”).
These purines help in fish development and in spawning. Purines are
also found inside all cells as building blocks of DNA and RNA, the
genetic material. As well, purines are the energy currency of cells.
But purines have very important roles outside cells, too. There are
also chemical messengers, purines released by one cell move in the
fluid outside cells taking information to other nearby cells. So,
for example, purines are one of the chemicals which transmit messages
from one nerve cell to another.
Substances from fish skin may help protect the spinal cord immediately
after injury: Over the last few years work from several laboratories,
particularly from Dr. Rathbone’s laboratory at McMaster University,
has shown that purines outside cells play important roles in spinal
cord and brain injury. When cells in the nervous system are damaged
they release large quantities of purines. Purines help protect cells
from further damage. As well, purines carry special messages to cells
surrounding the damaged area. This makes them release “trophic” substances
which help repair nerves in the brain and spinal cord.
Unfortunately, in most cases not enough purines are released and
substantial damage results. In research funded by the CSRO, Dr. Rathbone
and his colleagues have tried to increase the purine levels after
spinal cord injury (SCI). They found that when the synthetic purine
4-{[3-(1,6dihydro-6-oxo-9-purin-9-yl)-1-oxypropyl]amino} benzoic
acid, also called leteprinim potassium, is given following SCI, the
effects of the injury are minimized. Currently they are attempting
to find how exactly this substance improves the outcome of SCI. “We
are attempting to boost the naturally occurring protective and repair
processes in the spinal cord, said Dr. Rathbone. “We are using
a modified purine which is even more effective than those found in
fish skin and in the nervous system”.
One of the types of cells which the purines affect are known as glia.
Glia are supporting cells in the nervous system. There are several
types of glia. One type, astrocytes, has many functions. Astrocytes
form the scars in the nervous system after injury. But astrocytes
can also make the protein trophic factors which help the nervous
system to recover after injury. Purines make astrocytes synthesize
and release more trophic factors. Rathbone and his colleagues think
that astrocytes and another type of glia, microglia or scavenger
cells, are important in helping the purines to reduce the effects
of spinal cord injury.
Cells from the intestine may help regeneration of nerves in the damaged
spinal cord. The problem of repairing the injured spinal cord long
after it has been injured is a different problem, but one that nevertheless
also may involve glia. After the spinal cord is injured a very complicated
series of processes occurs involving nerve cells and several types
of glia. The overall result of these is to prevent regrowth of nerve
cell processes across the region of damage. However, recently glia
from the nerves at the back of the nose have been transplanted into
the spinal cord. The glia from the nose then migrate, literally crawling
up and down the spinal cord. In doing so they seem to make paths
for regenerating nerve cell processes to follow, as though they are
towing the nerve processes along. But there are not many glia in
the nose, so the use of this technique in human SCI is potentially
limited.
Rathbone and his colleagues, funded by the CSRO, have taken another
approach. The intestine has a nervous system which makes the gut
move food along it. The intestinal nervous system contains glia which
are similar to astrocytes. Pamela Middlemiss and Shucui Jiang, working
with Dr. Rathbone, isolated and purified the glia cells from the
intestine of rats. They then added a substance to mark them and were
recognizable from the staining. Now these researchers are trying
to determine whether these glia from the gut will release trophic
factors which make the nerve cell processes grow as do the glia from
the nose.
Spinal
Cord Regeneration Research in the laboratory
of
Mark H. Tuszynski, M.D., Ph.D. |
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The Spinal cord shows little natural ability to recover from injury.
However, a number of advances in basic spinal cord injury research
over the last 10 years have begun to suggest that at least some degree
of recovery from injury can be achieved in animals with experimental
spinal cord injuries.
In the laboratory of Dr. Mark Tuszynski at the University of California,
San Diego, researchers have shown that the delivery of growth factors
(called “neurotrophic factors”) to the injured rat spinal
cord can improve regeneration of spinal cord connections. Gene therapy
techniques are used to deliver growth factor to rats with spinal
cord injuries, resulting in the new growth of injured connections
and partial functional recovery. Approximately 40 different types
of nervous system growth factors are known to exist, and each may
influence the growth of different types of injured connections in
the spinal cord.
Research is continuing to discover which factors influence spinal
cord connections, and how gene therapy can be used to deliver these
factors to the injured spinal cord (SCI). Gene therapy offers the
unique potential of taking an individual’s own cells, genetically
modifying them to produce enhanced amounts of growth factors, and
then placing these genetically modified cells into sites of SCI to
enhance recovery. Using this approach, there would be no limitation
on cell availability, and no risk of cell rejection since a person’s
own cells would be placed into their spinal cord.
When combined with recent findings from Switzerland and Sweden that
have also shown partial recovery of function after SCI in animals,
there is heightening optimism that some of these experimental results
may be useful in the future to treat humans with spinal cord injury.
However, testing of these potential treatments in humans will depend
on the continued success of animal research, and more research needs
to be done before clinical trials in humans are begun.
These photographs show the ability of gene therapy with growth factors
to promote axonal growth in the spinal cord. A type of cell called
a fibroblast can be genetically engineered to produce nervous system
growth factors. When these genetically modified cells are placed
into the spinal cord, they attract the growth of very large numbers
of axons (pictures B and D) compared to cells that have not been
genetically modified to produce growth factors (picture A and C).
Thus, gene therapy offers the possibility of enhancing axonal growth
after spinal cord injury. When cells genetically modified to produce
a growth factor called NT-3 were placed into rats with spinal cord
injuries, rats showed an improved ability to walk. (g, graft).
Dr.
Farhad Mosallaie
Understanding early stages of nerve injury |
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Dr. Mosallaie has been continuing on his primary research focus which
is to understand the influence of the anatomical and biophysical
properties of the myelinated axons on their function in both normal
and pathological states. He has primarily been updating an existing
electro diffusion model, which includes spatially distributed ionic
pumps and channels, to better represent the diffusion, electrophoretic
and radial components of ionic flow. This model allows study of the
dynamics of the sodium and potassium ion concentrations in the periaxonal
and intraxonal volumes of myelinated nerve fibre during conduction
of action potentials in normal and diseased states. During the last
few months, he has mainly focused on both the short and long term
effects of activity dependent ionic changes in the myelinated axons
including threshold modification, supernormal period and repetitive
firing. He plans to address electrical stimulation of the nerve fibre
and the role of ion concentration dynamics on the injured axon using
the model.
This model can be used to better understand the early stages of nerve
injury such as transection, resealing process and conduction block
in response to primary injury. Beyond the immediate damage, conduction
properties of neurons due to other consequences of spinal injury
such as demyelination, incomplete remyelination, thin remyelination
can be studied using this model.
You can think of the state of spinal cord research as being similar
to the challenge of putting a man on the moon. From the beginning
of time until 1903, man was incontrovertibly earthbound; within 70
years, Neil Armstrong had walked on the moon’s surface. When
you think about it in those terms, spinal cord research is at Sputnik.
The prognosis for individuals with spinal cod injury (SCI) remained
unchanged from ancient times until fairly recently. Scientific advances
in the 1970’s made it possible to save the lives of many individuals
who had sustained a SCI, but until recently there were no treatments
available that could help improve their condition in the period after
their injury.
In the last decade, however, all that has changed. Dramatic advances
in researchers’ understanding of the mechanisms of SCI have
given scientists the confidence to say what would have been unthinkable
a generation ago - that effective therapies to treat SCI can and
will be found.
Enter Acorda Therapeutics, Inc., in Hawthorne, New York. Ron Cohen,
a physician and principal in the start-up of Advanced Tissue Sciences
in the 1980’s, was by 1992 ready to turn his attention to a
new challenge, and one close to his heart. Neurology had always had
special interest for him - his father is a neurologist, and he had
even considered specializing in neurology in medical school, but
was put off because there were so few treatments available to patients.
(“In those days, it was ‘diagnose and adios’,” says
Cohen.) By 1993, it was apparent that this was changing dramatically
in the area of treatment for SCI. Suddenly new, exciting scientific
breakthroughs were bubbling to the surface on a number of fronts,
and Cohen was surprised to discover that industry had not yet caught
on to the promise these advances held.
Acorda Therapeutics was launched in early 1995 with the help of start-up
money raised from a group of private investors, government grants,
and foundations (including the CSRO). Cohen has assembled a team
of scientists that reads like a Who’s Who of spinal cord research,
including Dr. Wise Young, Director of the Center for Neuroscience
at Rutgers University, and Dr. Andrew Blight, Acorda’s Vice
President of Research and Development, and most recently Professor
and Director of the Neurosurgery Research Laboratory at the university
of North Carolina at Chapel Hill.
Dr. Blight was instrumental in the discovery of the effects of demyelination
on SCI, and was the first to suggest the use of 4-AP (“fampridine” or “4-aminopyridine”)
to counteract the symptoms of demyelination. For a company still
so young, Acorda has made impressive progress in the effort to develop
effective therapies and bring them to market. The company currently
has one product (4-AP) in Phase II clinical trials, two therapies
(M1 and L1) in advanced pre-clinical research, and a fourth, neuronal
stem cells, at an earlier stage of research.
4-AP is a nerve conduction-enhancing compound. It acts to amplify
the signal of electrical impulses as they move through the neuronal
processes, or axons. Contrary to a commonly held belief, people with
SCI do not have severed spinal cords, they have badly bruised spinal
cords. In these instances, there are surviving nerve axons, but the
insulation around the nerves, myelin, is very often damaged or worn
away. The effect is similar to what happens when you cut the insulation
around an electrical cord - the electrical signal short circuits.
4-AP does not re-grow myelin; rather, it makes the electrical signal
loud enough and strong enough so that in many cases it can pass through
the demyelinated areas, allowing patients to regain some level of
function.
Acorda has the exclusive license to develop a high-quality, oral,
sustained-release formulation of 4-AP, which is manufactured by the
Elan Corporation of Athlone, Ireland. Their agreement with Elan allows
Acorda to develop 4-AP for the treatment of both SCI and multiple
sclerosis (MS). This formulation has been tested on approximately
100 people with chronic SCI to date, and the results have been encouraging.
Acorda conducted a Phase II trial of 60 volunteer subjects in 1998.
Apparent benefits of the drug include: increased bowel or bladder
control, increased sexual function, and / or decrease stiffness or
spasticity.
Dr. Cohen and his team know that 4-AP is not the ultimate therapy
for chronic SCI, but see it as an encouraging first step. “No
one is likely to get up and run a marathon after taking 4-AP,” says
Cohen, “but to give people back the promise of regaining something
as fundamental as bowel and bladder control is more important to
many of the patients we see than running a marathon. It restores
a level of autonomy and dignity to their lives that you can’t
overestimate.”
Acorda plans to refine the clinical data it has obtained on 4-AP
through a handful of small, targeted studies in 1999. If the results
continue to be promising, the company hopes to begin a “pivotal” Phase
III clinical study in collaboration with a network of leading hospitals
and rehabilitation centers. Dr. Blight expresses “cautious
optimism” about 4-AP’s prospects. “I believe that
this therapy can bring real improvement in people’s lives,
but there is still a good deal of testing that needs to be done.
We are definitely looking forward to the day when it can be made
available to everyone who can potentially benefit.” Assuming
that things continue to progress well, the company hopes to be able
to apply to the FDA for approval of 4-AP in two to three years.
Acorda’s scientific pipeline does not end there. The company
has two other therapies that are in advanced pre-clinical research. “M1” is
a monoclonal antibody that has been licensed from the Mayo Clinic.
Pre-clinical research indicates that these antibodies can stimulate
the regeneration of the myelin sheath (the insulation around nerve
axons) and restore neurological function.
“L1” is a protein that seems to allow damaged axons in the central
nervous system to re-grow by inhibiting the factors that stop that growth. Pre-clinical
research indicates that this protein may help restore significant function after
SCI. The company is continuing to study the potential therapeutics benefits of
this protein.
Individual who are interested in finding out more about Acorda Therapeutics
and future clinical trials are invited to contact them by email at
acorda@acorda.com
Building
bridges
By William Thorsteinson
Chairman, Ontario Neurotrauma Foundation |
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A momentum has been building in the various fields of neurotrauma
(NT) over the past couple of years. And while its full impact will
not be apparent for some time to come, it signals a new, growing
spirit of cooperation in Canada. On both the national and provincial
levels organizations, stakeholders and consumers are recognizing
the need to work together towards finding effective treatments supported
by measurable outcomes and ultimately that elusive goal of a “cure” for
spinal cord and brain injuries.
Since the Rick Hansen Man in Motion Foundation, now a part of the
Rick Hansen Institute, led the creation of the Canadian Neurotrauma
Initiative two years ago, nine provinces are allocating more than
$37.8 million over five years to neurotrauma research, prevention
and rehabilitation projects. With up to $5 million committed per
year for five years by the Ministry of Health , the Government of
Ontario is making the largest single contribution to this initiative.
As the administering organization for NT funds in Ontario, the Ontario
Neurotrauma Foundation (ONF) is working to fund excellence in research,
prevention and rehabilitation projects across the province. Since
ONF’s establishment in April, 1998 we approved 67 grants worth
$4.6 million over three years, including more than $2 million for
biomedical research.
Our Board of Directors includes experts in prevention, rehabilitation
and biomedical science, persons living with spinal cord injury and
brain injury as well as representative from our founding organizations:
the Canadian Spinal Research Organization, the Canadian Paraplegic
Association of Ontario and the Ontario Brain Injury Association.
It is through exceptional efforts of dedicated advocates from our
founding organizations, such as CSRO President, Ray Wickson and Vice-President,
Barry Munro, that the ONF is able to fund excellence in the NT field
in Ontario.
Together, we are committed to achieving our vision - to have people
with brain and spinal cord injuries participating as full members
of society will achieving reduced impact, incidence and prevalence
of NT injuries.
As we to explore widening strategic alliances and collaboration with
other provincial, national and international organizations, we continue
to recognize meaningful consumer input and participation as one of
our integral core values. In October, 1998 we consulted with consumers
and stakeholders in developing funding objectives and priorities
for Ontario. These priorities emphasize meaningful consumer involvement
and are key criteria in the adjudication of grant applications.
ONF’s Board and Staff is currently focussing on developing
ways to enhance information exchange within and between consumer
and stakeholder communities in the various fields of NT. Biomedical,
Rehabilitation and Prevention Committees are being established to
consolidate and utilize the broad base of expertise that exists in
Ontario to inform future funding priorities.
In December, in collaboration with the Rick Hansen Institute and
with the help of regional health units, the ONF organized workshops
in Ottawa, Kingston and Toronto to provide tips to community-based
organizations to improve the quality of their 1999 project grant
submissions.
We believe that this coordination will result in increased awareness,
cooperation and a balanced approach to reducing and eliminating the
impact and incidence of NT. We are committed to exploring new opportunities
to further this dynamic of cooperation in Canada, and do our part
to help move the NT field forward into the new millennium.
If you would like more information about the Ontario Neurotrauma
Foundation (ONF), please call (416) 422-2228, fax (416) 422-1240
or E-mail: onop@cpaont.org. You can also write to us at 520 Sutherland
Drive, Room 201, Toronto, ON M4G 3V9
William Thorsteinson is Chairman of the Board of Directors of the
Ontario Neurotrauma Foundation and Senior Consultant with Benchmark
Performance, a Toronto consulting and custom design firm he founded
in 1986 which focuses on performance improvement.
4th AnnualCSRO & Great White North DRAGON BOAT challenge
The 7th Annual Spinal Tap Mixed Bonspiel
CSRO ON TRIAL???
Jonathan
Eric Verhoeven
4th Annual CSRO & Great White North
DRAGON BOAT challenge
The CSRO and Great White North Communications Inc. held the 4th Annual
GWN Dragon Boat Challenge at Ontario Place on September 19 and 20.
Twenty-two hundred competitors paddled through out the weekend raising
over $30,000 for spinal research. A special thanks to all the volunteers
and to Great White North for making this event a wonderful experience
for everyone involved. Be sure to get involved and have some fun
in 1999 5th Annual Dragon Boat Challenge.
The 7th Annual Spinal Tap Mixed Bonspiel
The 7th Annual Spinal Tap Mixed Bonspiel was held at Thornhill Country
Club. It was a huge success raising $8,000 in the search for a cure
for paralysis resulting from spinal cord injury. This brings the
7 year total to over $32,000 raised. This year’s winning team
was skipped by Frank Boal from Scarborough Country Club. Second place
went to Rob Lobel from Thornhill Country Club. Twenty-five teams
participated in the 1 day event and a great time was had by all!!
One of the highlights of the day was participation by George Karry,
silver medallist from the Canadian men’s curling team. There
were many lucky draw prizes given away including a round trip in
the Windsor/Quebec City corridor, donated by Via Rail and a Keg Party
donated by the Brick Brewing Company. We would like to thank this
year’s sponsor, Ross M. Durant Insurance Brokers. Their ongoing
support has helped clear the path toward a cure for paralysis. A
big thanks to everyone who participated in the event for their continual
support of the Canadian Spinal Research Organization.
CSRO ON TRIAL???
Thanks to the brilliant efforts of Mark Woitzik, CSRO received over
$5,000 for research from Osgoode Hall Law School. Every year the
students at Osgoode present a Mock Trial, and all the proceeds from
this event benefit a different charity. This year CSRO was chosen.
Mark is not only a volunteer with CSRO, but has a vested interest
in the research CSRO is currently doing, since an accident has left
Mark with a spinal injury. During the Mock Trial the students put
on skits, sang songs and generally had a good time poking fun at
their teachers. Everyone had a wonderful time. Thanks again to Osgoode
Hall Law School.
Jonathan
The race goes on but with people like Jonathan De Haas we will reach
that finish line. Jonathan donated $8000 that he garnered through
racing sponsors and his Mom’s garage sale toward spinal cord
research.
Eric Verhoeven
Many thanks to Eric Verhoeven and his Believe in a Dream fundraiser
held in May of 1998, for raising over $9000 for research. Eric also
raised awareness of spinal cord injury through the event that had
students and staff spend a day in a wheelchair
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