I'm tired of hearing about testing on rats, test that s___ on me. The faster
they test on humans the quicker the cure. Being like this sucks."
--Austin, on the cureparalysis.com bulletin board
"I want a cure! Plain and simple. ... Hey! I am sick of reading about
rodents. Scientists who have a serious method will try it on primates, until
that they are all preliminary and full of bulls___. So, who has experiments
with primates? F___ing no one! That's who."
--Ken, on the same board
It's little wonder that some of the natives are agitated. They've been on the
Internet and they've heard that a cure is coming any day now, and like,
they're not cured yet.
True enough, a week doesn't go by without a news report about some experiment
somewhere--usually involving paralyzed rats getting better--that might
someday help people with spinal cord injuries.
The big neuroscience sizzle last year was about stem cells. Research suggests
that they can become any kind of cell we want.
More than ever, expectation verges on entitlement. There's extra exposure to
spinal cord injury research news because of the Reeve Effect [see sidebar].
Plus, there's the fermentation of cure chatter online. The Internet offers
reliable news and plenty of data abstraction, but it's also a pit of
misinformation, rumor and full-faith conclusion-jumping.
Closer to the ground, below the storm and fury, real scientific progress
justifies rising hopes for restoring function. It is important to keep in
mind that most spinal cord injury experiments involve newly injured animals.
The chronic human injury is a much tougher problem.
Even if you're loathe to hear about regenerating Reeve and trying to ignore
the whole "maybe someday" cure concept (bless her heart if your Aunt Polly
doesn't keep those clippings coming) there's momentum in spinal cord injury
research. Someday, at least we can say, is getting closer.
As we've done in past cure updates, we'll break coverage into three general
categories:
Rejuvenation of existing, connected but not functional nerve fibers (axons).
Replacement of nerve cells to do the job of damaged ones.
Regeneration of axons that have been broken and lost connection.
Rejuvenation
A weak but unbroken neuron can't conduct nerve signals properly, usually
because it has lost its myelin--the fatty coating that acts as a sort of
insulation around nerve fibers, or axons. Two general strategies have been
considered for restoring demyelinated nerves. One is to adjust the
neurochemistry of the system to compensate for poor conduction. This is the
basis of the compound 4-AP, a potassium channel blocking agent that in effect
gooses up impulse conduction.
4-AP and fampridine
"It's like in baseball--you don't walk up to bat your first time and try to
hit a home run. If you can get on base, you can set the stage for something
bigger later."
--Douglas Kondziolka
This compound, as we have noted before, is not a drug per se; you can get it
by prescription at certain pharmacies that batch it up. Thousands of people
with spinal cord injury and multiple sclerosis (the classic demyelinating
disease) are getting 4-AP this way, and it's perfectly legal. For now. An FDA
panel is set to review a list of compounded drugs, and don't be surprised if
this one is pulled. One of the main issues with compounded 4-AP is that it's
a full-blast concentration, which forces the user to determine dosage by
trial and error. The other problem is that 4-AP has a limited shelf life.
After a couple of weeks it's not nearly as strong as when you first got it.
So, people double up dosage. This is not good stuff to fool around with.
Seizures are not uncommon as a result of overdose.
A much more sophisticated, time-release version of 4-AP (known generically as
fampridine) from Acorda Therapeutics is grinding its way through the FDA
approval system. Acorda completed FDA Phase II clinical trials for fampridine
in 1998 but has not yet been green-lighted to move on to critical Phase III
trials. The people at Acorda are certain their formulation will eventually
get the nod, but a major problem from the FDA perspective is that effects of
4-AP are impossible to predict. First, 4-AP seems to work only in a third of
people with SCI--you don't know which ones until you try it--and only then
can you see what the effect is. It seems to work better in people with
incomplete injuries, some of whom get dramatic improvement in strength and
sensation, reduced fatigue, better bladder function and, in some cases,
reduced pain and spasticity and better sexual function.
Making myelin
The other strategy for treating demyelination is to replace or restore myelin
so nerve conduction can occur normally. (In this case, 4-AP could be used to
screen candidates--if you don't respond to 4-AP, you won't benefit from
remyelination therapies.)
Myelin in the central nervous system does not readily rebuild itself. It must
be seeded and cultured. There are several ways this might happen. Myelin
appears to respond to certain growth factors added to the system. Glial
growth factor 2, for example, promotes growth of support cells called
oligodendrocytes, which in turn, at least in mice, lead to remyelination.
It is possible to transplant myelin-forming cells into the nervous system.
This is experimental but getting closer to the clinic: Doctors at Yale are
ready to transplant Schwann cells into five humans with severe symptoms of
multiple sclerosis. Schwann cells are the source of myelin in the peripheral
nervous system but are not very active in the central system. The transplants
will be autologous, that is, the Schwann cells will be harvested from the
patient's own peripheral nervous system. The necessary preclinical safety
studies of Schwann cell transplantation have begun in artificially
demyelinated primates.
In other experiments, myelin-forming transplants have been enhanced using
genetically modified Schwann cells that excrete growth factors. Mark
Tuszynski at the University of California, San Diego, modified adult rat
Schwann cells to produce and secrete high levels of human nerve growth factor
(NGF). After being injected into adult rat spinal cords, the cells grew and
NGF was plentiful.
A Miami Project team blended Schwann cell transplants with acidic fibroblast
growth factor, a fibrin glue compound, and Swiss scientist Martin Schwab's
IN-1 antibody, which blocks a major growth inhibitor. Some regeneration
occurred in the rat model.
Ian Duncan of the University of Wisconsin School of Veterinary Medicine
injected myelin-producing fetal glial cells into the spinal cords of dogs
born with a genetic mutation that produced lesions similar to those caused by
multiple sclerosis. Duncan reported significant myelin growth on target
nerves for as long as 27 weeks.
Other transplantation strategies involve stem cells (see below) and olfactory
ensheathing cells (OECs). In rats, this again at Yale, transplanted OECs,
which have the properties of both astrocytes and Schwann cells, promoted
extensive and functional remyelination of dorsal column axons.
Another pathway to remyelination is to find the switch to turn on the body's
own oligodendrocytes to make new myelin. Mayo Clinic researchers and others
are working on immunoglobulin antibodies that enhance myelin growth. A small
human clinical trial has encouraged the effort.
The Mayo team, led by Moses Rodriguez, M.D., recently found a set of genes
related to nerve damage in multiple sclerosis. Says Rodriguez, "These genes
somehow 'tell' killer T-cells, which are a type of immune cell involved in
MS, to secrete factors that accidentally destroy nerve fibers while
attempting to fight the disease." Next step: Find out how to turn the genes
off. The ultimate remyelination strategy may be to modulate the immune system
to disable (so to speak) the self-destructive process that wiped out the
myelin to start with.
Replacement
The working theory of replacement is that function lost because of cell loss
might be restored with the addition of new cells derived from fetal tissue,
from one's own body, from outside cell lines, from stem cells or even from
other species. Human trials began two years ago in Sweden and Gainesville,
Fla., implanting fetal tissue into the spinal cavities of people with
syringomyelia, a cyst at the lesion site of many cord injuries. The good news
is that the cysts filled and the symptoms of syringomyelia (pain, loss of
sensation and muscle function) were treated. Moreover, the Florida group
reported that the transplants appear to have increased sensory and motor
function in the first two patients.
Fetal tissue has promise but it has ethical baggage that will limit its use
outside of laboratories.
Stem cells
The big neuroscience sizzle last year was about stem cells. These are "mother
cells," abundant in the embryonic stage, that have yet to take on a specific
identity. Research suggests that they can become any kind of cell we want.
What has raised the excitement level is the cloning of stem cells in mature
animals. Because stem cells can come from one's own body, the benefits are
tremendous: the ethical issues of fetal tissue go away, and the immune
rejection of outside cells becomes a non-issue.
Evan Y. Snyder, M.D., at Children's Hospital in Boston, injected living human
neural stem cells into mice. The new neurons became fully integrated into
their brains. He doesn't know yet if the cells are functional but he's ready
to explore using the human cells in animal models of human diseases,
including spinal cord injury and brain injury.
Can cells from one's own body be used to heal it? Italian scientist Angelo
Vescovi of the National Neurological Institute in Milan reported in February
that mouse neural stem cells have the ability to transform into bone marrow
stem cells that make blood. This finding is a surprise, since brain and blood
come from different germ layers created in the early embryo. Cells are not
locked to a particular fate. Vescovi describes a new branch of medicine
evolving from stem cell biology. "The resource to heal a sick body lies in
the body itself," he says.
Vescovi is ready to put stem cells to work. Along with a University of
Calgary technology (commercialized as Neurospheres, Inc.) and with funding,
in part, from the U.S.-based Spinal Cord Society, he has established
"continuous non-transformed cell lines from the human spinal cord, cortex and
diencephalon that would provide a renewable source of neural cells to be
differentiated into transplantable neurons and glia." Vescovi plans animal
studies and promises to consider the human chronic SCI model soon.
In similar research, a "neurofunctional" surgical team at Cedars-Sinai
Hospital in Los Angeles announced last October their intention to start a
"treatment protocol" to reverse nerve and brain damage caused by stroke,
Parkinson's disease, epilepsy and spinal cord injury. The protocol would
harvest stem cells from the brains of patients, cultivate them and insert
them in areas of damage. The announcement was accompanied by a timeline--six
months to the SCI human trials--which would be right about now. The hospital
has retreated on the timetable but not on the concept. Parkinson's disease
patients will be first to get stem cell therapy. If that works, the spinal
cord injury protocol can evolve.
Meanwhile, human stem cell trials have begun in a stroke model. Douglas
Kondziolka, a neurosurgeon at the University of Pittsburgh, recently treated
memory and speech problems in a small number of people who had strokes by
injecting human neurons directly into the damaged parts of their brains.
Kondziolka used neurons produced from a testicular cancer tumor, which
derives from the stem cells that become sperm. The tumor cell can become many
kinds of tissue--including brain or spinal cord cells.
Of the seven patients who have been treated, all have been able to leave the
hospital within 24 hours and three have noticed small improvements in motor
skills, says Kondziolka. The patient who received the first transplant--a
62-year-old woman with stroke--has felt well over the first seven months and
has had slight improvements in speech, according to Kondziolka. He says the
primary goal of this trial is to determine whether the therapy is safely
tolerated by patients.
"If this first study is safe," says Kondziolka, "we hope to move on to a
second study that will address patients with more diverse problems, using
more cells and putting them in different areas." But, he adds, "It's
difficult to say whether the functional gains some patients have described
are due to what we've done or something else."
Kondziolka says the early stem cell work is really a setup: "It's like in
baseball--you don't walk up to bat your first time and try to hit a home run.
If you can get on base, you can set the stage for something bigger later."
To restore major sensation and motor control after injury, the long axons in
the white matter of the spinal cord have to grow again and connect over long
distances to precise targets. If you've been reading neuroscience during the
last 90 years, you know that these central nervous system axons try to
regenerate but don't succeed unless the path is cleared of poisons, enriched
with growth vitamins and paved with an attractive roadbed. Regeneration
researchers have identified numerous inhibitory factors, growth factors and
scaffoldings. They can grow spinal nerves long distances. They think they can
hook them to the right connection and they think that as few as five percent
successful connections will add significant function. They have ideas about
how to turn on regeneration in a human model.
Someday.
Schwann cells
The story of Martin Schwab's antibody illustrates why someday isn't today.
Eleven years ago Schwab identified a substance in spinal cord myelin that
stopped axons dead in their tracks. But he also found a way, using the
antibody, to neutralize the inhibition. After a few years he showed
remarkable recovery of function in animals that got IN-1 or later, IN-1 and
NT-3. The headlines at the time were triumphant. This was perhaps the major
spinal cord injury cure story of the decade.
Where has the research gone? For several more years Schwab and his group have
tried to "humanize" the antibody, which derived from mouse proteins. The
human immune system would attack the nonhuman antibody, and even with immune
suppression, the protein might not act the same in people as in rodents.
After millions invested, there is still no stable form of the human antibody
for clinical trials. Recently, Schwab's group found the molecule that IN-1
binds to in cow brains. Working backward, they are now looking for that
molecule in human brain tissue. When they find it, they will create a new set
of antibodies from humans.
Leukemia inhibitory factor
The latest growth factor to show potential is leukemia inhibitory factor
(LIF). Tuszynski delivered LIF to the spinal cord using gene therapy. This
promoted the growth of corticospinal tract axons, useful for motor function.
Lab animals appear to improve function over time, indicating that new growth
of motor axons continues.
Tuszynski says that in addition to augmenting axon growth, LIF increases
production of neurotrophin-3 (NT-3), which also stimulates the growth of
corticospinal axons.
LIF may also help reduce other cell damage after injury. There is evidence
that LIF either activates neural support cells called astroglia and
oligodendrocytes to produce other nerve growth factors, or removes cellular
debris and myelin degradation products from the injury site. LIF may reduce
secondary degeneration and apoptotic (programmed) cell death, too.
Neurophilins
Another group of growth factors getting a lot of attention is the
neurophilins. These are small molecules that, unlike other nerve growth
factors, penetrate the blood-brain barrier. This means they can be taken
orally. Vertex Pharmaceuticals, a Boston biotech company, announced in late
1997 that a neurophilin compound could enhance functional recovery through
neuronal regeneration in animal models of peripheral nerve injury,
Parkinson's disease and spinal cord injury. A clinical trial is set to begin
testing the compound on diabetes. Another biotech company, Baltimore-based
Guilford Pharmaceuticals, partnering with giant Amgen, has its eyes on the
same market with a neurophilin product of its own.
There's a lot of excitement about neurophilins, much of it coming from the
investor relations offices of the two publicly traded companies. For now, no
one knows if the drugs work in people.
Immune privilege
Until recently regeneration science has ignored the role of the immune system
after injury. Michal Schwartz, of Israel's Weizmann Institute, has discovered
a way to activate a person's immune cells as a therapy for neurological
conditions, including spinal cord injury. Schwartz explains that most immune
cells, including macrophages and T-cells, are excluded from the central
nervous system because of a physiological property called immune
privilege--macrophage and T-cell activity is inhibited because it can
endanger neurons. However, immune privilege also limits the ability of
central nervous system cells to protect themselves from disease and injury.
Schwartz and her company, Proneuron Biotechnologies, believe that activated
T-cells might selectively neutralize immune privilege and thereby boost the
body's natural defense mechanisms. In January Schwartz reported that
activated immune cell therapies promoted regrowth of severed nerve fibers,
and protected nerve cells from secondary damage triggered by an initial
injury. Last summer Proneuron's implanted macrophages restored movement in
paralyzed rats. Macrophages were stimulated outside the body by exposure to
segments of regenerating peripheral nerves and then implanted in the severed
spinal cords of 22 rats. Seventy percent of treated animals--15 of 22--showed
significant recovery of motor and behavioral activity, including vigorous
voluntary movement in the hind limbs equivalent to approximately 40 percent
of normal voluntary movement. No control animals showed any recovery.
Says Schwartz, "In this study, the improved motor activity was strongly
linked to regrowth of severed nerves. I believe that implanted macrophages
have the ability to induce and accelerate powerful healing processes inside
the central nervous system. This research offers new hope to victims of
spinal cord injury."
According to a Proneuron press release pulled from the Internet, the company
expects to initiate human clinical trials of autologous macrophage therapy to
treat spinal cord injury this summer in Israel. They will be conducted under
an Investigational New Drug application filed with the U.S. Food and Drug
Administration.
And so?
So, when the day is done, the cure scientists and their rats move closer to
the time when they'll have to put their theories and their hunches, their
surgeries and their drugs, to the real test: Will they work on any or all of
the people desperately waiting for the big fix? Right now, most of them
almost certainly won't.
To make sense of the agonizingly slow progress, try to appreciate the
incredible complexity of the spinal cord. This is not an easy problem.
Understand that headlines in the newspaper don't relate in any significant
way to what your doctor is ready to do for you. Understand also that when
therapies become available, they won't instantly transform you to pre-injury
status. Remember that, as veteran researcher Wise Young puts it, "science is
a process, not an event."
New Mobility founder Sam Maddox is now editor-in-chief of www.spinewire.com,
a new Internet community for people with spinal cord injuries and related
disabilities.
Wonder Concoction?
Can you believe everything you read on the Internet? Sure you can, just like
everything you hear in a pub after midnight is gospel.
Over the past six months or so, claims have been made for a seemingly
miraculous treatment for people with transverse myelytis, spinal cord injury,
Parkinson's disease, chronic pain and multiple sclerosis. Neuralyn, invented
by Frank Vigil, a naturopathic physician in Boise, is said to restore
function even in patients with decades of disability. A handful of
testimonials in favor of the stuff have appeared on Web boards. There's
plenty of online skepticism, too, but so far no one has reported any harm
from or complaints about neuralyn.
Neuralyn is a clear, pinkish liquid made of vitamins, botanic extracts, amino
acids and other natural ingredients. It is applied via hypodermic needle just
under the skin around the affected area. Patients get twice-a-day treatment
during three two-week periods. The cost is $10,000 for the whole regimen
including annual follow-ups.
Vigil told New Mobility he doesn't know what neuralyn does, but suggested it
helps remyelinate nerves and provides a hospitable environment for nerve
regeneration. He says he'd do the research to prove this but it's too costly.
Vigil claims about 100 people with spinal cord injuries have been treated (in
his affiliate clinics in Idaho, Utah and California) and only two cases "did
not respond." Some wheelchair users go to walkers. Some just get back some
sensation. Six in 10 notice bowel and bladder improvement, the clinic says.
No side effects, other than surprise benefits such as improved eyesight, have
been reported. "We've seen delightful clinical results," says Vigil.
Check out neuralyn.com for the party line, and the "experimental" board at
cureparalysis.org for the debate.
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Cure Web Sites
www.cureparalysis.org maintains five active bulletin boards where you can read most of the news reports on SCI cure and lots of commentary. The boards are sponsored by the American Paralysis Association, one of the major funding sources for cure research, apa-cure.com
New to the Web, www.spinewire.com offers well-distilled news and comment about cure and other disability lifestyles, updated frequently.
Other places to surf for cure news: www.miamiproject.miami.edu (home of the Miami Project to Cure Paralysis);
www.paralysisproject.org (home of the West Coast based Paralysis Project); members.aol.com/scsweb/private/scshome.htm, (Spinal Cord Society).
If you want to check the science literature yourself, try www.nlm.nih.gov/medlineplus to access the National Library of Medicine archives.
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The Reeve Effect
It's coming on four years now since actor Christopher Reeve broke his neck and became the human face of disability for the world, the not-so-reluctant poster boy for restoring paralyzed people to their full, upright positions.
The Reeve Effect has been profound. News managers love to cover his health and lifestyle, his book, his movies, his speeches and his progress toward his goal of walking by the time he's 50. Reeve will start an instant argument in just about any group of people who use wheelchairs. There are those who appreciate his steadfast attention to cure, others who think he ought to be more focused on social justice and care issues. They say he's good for all disabled people, that he's set the community back a couple of decades, etc., etc.
What's clear, though, is that Reeve is one heck of a fundraiser. Give him credit for raising the National Institutes of Health's budget for spinal cord research by about $40 million a year. Spinal cord injury is now considered one of the top three priorities at the National Institute of Neurological Disorders and Stroke, the agency that funds the bulk of spinal cord injury research in the U.S.
The Christopher Reeve Foundation and the American Paralysis Association, which is chaired by Reeve, bring in a few million more in private funds for research. APA says its annual revenues have more than doubled since Reeve's injury.