GENERAL RESEARCH
The Myelin Project of Canada
Research News: December 1998 Volume IV
Neural stem cells, the brightest star in the new millennium of brain
repair. Wayne & Julie Simmons
Barely on the eve of its first anniversary the Canadian Glia
Transplantation Unit at the University of British Columbia (UBC), under the
direction of Dr. Seung U. Kim and in extensive collaboration with Dr. Evan
Snyder of Harvard Medical School, has produced a stunning result: the
isolation of immortal human neural stem cells. The critical
research initiative that we had hoped to complete at UBC in two years has
been impressively accomplished in one._ The discovery was heralded on the
front page of The Washington Post: Brain Cell That Multiplies Is Isolated
By Rick Weiss
Washington Post, Saturday
October 31, 1998
"Scientists have isolated a unique type of brain cell that can multiply
indefinitely and develop into all the major kinds of human brain cells.
Researchers said a single batch of the so-called neural stem cells could,
in theory, provide an endless supply of replacement cells that could be
transplanted into people with neurodegenerative diseases such as MS, the
leukodystrophies and spinal cord injury."
What are neural stem cells?
Neural stem cells (NSCs) are self-renewing (can reproduce themselves);
produce a great number of lookalike offspring; develop into all the major
brain cell types and produce new cells in response to injury or disease.
They respond to cues in the brain, making a choice of what kind of brain
cell to become and as a result where to place themselves in the brain.
Researchers have pursued the elusive human NSC for generations. They
believed there existed a renewable source of all cells capable of
repeatedly dividing and developing into three types of neural cells;
astrocytes, oligodendrocytes and neurons. Historically the rodent NSC had
been our only point of reference. Researchers had failed to prove the
existence of its human counterpart. Until now!
Research News: December 1998 Volume IV
Drs. Snyder and Kim have at this time blazed a trail in NSC research with
their cutting-edge breakthrough; the creation of an immortal human neural
stem cell line. The promise of this accomplishment, a key component for the
repair of damage in those with MS, the leukodystrophies and spinal cord
injury, is immense. We are contemplating the future of a new star full of
brilliant promise in the universe of brain sciences. We are ecstatic!
What is the significance of this discovery?
Fascination with the neural development process and the allure of
developing effective therapies for neurological diseases has stimulated
interest in NSC research. Generally injuries to the brain and spinal cord
can not repair themselves. Work already done to transplant nerve cells in
patients with neurodegenerative diseases has shown limited success, because
the cells used were from an embryonic source and difficult to secure. Now,
the human neural stem cell, " matriarch of all cells " has finally been
found. With Drs. Kim & Snyder's collaboration resulting in the
unprecedented isolation of the engraftable human NSC comes the potential
to use cell replacement to repair the human central nervous system (CNS),
changing
the blueprint of medical therapy as we understand it today. Drs. Snyder
and Kim are able to show in vitro and in vivo that the newly created human
NSCs are able to perform all the critical functions of their rodent
counterparts. Clones of human NSCs can be effectively and safely
reproduced. These clones behave identically, differentiate into neurons and
glial cells, with each clone containing new immature cells that can be
manipulated again. An immortal lineage is created which
allows a new population of clonally related cells to emerge securing the
self-renewal process. We now have a human cell factory that essentially
eliminates the need for human fetal tissue. Drs. Snyder and Kim have patent
pending on this new cell line.
Drs Kim, Snyder and their colleagues at UBC and Harvard are conducting
research that will enable the self-renewing cells to prevent ongoing
degeneration and replace dysfunctional neurons and glial cells by
delivering cell and gene products to damaged areas of the brain. Batches of
NSCs showing extensive remyelinating capabilities are expanding,
self-renewing, frozen and stored at both laboratories. These cells have
vast therapeutic potential and are capable of 'making a decision' to mature
into the correct cell required to repair damage in many neurological
conditions.
Human Trials
Now that we have a choice of viable transplant material, Dr. Kim and his
colleagues at UBC have initiated a process for human trial approval. There
appears to be an appreciable body of objective evidence to justify a trial
to transplant human cells into humans to demonstrate their capacity for
safety, survival and repair.
Research News: December 1998 Volume IV
Sufficient progress has been made for Dr. Lorne Kastrukoff, Associate
Professor of Neurology at UBC in consultation with his colleagues Drs.
Barry Woodhurst, Donald Paty and Wayne Moore to write a protocol for a
Phase 1 trial to transplant human cells in patients with MS. The proposed
trial requisitioned by Dr. Kim will include 6 clinically volunteer patients
will be drawn from the MS clinic at UBC which was established in 1980 and
follows over 4000 patients. These patients are
all clinically well documented and have undergone laboratory investigations
including serial MRIs. The volunteers will be given therapeutic levels of
interferon beta as part of the protocol. They will experience two separate
procedures. The
first cellular transplantation of human oligodendrocytes or human Schwann
cells will be deposited in two places in the patient's brain through a
single burr hole. A subsequent identical procedure will occur 6 months
later. Risks will be minimised by restricting the procedures to the non
dominant hemisphere of the brain. However, uncertainty always exists
surrounding any anaesthetic or surgical procedure and the consequent
potential for haemorrhage. Safety will be the fundamental component of the
Phase 1 study that will answer a number of questions comparing the
potential remyelinating value of oligodendrocyte and Schwann cells in
demyelinated areas of the brain. (Pending the outcome of Dr. Kim's
characterisation of his immortal human neural stem cell line, there will
feasibly be yet another leading
contender for transplantation). Outcome measures will include serial MRIs
prior to biopsy at the 3, 6 and 12 month junctures. Drs. Paty and David Li
will use MRI spectroscopy. As well, there will be clinical
electrophysiology and neuropsychological evaluations completed. The
protocol for the Phase 1 trial will be submitted for approval
to the Clinical Screening Committee For Research Involving Human Subjects.
Dr. Kim has all three human cell types in The Myelin Project of Canada
Glia Transplantation Unit at UBC.
Human oligodendrocytes, human Schwann cells and an immortal human neural
stem cell line. Human
trials are now attainable. Kyushu Adrenoleukodystrophy (ALD) Research Unit
As planned, the extraordinary collaborative thrust between Japan and
Canada strengthened as Dr. Takeshi Yamada of Kyushu University in Fukuoka
Japan (a member of the Japanese ALDP knock out (KO) mouse team) worked
together with Dr. Kim's team at UBC in July and August of 1998. Dr. Yamada
also met with Dr. Snyder at The Myelin Project of Canada's Workshop at
McMaster University in August.
Research News: December 1998 Volume IV
Strategies were discussed relative to developing a gene therapy for human
ALD using the ALDP-KO mouse and immortal mouse NSCs. Dr. Kim has now
provided Dr. Yamada with the required C17-2 cell line originally developed
by Dr. Snyder in 1992. The Japanese team intends to overexpress the ALDP in
C17-2 cells. Corrected cells will then be implanted into the brain of the
original mutant mouse. After several weeks the biochemical status of the
very long chain fatty acids ( VLCFA in the host brain will be analysed.
The next few months will show whether the amount of VLCFA is reduced by
the implantation of NSCs and whether a genetic correction has occurred. If
this approach is successful, then human NSC lines will also be utilised for
gene therapy in the ALDP-KO mice. Dr. Snyder has already shown the ability
of human NSCs to correct a genetic defect in an in vitro model; the defect
chosen was Tay-Sachs disease, a storage disease that leads to progressive
neurodegeneration. In this instance the metabolic defect in primary neural
cultures was corrected by human NSCs. These are very exciting times!
Further Progress Discoveries at UBC and in Dr. Kim's collaborative
projects have proven the soundness of our remyelination strategies. The
stunning achievement of creating human NSCs is a direct result of Dr. Kim's
provision of human cell preparations to Dr. Snyder. Further collaborations
to characterise these cells for transplant are well underway. Dr. Kim and
his team has gone on to successfully generate several clones of human
NSCs similar to the ones produced earlier. The momentum is building!
McMaster University Long Evans Shaker (LES) rats. Oligodendrocytes isolated
from the adult human brain, Schwann cells from embryonic human root
ganglion and glial cells (mixed populations of oligidendrocytes, their
progenitors, astrocytes and neurons) were transplanted into the brain and
spinal cord of the rats. Survival of grafted human cells were confirmed in
the graft sites of 4 animals 10, 14, 21 and 24 days post transplantation.
The status of remyelination in these animals is under
investigation.
Since the mortality rate of the LES rats before and after transplantation
is considerably high, we have decided to also use the shiverer
dysmyelination mutant mouse as a recipient of transplantation. Dr. Alan
Peterson of McGill University has kindly agreed to provide breeding pairs
of the shiverer mouse. We will graft the human NSC line into the shiverer
mouse and LES rat from mid January 1999.
Drs. Jean de Vellis and Araceli Espinosa, our collaborators at the
University of California at Los Angeles (UCLA), informed us that the
primary human NSCs Dr. Kim sent to them earlier were grafted into myelin
deficient (MD) rats and were found to survive well in the MD brain. In
addition, the grafted human NSCs were seen migrating great distances to
other brain regions far from the site of transplantation. The status of
remyelination is under investigation. Dr. Kim and his UCLA colleagues will
continue to share data to apply to the research at both facilities.
This material is provided as general medical information and is not
intended as advice for individual patients; please contact your physician
for specific recommendations.
¨ 1998 International MS Support Foundation
International MS Support Foundation
P.O. Box 90154
Tucson, Arizona 85752-0154