" I. INTRODUCTION
In mid-June The Myelin Project held a special meeting in Leesburg, Virginia,
to hammer out a consensus on the feasibility of transplanting myelin-forming
cells into humans. The meeting concluded that enough animal experiments had
been conducted and scientific data existed to go for clinical trials. (my
emphasis)
Dr. Timothy Vollmer of the Yale University School of Medicine, who was crucial
in organizing the Consensus Meeting, is already implementing the meeting's
central recommendation. He and his Yale colleagues are writing a protocol to
transplant myelin-producing Schwann cells in multiple sclerosis (MS) patients
as early as June 1999. (my emphasis)
Since last we reported to you, The Myelin Project has pressed forward on other
fronts: our Cell Culture Units are working hard to develop a pure source of
oligodendrocytes, the other type of myelin-producing cells. Research on the
roles of progesterone and fatty acids in myelin repair is moving forward at
full speed. Also, research progress on specific myelin disorders has led to a
better understanding of the demyelination/remyelination process.
Scientific achievements have been matched by the fundraising success that we
have achieved with your help. All told, in 1997 our receipts totaled more
than one million dollars.
II. RESEARCH
Transplantation
a) Consensus Meeting
The Consensus Meeting was attended by researchers and clinicians from both
within and outside of The Myelin Project Work Group. Participants debated
whether the time had come for clinical transplantation trials. They concluded
that sufficient data from animal experiments existed to "justify a phase I
trial to transplant cells with adequate myelin-forming capacity to demonstrate
safety, cell survival and myelination in humans." We have asked Dr. Arturo
Camacho, a neurosurgeon who attended the meeting as an observer, to write a
paper describing the meeting's major conclusions. We shall submit this paper
to a major medical journal. Given the eminence of the meeting's participants,
publication would give a boost to remyelination research worldwide.
Participants considered several disorders as possible candidates for
transplantation, including multiple sclerosis, metachromatic leukodystrophy
(MLD), adrenoleukodystrophy (ALD), transverse myelitis, Krabbe's (Globoid
Cell) leukodystrophy and Pelizaeus-Merzbacher disease. (Ideally, prior to
transplantation, the disease process should be arrested and patients'
condition stabilized.)
They also discussed the types of glial cells transplantable into humans:
oligodendrocyte precursors (OPs), Schwann cells (SC) and olfactory ensheathing
cells (OEC). It was agreed that SC should be used first, for three reasons:
First, the risk of rejection entailed by SC transplantation would be minimal
since these cells could be extracted from the subject's own peripheral nervous
system (PNS). Second, in previous studies Dr. Jeffery Kocsis of Yale
demonstrated the ability of human SC to produce functional myelin in rat
central nervous system (CNS). Third, SC are not targeted by MS, eliminating
the risk that they would be destroyed in subsequent attacks by the disease.
During the meeting, Dr. William Blakemore of the University of Cambridge
described how he restored function in demyelinated rats following
transplantation of myelin-producing cells. In his experiment, he had the rats
walk on a tightrope before and after transplantation. As will soon be
reported in a medical journal, he observed that the gait of these rodents
returned to normal following transplantation.
Dr. Kocsis elaborated on an experiment in which OECs were transplanted into
demyelinated rat spinal cord, causing remyelination and enhancing axonal
conduction. We have circulated his manuscript to the Work Group.
b) Human Trials Protocol
By the end of September 1998, Dr. Vollmer and his colleagues will submit to
The Myelin Project a proposal for funding a short preclinical study as well as
a phase I human transplantation trial. The preclinical study will aim to
demonstrate the safety of transplantation. Researchers will induce lesions in
the CNS of rats and monkeys by injections of ethidium bromide followed by X-
irradiation (EBX). They will then implant into these lesions SC extracted
from the subjects' own PNS. The study should be completed in a relatively
short time. The EBX demyelinating method, first developed by Dr. Blakemore,
is now well established; producing myelin lesions thus should present no
problem. At the same time, if adverse effects (e.g., rejection of the newly
implanted cells, disruption of neural structures) do not develop within a few
months, they are unlikely to appear later and the procedure should be
considered safe for all practical purposes.
The phase I human transplantation trial will begin soon after the animal
safety hurdle has been cleared. It will aim at ascertaining safety in MS
patients and at establishing dose-response (i.e., so many cells implanted, so
much myelin produced.) If phase I is successful, researchers will move to
phase II, to prove the efficacy of the procedure in terms of remyelination and
clinical improvement.
The phase I trial would be carried out by an international team of clinicians
with expertise in neurology, neurosurgery, immunology, anesthesiology, and
imaging. The Work Group already includes some of the specialists required.
We will do our best to identify the others over the next few months.
c) Other Transplantation Research
Researchers at The Myelin Project's Cell Culture Units at Lund, Sweden and at
Madison, Wisconsin continue to work on establishing immortal lines of human
oligodendrocyte precursors (OPs). They have made several attempts -- using
different methods of isolating cells, cells of different ages and various
combinations of growth factors -- but, so far, without success. However, even
if an immortal line is not achieved, these researchers feel confident that
they can soon come up with OP preparations suitable for human
transplantation. (In transplanting dissociated human glial cells into
dysmyelinated rodents, they have observed cells surviving -- significantly --
up to two weeks.)
In Dr. Annick Baron-Van Evercooren's experiment at the Salpjtrihre in Paris,
transplanted monkey SC have failed to remyelinate the optic nerves of either
monkeys or rats. By contrast, these cells have remyelinated lysolecithin-
induced lesions in rat spinal cord. One possible reason for the different
outcomes of these experiments is that the optic nerve may be an especially
difficult site for transplantation because of the non-permissiveness of its
environment. Specifically, astrocytes of the optic nerve, which seem to be
different from those of other CNS structures, may be unable to provide the
growth factors necessary to promote differentiation and remyelination. To
test this hypothesis, Dr. Baron plans to transplant in the monkey optic nerve
exogenous astrocytes together with SC. If this attempt falls short of the
mark too, she proposes to transplant oligodendrocytes rather than SC into the
monkey optic nerve or to move to the spinal cord.
The Myelin Project has this year awarded Dr. Hans Althaus of the Max Planck
Institut in Gvttingen, Germany a grant to transplant human cells from our Cell
Culture Unit in Sweden into his demyelinated mini-pig model."