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PRONEURON
BIOTECHNOLOGIES
Lowering the blood brain barrierto-entry for autologous immune
cells
When a person breaks a bone, suffers
infection organ damage or other injury, the
body mounts an immune response, cleaning
up the dead and damaged cells, killing
bacteria and cells infected with viruses, and
stimulating re-growth and repair. Unless the
injury occurs to the brain, spinal cord or optic
nerves. Certain components of the central
nervous system are ''immune-privileged,'' that
is, they are cut off from the immune system
by barriers that serve to protect the central
nervous system (CNS) from degenerative
disease. The blood brain barrier, which
prevents immune cells from entering the
CNS, is backed up by a molecule called
immune privilege factor (IPF) that inhibits the
few immune system cells which do make it
in. Says Adrian Harel, PhD, manager of
Proneuron Biotechnologies Ltd., "This
situation is great for preserving the integrity
of a healthy neural network, but it means that
immune cells aren't there to help when you
are sick or suffer a CNS trauma."
Michal Schwartz, MD (PhD), scientific
founder of Proneuron and a neurobiologist at
the Weizmann Institute of Science, devised
a way to circumvent this barrier by placing
immune cells, specifically macrophages, at
the site of injury. Macrophages clean up cell
debris and secrete a collection of factors—
cytokines, growth factors and interleukins—
which stimulate and support axonal growth.
Based on 20 years of research conducted by
Dr. Schwartz, Proneuron will develop new
cell therapies and treatments for neurological
disorders such as multiple sclerosis,
Parkinson's disease and Alzheimer's disease,
ophthalmological disorders including anterior
ischemic optic neuropathy and glaucoma; and
immune disorders.
In rat models of spinal cord injury,
Proneuron has demonstrated proof-of-concept
of its CNS regeneration approach. Scientists
paralyzed rats by severing the spinal cord.
After two weeks of paralysis, researchers
transplanted autologous macrophages, which
had been activated using a proprietary technique, into the spine of one group of animals.
The control group received a local transplant
of the growth medium used to grow and
JUNE 1999
prime the macrophages. After 12-16 weeks,
the rats that had received the activated
macrophages regained the ability to move
their hind legs; some were also able to move
their tail, as measured by the BBB scale, an
international scale used to measure muscle
movement recovery. "The animals may never
regain 100% of their muscle movement, but
this is a huge leap compared to what can
currently be achieved," believes Harel. All the
rats in the control group remained paralyzed
and showed no signs of recovery.
The macrophage therapy was also tested
using a transected optic nerve as a model.
After treatment with activated macrophages,
axons regenerated. Schwartz demonstrated
axonal continuity by showing the passage of
colored dyes along the optic nerve to the
retina.
Furthermore,
electrophysiology
measurements showed conductivity of signals
along the nerves. "The fact that electrical
signals are going from the eye to the brain is
strong evidence that neural function has been
restored," claims Harel.
Based on animal models, the optimum
therapeutic window for this therapy is within
2-4 weeks following the injury. Therefore,
this therapy would not be an option for
patients who have sustained injuries months
or years ago.
The company hopes to begin clinical trials
for its autologous macrophage therapy in the
third quarter of 1999. It has filed an IND with
the FDA to begin trials in Israel. Proneuron
plans to complete Phase I in Israel before
investing resources to build cell processing
centers in the US.
Proneuron is developing another cell based
therapy to combat the secondary neural
degeneration that follows injury. Cells
damaged or killed by the initial trauma
release chemicals that in turn cause the death
of adjacent cells. While many companies are
attempting to develop neuroprotective drugs,
Proneuron feels it is unique in taking a cell
therapy approach. The therapy will involve
taking a sample of a patient's own Tlymphocytes, multiplying and sensitizing the
population against a specific epitope, and then
systemically reintroducing the T-cells into the
patient. "The T-cells hone in on the site of the
injury, because they have been sensitized, and
attach to the surviving cells or axons to
prevent them from dying," says Harel.
In studies published in the January issue of
Nature Medicine, Schwartz showed that rats
with a partially crushed optic nerve retained
300% more retinal ganglion cells after
treatment with activated T cells specific for
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myelin basic protein, compared to rats that
were treated with activated T cells specific for
other unrelated epitopes.
Proneuron's T cell therapies are still at the
preclinical stage. Harel estimates that they
will require another nine months of preclinical studies followed by about six months
to plan a protocol for clinical trials. The
company hopes to file an IND within the next
18 months. Proneuron's ultimate goal would
be to combine its macrophage and T-cell
therapies to achieve nerve regeneration, and
to also prevent secondary degeneration. The
company hopes to establish other cell
processing centers outside Israel to handle the
proliferation and activation stages for both the
macrophage and the T cell therapies. Long
term plans include collaborations with big
Pharma to help with the marketing aspects
and the creation of cell processing centers.
In the field of immunology, Proneuron
hopes to develop drugs based on its
identification of a small peptide called
'Immune Privilege Factor' (IPF), which has
potent
immunosuppressive
and
antiinflammatory properties. IPF is found in the
brain and "works like steroids, without the
side effects," according to Harel. In animal
models, IPF has demonstrated potential
against such neurological disorders as
multiple sclerosis as well as ophthalmological
diseases, uveitis, and corneal transplant
rejection. Although the least developed of
Proneuron's programs, it is the company's
most promising project in terms of the huge
market for a less hazardous alternative to
steroids, Harel believes.
Proneuron has acquired worldwide
exclusive licenses to all three of its core
technologies in exchange for royalties, from
YEDA Research and Development Co. Ltd.,
the commercialization arm of the Weizmann
Institute. YEDA holds all the patents for the
work done in animals: Proneuron will share
the patents for human applications. The
company is currently in the process of filing
more patents for new technology and
indications.
Proneuron was founded in 1996 with $3.5
million in initial seed funding from the
Hudson Investment Group. Another $3.5
million came from four Israeli VC firms: D.S.
Polaris Ltd., Lapid Medical Ventures,
Nassua-Zannex Venture Capital Management
Ltd., and Infinity Venture Capital Fund L.P.