Saturday, December 16, 2006
Searching for a Cure for Parkinson's Disease
With a heightened interest in Parkinson's disease (PD) a new optimism is
emerging. Some scientists are predicting that if research into this disease
continues at its present rate, PD may be preventable in the early 21st
century. Let us hope they are right.

The discovery of growth factors, new genes, stem cells, and new surgical
techniques, just to name a few, all hold promise. But defeating PD will most
surely require new discoveries that no one can yet predict. A "cure" for PD
may come from an area of science that we never even suspected. Major
discoveries are sometimes serendipitous. So when we speak of a cure, what do
we mean? A treatment that slows or stops the disease progression, or ideally
a treatment that relieves all major symptoms permanently and without risk of
significant side effects.

The following is an up-to-date review of those areas of research that show
the most promise, to include a disappointment or two.

* Neuroimmunophilins-Ligands
* Neurotrophic Factors
* Neural Tissue Transplants
* Retinal Cell Transplants
* Stem Cell Transplants
* Gene Engineering and Therapy

Neuroimmunohilins-Ligands
In my opinion, this is the most promising discovery so far as a potential
cure for PD. Let me give you a brief review of how these compounds were
discovered and how they appear to work.

The drug that started all this was FK-506, now known as Cyclosporin, an
immuno-suppressant used to prevent rejection of organ transplants. It is
also the first drug discovered that showed, in the test tube and in tissue
cultures, that it could stimulate the growth of brain cells and help
partially rejuvenate nerves. Because cyclosporin is a powerful
immuno-suppressant with troublesome side effects, scientists had to try and
isolate just the portion of the drug that was beneficial to the neurons and
nerves.

They were indeed able to isolate drug-like molecules called GPI-1046 or
ligands that had the desired properties and not the unwanted ones. When
given to animals with PD-like induced symptoms they were found to stimulate
the regrowth of damaged neurons and eliminate all signs of PD. Another
important feature is that these ligands can be given by mouth and cross the
blood-brain barrier. A series of these ligands have now been synthesized.
They bind to cellular proteins known as immunophilins, which are receptors
on the cell surface that turn on repair genes within damaged nerve cells.


This growth factor, GPI-1046, when given to Rhesus monkeys with MPTP-induced
PD, resulted in a dramatic improvement in symptoms. Monkeys with difficulty
walking, climbing and feeding themselves regained these abilities. The
brains of these monkeys, under the microscope, showed evidence of re-growth
of dopamine nerve terminals. So far in animal studies no toxicity or side
effects have been observed. These drugs can regenerate damaged nerves with
out affecting normal, healthy neurons.

In summary, these drugs work by regenerating damaged neurons, resulting in a
90 percent recovery of normal behavior in animal trials. The scientists hope
to be able to reverse PD in humans, which is unprecedented. Just think, an
orally active molecule that crosses the blood-brain barrier and puts PD
patients back to normal function. While this sounds like a potential cure,
we await the results of clinical trials that may take a few years to
complete.
Neurotrophic Factors

A substance called glial-derived neurotrophic factor (GDNF) was discovered
in 1993. It was shown to promote the survival of neurons. What more do we
know about this substance?

All cells, including nerve cells, self-destruct when they are no longer
needed. This type of suicide cell death called apoptosis is, in the brain,
under the control of a genetic program that is permanently "on." Unless
these suicidal cells are given the message not to, they will self-destruct.
In the brain, the survival signals that save these cells are called
neurotrophic growth factors. It was first thought that these neurotrophic
factors were only involved in early brain development, but it has been shown
that they are also involved in the survival of adult neurons. This raised
the obvious question, could neurotrophic factors help PD? Further studies
have shown that this factor appears to not only slow down the loss of nerve
cells, but to prevent further neuron cell suicide. This could result in a
treatment that could slow or prevent the further march of PD in the patient.

Using a recombinant form of GDNF, Amgen has demonstrated in its
laboratories, that r-metHuGDNF, which has to be injected into the brain,
works to protect dopaminergic neurons against chemical insult and can
ameliorate PD symptoms in chemically lesioned animals.

The r-metHuGDNF has been injected into brains of Rhesus monkeys with
MPTP-induced PD; significant improvement occurred in these primates with a
marked reduction in slow movement, rigidity and postural instability. All
the results indicate that GDNF may be of benefit in treating humans with PD.
Perhaps this treatment's main drawback is that this molecule cannot be given
by mouth, or injected into the blood stream, nor does it cross the
blood-brain barrier. It must be injected, once a month, directly into the
brain through a surgically placed catheter. This study is ongoing at
multiple PD centers in North America.

Neural Tissue Transplants

In the 1980s, neurosurgeons in Sweden and China transplanted tiny bits of
aborted fetal brain tissue into the brains of patients with PD. The idea was
that if these cells "took" the PD patient would be able to produce more
dopamine. However, success of this procedure has been slow in coming,
hampered by ethical and moral issues; the controversy is over the use of
human fetal tissue for the implants. A Federal ban, lifted in 1993, will
probably resume under the new US administration. If this happens, funds for
this research may no longer be available from government agencies.

Results released this year from the first randomized, controlled clinical
study of fetal implants for PD patients show that the surgery only helped a
small number of patients under age 60. This was a study led by Dr. Curt
Freed from the University of Colorado in Denver and Dr. Stanley Fahn of the
Columbia-Presbyterian Medical Center in New York. Their study included 40
patients with advanced PD present for an average of 14 years. After one year
the treated patients under age 60(nine in total) showed some improvement
especially in movement. However, no patient over age 60 or the placebo group
showed improvement.

The most shocking finding was that in 15 percent of patients, the cells grew
too well resulting in too much dopamine produced in the transplant patient's
brain. As a side effect, these patients developed uncontrollable writhing
and jerking movements, known as diskinesias with a severity rarely seen. The
scientists say they have no way to remove or deactivate these transplanted
cells so this nightmarish side effect may be permanent.

Although some scientists are eager to proceed, the results of this study,
plus the dispute over ethical issues surrounding it may mean that the
grafting of human fetal tissue into the human brain may no longer be
considered a safe, viable option for treating PD.

Retinal Cell Transplants

Scientists from Emory University in Atlanta have recently reported on a new
approach to the transplantation of dopamine producing cells that does not
rely on controversial human fetal cells. Instead it uses what are known as
retinal pigment epithelial cells, a readily available source of dopamine
producing cells found in the retina of the eye. Why these cells are there
and their function is unknown, but they appear to be effective when used in
human brain transplantation. The cells can be obtained from donor eyes at
organ banks grown and multiplied in the laboratory. For brain implantation
the retinal cells are deposited on the surface of tiny gelatin spheres
barely visible to the naked eye. Hundreds to thousands of these spheres,
called Speramines, are injected into the brain.

One donor eye can potentially provide enough cells to perform thousands of
transplant operations on PD patients. Unlike fetal cells, immune cells in
the brain do not attack these retina-derived cells, which is a significant
finding.

At Emory six patients with moderate to severe PD underwent the
transplantation. Within the first three months of the treatment all six
patients showed a 35 percent improvement in their symptoms. Some were even
able to reduce their medications. The results are encouraging, but because
this was not a placebo-type study, the results are open to question.
Controlled clinical trials are needed before any conclusions can be drawn.

Stem Cell Transplantation

The discovery of stem cells in 1998 has refocused attention to brain repair.
Stem cells are the universal cells from which all cells are derived. They
can be grown in test tubes and made to specialize into any type of cell,
including neurons. (Theoretically, if this is proven to be true, PD patients
would get an injection of these newly produced stem cell-derived neurons
into the substantia nigra and be cured.) That sounds too good to be true and
considerable work needs to be done. There is also the issue of ethics as
these stem cells come from human fetal sources. At present the current use
of human pluripotential stem cells is under discussion and remains an
unresolved ethical controversy.

But scientists are resourceful. A recent study found that bone marrow cells
could be induced to develop into brain cells. This gives scientists a safe,
reliable uncontroversial source for stem cells. A recent report in the April
2001 issue of Tissue Engineering found adult stem cells in the human fat
from liposuction patients. The next step is to test if these cells will
transplant successfully, transform into the right kind of cell, and prove to
be as good as cells taken from a human fetus.

Scientists at Lund University, in Sweden, have reported that human neural
stem cells grown in the laboratory can be used to generate new neurons in
the brain. The main limitations are safety and ethical issues. Alternative
sources like bone marrow are needed. Many are convinced, however, that in a
matter of years it will be possible to use stem cells to repair damaged
tissues and organs including the brain. This sounds like a potential cure
for PD.

Gene Engineering and Therapy

I have alluded to genetic engineering whereby scientists modify the genetic
code of individual cells to create dopamine-producing cells from other
cells, even skin cells. The implications for PD are obvious.

The other important area is gene therapy. The recent FDA approval of the
first commercial use of gene therapy can open new ways in which this therapy
can supply PD patients with the neurotransmitters they lack. People with
hereditary diseases cannot make a certain protein because the gene that
codes it is damaged or missing. Gene therapy then is the implant of the
normal gene into the body so that the normal protein will be generated.
Although gene therapy sounds easy on paper, it is actually a difficult and
complex procedure that must be methodically done.

The main concern is safety. In present techniques a disabled virus is used
to introduce genes into cells. The risk is that the viral vector might
trigger the wrong genes in the persons DNA or become active. The other main
concern is possible severe side effects from the procedure that may be life
threatening.

Researchers from the Research Center for Brain Repair at the Rush
Presbyterian St. Luke's Medical Center, Chicago, used monkeys experimentally
induced with PD for a recent gene therapy study. The experiment relieved the
severe symptoms of PD and restored them to normal.
Posted by ushakanth at 12:59 AM

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