#67 Biomarker study, ganciclovir treatments
Roger Burns
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Chronic Fatigue Syndrome Electronic Newsletter
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No. 67 July 21, 1997 Washington DC
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BIOMARKER EVIDENCE PUBLISHED /
GANCICLOVIR TREATMENTS
CONTENTS
>>>1. Biomarker evidence found by Robert Suhadolnik, et al.
>>>2. Ganciclovir treatment in subset of CFS
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>>>1. Biomarker study by Robert Suhadolnik, et al.
A study which identifies a possible biological marker for CFS was
published on Thursday, July 17 in the Journal of Interferon and
Cytokine Research. This work was first described by researcher
Robert Suhadolnik at last October's AACFS conference in San
Francisco. The study shows a defective RNase L enzyme present in the
blood of CFS patients that does not appear in healthy controls. In
addition, patients whose illness is less severe appear to have both
normal and defective RNase L, and the researchers speculate that
further study might show that this aspect could be an objective
indicator of the severity of the illness.
The current study, as published, compares ten CFS patients who meet
the 1994 CDC criteria with ten healthy controls. However, the
researchers indicate elsewhere that they have since duplicated these
results with hundreds of patients, and two other studies in Europe
have confirmed this work and will be published later this year.
Further research is being supported by a grant from the National
Institutes of Health. Suhadolnik's research team is also beginning
to investigate whether there might be therapies based on correcting
the activity of the defective enzyme.
The current paper was published as:
Suhadolnik RJ, Peterson DL, O'Brien K, Cheney PR, Herst CVT,
Reichenbach NL, Ning K, Horvath SE, Iacono KT, Adelson ME, De
Meirleir K, De Becker P, Charubala R, Pfleiderer W.
Biochemical Evidence for a Novel Low Molecular Weight
2-5A-Dependent RNase L in Chronic Fatigue Syndrome. Journal of
Interferon and Cytokine Research, July 1997, 17:377-385.
"We are greatly encouraged by the trend we see. All CFS patients
tested have this new enzyme, while none of the healthy controls do"
says Suhadolnik in a press release from the CFIDS Association of
America, the major sponsor of the study. Robert Suhadolnik, Ph.D.,
is a professor of biochemistry at Temple University School of
Medicine in Philadelphia and is a member of the university's Fels
Institute for Cancer Research and Molecular Biology. His laboratory
has been involved in studies of virus-associated diseases and cancers
for the past 15 years and has been awarded research grants by the
National Institutes of Health to study CFS, and AIDS.
The Association's press release described the study as follows:
The findings ... are based on data from a limited number of
patients. However, larger studies are already underway and have
attracted financial support from the National Institutes of
Health.
The newly discovered enzyme, which has a lower molecular weight
than the normal enzyme found in the viral pathway in which this
protein is active, may explain common observations in patients
with CFS: an inability to control common viruses (like Epstein-
Barr virus and human herpesvirus 6) and an inability to maintain
cellular energy. According to Suhadolnik, the viral pathway known
as the 2-5A synthetase/RNase L antiviral pathway, may control both
processes. "This new enzyme in CFS may not function as well as
the normal RNase L found in healthy people. It may explain why
CFS patients' bodies have a hard time maintaining the energy
necessary for cellular growth."
The newly published study also indicates that the presence of the
low molecular weight enzyme and the absence of normal enzymes may
be related to the severity of CFS symptoms. While all CFS
patients tested positive for the low molecular weight enzyme, some
also had the normal RNase L. "It is interesting to note," said
Suhadolnik, "that extracts from the most severely disabled
individuals with CFS in this study contained only the low
molecular weight enzyme."
"Because the new enzyme has been found in CFS patients but not in
healthy controls, it is potentially the basis for a laboratory
test for CFS, which is diagnosed today only through its clinical
symptoms," says Dr. Antonio Goncalves, associate vice provost for
science and technology at Temple University. The university has
filed a patent application for such a test and is seeking a
corporate partner to further develop and license the test.
Goncalves and Suhadolnik caution, however, that additional studies
of much larger patient populations are required before the
clinical utility of the test can be demonstrated.
Suhadolnik explained this study at a Congressional briefing in
Washington on May 16:
The research in my biochemistry laboratory is directed to the
understanding of the atural antiviral defense pathways in humans.
This pathway is called the 2-5A synthetase/RNase L pathway. When
all components of this antiviral pathway are functioning
correctly, the human body can effectively control virus
infections. Our research has demonstrated that several components
of the antiviral pathway are not functioning properly in people
with CFIDS. Specifically, the antiviral pathway is upregulated
(or overactive) in people with CFIDS.
The name of the molecule that drives this pathway is
2',5'-oligoadenylate trimer 5'-triphosphate. With a name like
that, you can understand why the molecule has been nicknamed 2-5A.
What does 2-5A do in the human body? 2-5A is the molecule that
activates RNase L, the enzyme that degrades viral RNA. With RNase
L that works properly, we can overcome virus infections. However,
if RNase L is defective, we have a problem.
We can specifically measure RNase L activity in biochemical assays
of lymphocytes that we isolate from whole blood. From one tube of
blood, we isolate a lymphocyte pellet. When we measure the RNase
L in people with CFIDS, we observed something we had never seen
before. RNase L in people with CFIDS is overactive. In the first
study we did with Dr. Peterson, 13 of 15 people with CFIDS had
this overactive RNase L....
We have tested samples from more than a hundred people with CFIDS
from across the country.... We've learned that there is an enzyme
defect in people with CFIDS -- a defect in RNase L. Something new
is going on with CFIDS. RNase L was overactive, unlike anything
we had ever seen before, and we have studied RNase L activity in
people with AIDS, multiple sclerosis, lupus, human T-cell
leukemia, and kidney cancer....
In order to determine why the RNase L in people in CFIDS is
overactive, it was necessary to develop a new two-part technology
in the laboratory to advance our studies. We were able to develop
this technology using ultraviolet light and an antibody to human
RNase L....
From the blood samples we obtain, we can detect the presence and
measure the activity of RNase L. We have had another surprise in
CFIDS - we have seen a new form of RNase L, a smaller form of
RNase L, in all people with CFIDS....
On the basis of what we know now, it is tempting to speculate that
the presence and activity of the new form of RNase L correlates
with the severity of clinical symptoms in people with CFIDS.
I am pleased to be able to report to you today that our results
have been confirmed. Using CFIDS patients selected by an
independent physician and biochemical techniques similar to ours,
the presence of the small form of RNase L in CFIDS has been
reported from an independent research group.
There have been many reports about this study in European newspapers,
including an interview in Belgium's daily De Morgen with Prof. Kenney
de Meirleir, one of the study's co-authors. In an article titled
"Cause of CFS is found", De Morgen reported:
Many believed it was true, but now there is also scientific proof
for the very first time: chronic fatigue syndrome (CFS) is not in
the mind but a serious disease instead....
[According to de meirleir} "Many symptoms - extreme fatigue,
muscle pain, recurrent infections - can now be explained. If
something goes wrong with the synthesis of proteins, the
recuperation following exercise will occur much slower".
The problem of CFS has not been completely resolved. The quest
for an effective therapy just started and it will take another few
more years. Research grants for CFS are small.
In addition, developing of a new medicine is very expensive. "Five
to ten billion Belgian francs [150-300 million US dollars]", De
Meirleir estimates. And there are still many questions. Why do
enzymes overreact in certain individuals and why do they affect
the RNA ? De Meirleir: "There are many speculations. The cause
could be viral or even genetic. More research will be needed to
see what it is."
"This scientific breakthrough will encourage the patients", De
Meirleir says. "From now on, doctors will be able to diagnose
their patients, and their family and friends will no longer
dismiss the disease as 'all in the mind'. We have found a marker
and an objective cause. This is a giant step forward".
Please note that despite the enthusiasm of this last statement by
Prof. de Meirleir, no laboratory tests based on this research are
commercially available yet. Also, most scientists will likely hold
off on accepting this as a marker until the other confirmatory
studies have been published.
Other news resources
The full text of various related documents can be found on the
Internet. These include the CFIDS Association press release,
Suhadolnik's remarks at the Congressional briefing last May, and the
Belgian newspaper article featuring the interview with Prof. de
Meirleir. These latter three can be obtained by e-mail by sending a
message which says GET CFS-WIRE LOG9707 to address
LIST...@MAELSTROM.STJOHNS.EDU.
There are convenient links to these documents and others at the
following web pages:
http://www.cais.net/cfs-news/dr-bob.htm
http://www.dds.nl/~me-net/enzyme.html
http://www.temple.edu/medbiochem/rjs.html
[For special assistance in helping with this report, thanks go to
Prof. Robert Suhadolnik, the CFIDS Association of America, the staff
of the Journal of Interferon and Cytokine Research, Marc Fluks, and
Johan de Vis.]
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>>>2. Ganciclovir treatment in subset of CFS
A study of CFS patients whose cardiograms show aberrant T-waves and
who have been ill for less than two years indicates positive results
from intravenous ganciclovir treatments. Among 18 CFS patients in
the subset, 13 were able to progress from disability to being able to
work at 24 weeks after the 30-day treatment ended. The patients who
did not respond tended to have lower levels of HCMV IgG prior to
treatment.
This study was published as:
Lerner AM, Zervos M, Dworkin HJ, Chang CH, Fitzgerald JT,
Goldstein J, Lawrie-Hoppen C, Franklin B, Krotkin SM, Brodsky M,
Walsh D, O'Neill W. New cardiomyopathy: pilot study of
intravenous gangiclovir in a subset of the chronic fatigue
syndrome. Infectious Diseases in Clinical Practice, 1997, 6, 2,
110-117.
[Thanks to Ellen Goudsmit and the Melvin Ramsay Society for
assistance with this report.]
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