Gastroenterology News

John H. Walsh, Section Editor

Nervous Elements Influencing tious agents is not new, she considers the mechanism, and one that obvi-
Intestinal Inflammation and the extension of this paradigm to ously has therapeutic implications,
Rotavirus Diarrhea May viral-induced diarrheas and gastroen- because if you interrupt that neuro-
Lead to New Treatments teritis to be important. ‘‘As the au- transmission in some way, you should
thors point out, it’s difficult to under- be able to ameliorate the diarrhea.’’
wo recent articles have described
T enteric neural pathways that vi-
ruses and other agents that cause
stand why agents such as rotavirus
cause diarrhea when only a very
Another recent article describes a
mechanism by which mast cell activa-
small number of the cells actually get tion can stimulate neurogenic inflam-
intestinal inflammation and diarrhea
infected, and the cells that do get mation in the intestine. A large group
may use to produce these effects.
infected are not the ones whose of investigators headed by Dr. Nigel
Lundgren et al. used different drugs
function one might assume would be Bunnett of the University of Califor-
to inhibit enteric nervous system
altered in the setting of diarrheal nia, San Francisco published in the
functions in an experimental model
illness,’’ Barrett says. ‘‘So determin- February issue of Nature Medicine
of rotavirus diarrhea (Science, Janu-
ing that this is somehow mediated by that a trypsin-like enzyme released
ary 21). They found that the sodium-
the nerves in the gut is a very impor- from mast cells, known as tryptase,
channel blocker of nerve conduc-
tant step forward in understanding activates the proteinase-activated re-
tance, tetrodotoxin; the local
ceptor, type 2 (PAR-2), that is
anesthetic, lidocaine; and the
located on sensory neurons.
nicotinic synaptic blockers
Once activated, these neu-
hexamethonium or mecamyl-
rons release proinflammatory
amine all reduced the secre-
mediators including calcito-
tory effects produced by rota-
nin gene-related peptide and
virus infection in perfused
substance P, leading to local
segments of mouse intestine.
edema. Therefore, tryptase in-
Their results indicated that
hibitors and/or antagonists of
local enteric neural reflexes
the PAR-2 receptor may be
confined to the intestinal wall
developed for treatment of a
contribute to this form of
wide variety of intestinal in-
viral diarrhea. Thus, they pro-
flammatory processes that in-
posed effective neural-block-
volve mast cell activation.
ing drugs that act locally on
‘‘Although this is still a fairly
the intestine might become
useful additives to current glu- basic study,’’ observes Bar-
cose-sodium chloride regi- rett, ‘‘it’s very tempting to
ments to treat acute infec- speculate that there are set-
tious diarrhea associated with tings in the body where you
significant fluid and electro- might get inappropriate activa-
lyte loss. tion of proteolytic enzyme,
Proposed mechanism by which mast cell activation utilizes
Dr. Kim Barrett of the Uni- release of the proteolytic enzyme tryptase to activate the that the mechanisms they’re
versity of California, San Diego proteinase-activated receptor 2 on substance P-containing studying here might in turn
spinal afferent neurons. Substance P released locally from
says that while the concept these nerves acts on vascular endothelial cells to promote white mediate part of the inflamma-
that the enteric nervous sys- blood cell infiltration and edema. This mechanism implicates tory response that occurs in pan-
tem might be involved in me- local sensory neuronal activation and neuropeptide release in creatitis, for example, as well as
the inflammatory response produced by mast cells.
diating diarrhea through infec- inflammatory bowel disease.’’

Gene Therapy: Back to the
Drawing Board?
nce viewed as the most promis-
O ing of medicine’s new frontiers,
gene therapy’s future suddenly seems
murky after a high-profile death, re-
porting irregularities, and an an-
nounced crackdown by the National
Institutes of Health (NIH).
In February, the NIH announced
that it would compel scientists who
have conducted gene therapy re-
search to open their books and re-
port any side effects that occurred in
trials involving humans. The effort is
designed to identify adverse impacts
related to the therapy that may have
been missed previously. This follows
the disclosure that numerous deaths
and side effects among patients in

GASTROENTEROLOGY 2000;118:651–652
Gastroenterology News continued
gene therapy trials have not been
reported by researchers as required
by the NIH and the Food and Drug
Administration (FDA), which over-
sees the clinical trials. NIH’s own
inquiry into the failure of researchers
to report adverse events in their gene
therapy experiments revealed that
only 39 of 691 of these events were
reported immediately, as required by
the agency.
The most publicized failure in-
volved an 18-year-old patient, Jesse
Gelsinger, who had participated in a
gene therapy trial at the University of
Pennsylvania’s Institute of Gene
Therapy. Gelsinger died last year af-
ter receiving an infusion of a geneti-
cally modified virus into his liver in
an effort to cure a rare disorder, a
deficiency that prevented his liver
from breaking down ammonia, a nor-
mal by-product of protein digestion.
After an investigation, the FDA halted
all gene therapy trials at the institute.
It’s estimated that hundreds of gene
Increased Funding Doesn’t Add
Up to More GI Grants in 2000
or GI researchers, the FY 2000
F budget, which included a hefty
15% increase for the NIH, could only
be seen as good news. But anyone
expecting the federal largess to trans-
late to more new grants being funded
is bound for disappointment, at least
where the NIDDK is concerned.
Because of FY 2000 funding ear-
marked both for new initiatives and
for multiyear grants awarded in the
past couple of years, it appears that it
may actually be more difficult for
investigators to obtain new grants,
says Dr. Mark Donowitz, head of the
652
therapy studies are in progress, in-
volving nearly 3000 patients. A
spokesperson for the National Insti-
tute of Diabetes and Digestive and
Kidney Diseases (NIDDK) said that
the institute is currently funding gas-
trointestinal (GI)-related gene therapy
studies only at the basic level.
Although much of the controversy
has centered around incidents such
as the Gelsinger death and the report-
ing failures, gene therapy has also
begun to take hits from a number of
scientists and medical ethicists, many
of whom are questioning whether
the procedure, given its current limi-
tations, should be tested in people at
all.
Dr. David Baltimore, a Nobel laure-
ate who is the president of Caltech,
said at a meeting in Pacific Grove,
California, in February that he be-
lieves it is premature to hold clinical
trials. ‘‘I disagree we’ve had value
from gene therapy trials so far,’’ Balti-
more was quoted as saying in the Los
AGA Research Public Policy Commit-
tee, who met with new NIDDK direc-
tor Allen M. Spiegel in January.
Donowitz also notes that first-time
awardees are apparently faring more
poorly than in the past. When the
NIH stopped offering awards specifi-
cally for first-time investigators, it
promised that the number of grants
awarded to first-time investigators
would be maintained, but that has
not occurred, Donowitz says. In addi-
tion, it appears that only one new
NIDDK center will be funded this
year, at Washington University.
Along with the funding already
committed to multiyear grants,
NIDDK is supporting the develop-
Angeles Times. ‘‘A number of us are
asking, ‘What the hell are we doing
putting these things in people?’ ’’
Dr. William M. Pardridge of the UCLA
School of Medicine believes human
gene therapy should not continue ‘‘un-
til the field changes priorities.’’ Specifi-
cally, Pardridge contends that there
must be a recognition that the limiting
factor involves targeting genes across
biological barriers. ‘‘At present, genes
are delivered by either viruses or cat-
ionic liposomes,’’ Pardridge notes.
‘‘However, adenovirus is rapidly immu-
noneutralized by the immune system,
which necessitates the administration
of ever-increasing dosages until toxicity
from the reaction to the virus is reached.
The alternative to viruses, cationic lipo-
somes, do not offer much promise for
in vivo applications.’’
‘‘The current failures in gene
therapy are no surprise, because
gene-targeting science, like drug-
targeting science in general, was
never developed.’’
ment of clinical research networks in
GI diseases. Several will be funded
around establishing databases that
would be used by multiple centers.
‘‘If there’s a choice to be made, I’d
like to see more funding going to-
ward RO1s and centers than these
databases,’’ Donowitz says.
On the positive side, the request for
application for priority funding for this
year—motility, food-borne illness, in-
flammatory bowel disease and obesity—
are in line with the priorities of the AGA
committee, Donowitz says.
Stories by Dan Gordon
The section editor can be sent
suggestions for articles at
jwalsh@ucla.edu