- Email: [email protected]
Gene therapy: Back to the drawing board?
Gastroenterology News John H. Walsh, Section Editor
Nervous Elements Influencing Intestinal Inflammation and Rotavirus Diarrhea May Lead to New Treatments
the mechanism, and one that obviously has therapeutic implications, because if you interrupt that neurotransmission in some way, you should be able to ameliorate the diarrhea.’’ wo recent articles have described Another recent article describes a enteric neural pathways that vimechanism by which mast cell activaruses and other agents that cause tion can stimulate neurogenic inflamintestinal inflammation and diarrhea mation in the intestine. A large group may use to produce these effects. of investigators headed by Dr. Nigel Lundgren et al. used different drugs Bunnett of the University of Califorto inhibit enteric nervous system nia, San Francisco published in the functions in an experimental model February issue of Nature Medicine of rotavirus diarrhea (Science, Januthat a trypsin-like enzyme released ary 21). They found that the sodiumfrom mast cells, known as tryptase, channel blocker of nerve conducactivates the proteinase-activated retance, tetrodotoxin; the local ceptor, type 2 (PAR-2), that is anesthetic, lidocaine; and the located on sensory neurons. nicotinic synaptic blockers Once activated, these neuhexamethonium or mecamylrons release proinflammatory amine all reduced the secremediators including calcitotory effects produced by rotanin gene-related peptide and virus infection in perfused substance P, leading to local segments of mouse intestine. edema. Therefore, tryptase inTheir 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 inviral diarrhea. Thus, they proflammatory processes that inposed effective neural-blockvolve mast cell activation. ing drugs that act locally on ‘‘Although this is still a fairly the intestine might become basic study,’’ observes Baruseful additives to current glurett, ‘‘it’s very tempting to cose-sodium chloride regispeculate that there are setments to treat acute infectings in the body where you tious diarrhea associated with might get inappropriate activasignificant fluid and electrotion of proteolytic enzyme, lyte loss. 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 inflammathat the enteric nervous sys- blood cell infiltration and edema. This mechanism implicates tory response that occurs in pantem 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. inflammatory bowel disease.’’ diating diarrhea through infec-
T
Gene Therapy: Back to the Drawing Board? nce viewed as the most promising of medicine’s new frontiers, gene therapy’s future suddenly seems murky after a high-profile death, re-
O
tious agents is not new, she considers the extension of this paradigm to viral-induced diarrheas and gastroenteritis to be important. ‘‘As the authors point out, it’s difficult to understand why agents such as rotavirus cause diarrhea when only a very small number of the cells actually get infected, and the cells that do get infected are not the ones whose function one might assume would be altered in the setting of diarrheal illness,’’ Barrett says. ‘‘So determining that this is somehow mediated by the nerves in the gut is a very important step forward in understanding
porting irregularities, and an announced crackdown by the National Institutes of Health (NIH). In February, the NIH announced that it would compel scientists who have conducted gene therapy research 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 oversees 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 involved 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 after receiving an infusion of a genetically modified virus into his liver in an effort to cure a rare disorder, a deficiency that prevented his liver from breaking down ammonia, a normal 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
therapy studies are in progress, involving nearly 3000 patients. A spokesperson for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) said that the institute is currently funding gastrointestinal (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 reporting 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 limitations, should be tested in people at all. Dr. David Baltimore, a Nobel laureate who is the president of Caltech, said at a meeting in Pacific Grove, California, in February that he believes it is premature to hold clinical trials. ‘‘I disagree we’ve had value from gene therapy trials so far,’’ Baltimore was quoted as saying in the Los
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 ‘‘until the field changes priorities.’’ Specifically, 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 cationic liposomes,’’ Pardridge notes. ‘‘However, adenovirus is rapidly immunoneutralized 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 liposomes, do not offer much promise for in vivo applications.’’ ‘‘The current failures in gene therapy are no surprise, because gene-targeting science, like drugtargeting science in general, was never developed.’’
Increased Funding Doesn’t Add Up to More GI Grants in 2000
AGA Research Public Policy Committee, who met with new NIDDK director 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 specifically 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 addition, 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-
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 toward 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, inflammatory bowel disease and obesity— are in line with the priorities of the AGA committee, Donowitz says.
or GI researchers, the FY 2000 budget, which included a hefty 15% increase for the NIH, could only be seen as good news. But anyone expecting the federal largess to translate to more new grants being funded is bound for disappointment, at least where the NIDDK is concerned. Because of FY 2000 funding earmarked 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
F
652
Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]
Nervous Elements Influencing Intestinal Inflammation and Rotavirus Diarrhea May Lead to New Treatments
the mechanism, and one that obviously has therapeutic implications, because if you interrupt that neurotransmission in some way, you should be able to ameliorate the diarrhea.’’ wo recent articles have described Another recent article describes a enteric neural pathways that vimechanism by which mast cell activaruses and other agents that cause tion can stimulate neurogenic inflamintestinal inflammation and diarrhea mation in the intestine. A large group may use to produce these effects. of investigators headed by Dr. Nigel Lundgren et al. used different drugs Bunnett of the University of Califorto inhibit enteric nervous system nia, San Francisco published in the functions in an experimental model February issue of Nature Medicine of rotavirus diarrhea (Science, Januthat a trypsin-like enzyme released ary 21). They found that the sodiumfrom mast cells, known as tryptase, channel blocker of nerve conducactivates the proteinase-activated retance, tetrodotoxin; the local ceptor, type 2 (PAR-2), that is anesthetic, lidocaine; and the located on sensory neurons. nicotinic synaptic blockers Once activated, these neuhexamethonium or mecamylrons release proinflammatory amine all reduced the secremediators including calcitotory effects produced by rotanin gene-related peptide and virus infection in perfused substance P, leading to local segments of mouse intestine. edema. Therefore, tryptase inTheir 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 inviral diarrhea. Thus, they proflammatory processes that inposed effective neural-blockvolve mast cell activation. ing drugs that act locally on ‘‘Although this is still a fairly the intestine might become basic study,’’ observes Baruseful additives to current glurett, ‘‘it’s very tempting to cose-sodium chloride regispeculate that there are setments to treat acute infectings in the body where you tious diarrhea associated with might get inappropriate activasignificant fluid and electrotion of proteolytic enzyme, lyte loss. 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 inflammathat the enteric nervous sys- blood cell infiltration and edema. This mechanism implicates tory response that occurs in pantem 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. inflammatory bowel disease.’’ diating diarrhea through infec-
T
Gene Therapy: Back to the Drawing Board? nce viewed as the most promising of medicine’s new frontiers, gene therapy’s future suddenly seems murky after a high-profile death, re-
O
tious agents is not new, she considers the extension of this paradigm to viral-induced diarrheas and gastroenteritis to be important. ‘‘As the authors point out, it’s difficult to understand why agents such as rotavirus cause diarrhea when only a very small number of the cells actually get infected, and the cells that do get infected are not the ones whose function one might assume would be altered in the setting of diarrheal illness,’’ Barrett says. ‘‘So determining that this is somehow mediated by the nerves in the gut is a very important step forward in understanding
porting irregularities, and an announced crackdown by the National Institutes of Health (NIH). In February, the NIH announced that it would compel scientists who have conducted gene therapy research 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 oversees 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 involved 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 after receiving an infusion of a genetically modified virus into his liver in an effort to cure a rare disorder, a deficiency that prevented his liver from breaking down ammonia, a normal 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
therapy studies are in progress, involving nearly 3000 patients. A spokesperson for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) said that the institute is currently funding gastrointestinal (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 reporting 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 limitations, should be tested in people at all. Dr. David Baltimore, a Nobel laureate who is the president of Caltech, said at a meeting in Pacific Grove, California, in February that he believes it is premature to hold clinical trials. ‘‘I disagree we’ve had value from gene therapy trials so far,’’ Baltimore was quoted as saying in the Los
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 ‘‘until the field changes priorities.’’ Specifically, 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 cationic liposomes,’’ Pardridge notes. ‘‘However, adenovirus is rapidly immunoneutralized 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 liposomes, do not offer much promise for in vivo applications.’’ ‘‘The current failures in gene therapy are no surprise, because gene-targeting science, like drugtargeting science in general, was never developed.’’
Increased Funding Doesn’t Add Up to More GI Grants in 2000
AGA Research Public Policy Committee, who met with new NIDDK director 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 specifically 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 addition, 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-
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 toward 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, inflammatory bowel disease and obesity— are in line with the priorities of the AGA committee, Donowitz says.
or GI researchers, the FY 2000 budget, which included a hefty 15% increase for the NIH, could only be seen as good news. But anyone expecting the federal largess to translate to more new grants being funded is bound for disappointment, at least where the NIDDK is concerned. Because of FY 2000 funding earmarked 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
F
652
Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]