TEEN'S DEATH DEALT BLOW TO RESEARCH
 BY THERESA CHA -- Lincoln Journal Star

  The 1999 death of Jesse Gelsinger, a volunteer in a clinical trial in Philadelphia, cast a pall over gene therapy.
   Although no major breakthroughs had marked the field since the first gene therapy trial was approved in 1990, enthusiasm had burned brightly.
   One of the crown jewels of the field was the Institute for Human Gene Therapy at the University of Pennsylvania. Headed by Jim Wilson, it boasted an annual budget of $25 million, the largest academic gene therapy program in the nation. But the respected scientist and his program fell from grace when Jesse died Sept. 17, 1999.
   A National Institutes of Health advisory committee concluded Jesse died as a result of the gene therapy trial, not from his underlying condition.
   Jesse had a mild form of a genetic liver disease called ornithine transcarbamylase - or OTC - deficiency, which prevents proper processing of ammonia. The Arizona teen-ager's disease was under control with a low-protein diet and a regimen of 32 pills a day when he entered the phase I clinical trial testing an adenovirus vector carrying a gene intended to correct the defect. The study was aimed at developing a safe treatment for babies with a more severe form of the disorder.
   Each of the 17 trial participants before him received progressively higher doses of the treatment without developing "any serious, unexpected or untoward clinical responses," according to Penn's Institute for Human Gene Therapy statement on Jesse's death.
   In the statement, Wilson said: "We are deeply saddened and surprised by the death of Jesse Gelsinger, an energetic and bright young man who unselfishly participated in this important study so that, in the long-term, an effective therapy might be developed to prevent or treat OTC deficiency."
   On the morning of Sept. 13, 1999, doctors injected 30 milliliters of the experimental gene therapy vector over two hours through an IV. Later that day, Jesse got sick and developed a fever, as had other patients. But his condition worsened drastically.
   By the next morning, a test confirmed his liver was failing. By mid-afternoon, Jesse had fallen into a coma. By night, his ammonia level had skyrocketed to more than 10 times normal.
  Dialysis and other medical interventions seemed to stabilize Jesse the next day. But later that night, he got worse - this time his lungs were failing. The next day, it was his kidneys. The following morning, four days after Jesse had received the gene therapy injection, he was brain-dead.
   "It's incomprehensible to me that what happened happened," said James Talmadge, professor of pathology and microbiology at the University of Nebraska Medical Center. "We knew too much. We may not know exactly how adenoviruses are toxic but we know that if you IV-inject adenovirus, 90 percent of the virus goes to the liver."
   "(Wilson's) own protocol said you don't give this to someone who has compromised hepatic function," Talmadge said. "Jesse had compromised hepatic function. We all make mistakes but this was a comedy of errors and the ultimate responsibility rests with (Wilson.)"
   The fallout from Jesse's death included an Food and Drug Administration investigation and suspension of all human experiments at the institute in Pennsylvania, Wilson's resignation as the head of medical genetics in the department of medicine and Jesse's family filing a wrongful death lawsuit against the university. It also dispirited the gene therapy community.
   "There was a big damper on gene therapy protocols right afterwards," said Dr. Ira Fox, associate dean for research and development at the UNMC medical college. "But I think what happened in the Parisian experiments and also the recent studies in the hemophilia patients have really gotten the gene therapy community energized again and gotten the public energized again for the potential of gene therapy."
   In April, a French team released results scientists regard as the first unequivocally successful proof that gene therapy works. Doctors administered gene therapy to babies without a complete immune system who otherwise may have died from the disorder. Three months later, the babies were home from the hospital leading normal lives. And 10 months later, their immune system was indistinguishable from a healthy child's.
   The results were exciting, but Fox cautioned just because gene therapy worked for one condition doesn't necessarily mean it will work for others. He remained ambivalent about the research community's renewed zeal.
   "Whether again this is all justified or not," Fox said, "is all in the eyes of the beholder."