Arrested Development
Authors: Kevin Davies
Journal: Molecular Therapy (2000)

In the summer of 1968, William French Anderson, a researcher at the National Institutes of Health, submitted a somewhat speculative manuscript to The New England Journal of Medicine titled “Current Potential for Modification of Genetic Defects.” Anderson's article laid out the challenges ahead to make human gene therapy a reality, drawing in part on themes outlined by his boss, the soonto-be Nobel laureate Marshall Nirenberg, in an editorial in Science 12 months earlier. One member of the journal's editorial board praised Anderson's views as “a worthwhile adventure in pure speculation,” but the article was duly rejected. Nevertheless, Anderson's controversial views did go on record that year—a newspaper reported a speech he delivered at a medical society meeting. Two decades later, as he nervously prepared to begin the first official gene therapy trial for a genetic disease, Anderson dug out his prized clipping and pinned it to the lab bulletin board. While many of his co-workers assumed it was simply more adulatory press for the “father of gene therapy,” Anderson's secretary chided him: “You mean, you haven't had a new idea in 20 years?” The goal of transforming gene therapy from fanciful theory into clinical reality truly got off the ground on September 14, 1990, when R. Michael Blaese, Ken Culver, and Anderson began treating Ashanthi DeSilva, a brave 4-year-old girl suffering from adenosine deaminase deficiency. Although skeptics muttered that there were more doctors working on the disease than there were patients, gene therapy was soon being applied to dozens of genetic disorders and cancers. The “gene-as-the-drug” became the unofficial campaign slogan of the new molecular medicine era as hundreds of patients enrolled in dozens of clinical trials in the United States and Europe. Cystic fibrosis (CF) was a particularly attractive target because of the amenability of the dysfunctional epithelial cells lining the airways to aerosols containing the healthy CF gene. Many more elaborate procedures were conceived, however, perhaps none more so than the ex vivo protocol developed by Jim Wilson and colleagues to treat five patients with homozygous familial hypercholesterolemia (FH). The procedure involved resecting a portion of the liver, administering retroviral vectors containing the normal low-density lipoprotein receptor gene to the cultured hepatocytes, and reinfusing the corrected cells directly to the liver. The early results, published in Nature Genetics in April 1994, were so seductive that the authors dared to declare the experiment “successful” in the title of the paper. But that same year, the first warning signs appeared. Ron Crystal's phase I trial for CF using adenoviral vectors hit a serious snag when the patient receiving the highest dose developed an inflammatory response that necessitated his removal from the trial. Blaese and Culver had to keep their first two immunodeficient patients on PEGADA to ensure adequate amounts of the ADA enzyme. And 18 months after their first report, despite seeing lowered levels of LDL cholesterol in three patients, Wilson's group had little option but to recommend a moratorium on the broader use of their ex vivo FH protocol until the levels of gene transfer could be reproducibly enhanced. The dual disappointments of limited viral uptake and transient gene expression, noted by a growing band of investigators, were underscored by the 1995 report of a specially convened NIH panel, cochaired by Stuart Orkin and Arno Motulsky. The influential report urged researchers to tone down the “hype” and refocus on the technical problems. Those recommendations have been heeded so diligently that, as Martin Bobrow succinctly observed in The Lancet recently, the field of gene therapy is now in “a phase of sober consolidation after an exuberant youth.” Publication of The Development of Human Gene Therapy comes at an opportune time, given the upheavals that the gene therapy field has experienced over the past few years. The book is edited by the highly experienced Ted Friedmann, who not only was one of the first advocates of gene therapy but also has become an astute chronicler of the field's recent ups and downs. In his introductory comments, Friedmann wryly reflects on the earlier “period of overexpectation and overstatement” that has dogged his field. Ironically, in the very next sentence, Friedmann hails the conceptual success of gene therapy as nothing short of “phenomenal … a truly epochal new direction for medicine!” (Then again, if the editor can't get excited about a book, who can?) It is a rare and uncharacteristic lapse, however. Friedmann has succeeded in putting together a meticulous and timely book that admirably captures the gene therapy roller-coaster ride over the past decade. The first third of the book offers a comprehensive account of the most commonly employed viral vectors, with solid chapters from Verma, Wilson, Samulski, Glorioso, and colleagues outlining the relative merits of lentiviruses, adenoviruses, adeno-associated viruses, and herpesviruses. There is also an intriguing chapter from Jolly on the potential uses of emerging viral vectors. The remainder of the book is largely divided into chapters focusing on specific therapeutic sites (hematopoietic cells, nervous system) and strategies (anti-angiogenesis, “suicide” genes). It concludes with a curious chapter from Wivel and Anderson on the history of the Recombinant DNA Advisory Committee and Juengst and Walters' useful consideration of ethical issues, including the thorny issue of genetic enhancement. As a treatise on the current state of the field, with particular emphasis on the design and applications of viral vectors, this handsomely produced book could hardly be bettered. The cast of authors is an imposing one; however, it should be noted that the line-up is heavily skewed in favor of the West Coast—almost one-third of the contributors are from Friedmann's base of La Jolla, California. More important, however, only 2 of 25 chapters are contributed from researchers in Europe—hardly reflective of the important contributions that laboratories in Italy, France, Britain, and elsewhere have made over the past 10 years. Some readers might also find the scope of the book somewhat limited. With so much attention focused on relatively conventional modes of gene therapy, potentially exciting methods of gene modulation, such as ribozymes, antisense molecules, and human artificial chromosomes, are almost completely neglected. There is one notable exception to this pattern, however, in the form of a chapter from Eric Kmiec, Clifford Steer, and colleagues on chimeraplasty. This potentially exciting technique uses DNA/RNA hybrids to first target the errant gene and then trigger the body's own DNA mismatch repair system to correct the mutation—what Friedmann affirms as “one of the Holy Grails of human gene therapy.” Although rather disjointed, the chapter outlines the design parameters of the chimeric oligonucleotides before describing recent encouraging results correcting the Gunn rat model for Crigler–Najjar syndrome (see also the recent paper from Steer and co-workers in Proc. Natl. Acad. Sci. USA 96:10349–10345, 1999). Crigler–Najjar syndrome is a rare liver disorder caused by the body's inability to metabolize bilirubin. Affected children must endure hours of phototherapy under blue fluorescent lights every day to help break down the toxic pigment. As the efficiency of the procedure inevitably wanes over time, a liver transplant is the last resort. Later this year, Kimeragen, a biotech company based in Newtown, Pennsylvania, hopes to begin the first clinical trial using chimeraplasty on three children from the Pennsylvania Mennonite community in which the incidence of the disease is relatively high. Friedmann's stated goal in this book was to highlight the recent developments in the history and technology of gene therapy, and in that he has succeeded. Looking ahead, he believes that the now firmly established “concept for a completely new paradigm for the control of human disease … is about to prove itself clinically.” Although there is certainly cause for optimism, the risks of pushing ahead too quickly are more apparent than ever. On September 17, 1999, Jesse Gelsinger, an 18-yearold boy who suffered from ornithine transcarbamylase deficiency, died tragically of multiple organ failure after volunteering to take part in a gene therapy trial at the University of Pennsylvania. Gelsinger's death marks (almost to the day) the ninth anniversary of Anderson's first gene therapy trial. Ironically, just 1 week after the tragedy, Science published a review by Anderson and Esmail Zanjani on the potential of a new form of transient gene therapy—in utero gene therapy (IUGT). According to the authors, “It is not clear which genetic diseases would be the best initial candidates for IUGT. At a minimum, the disease should be life-threatening or cause significant disability either during gestation or in early infancy….” One would think that, after all the difficulties that gene therapy has endured of late, researchers would think twice before scouting for a convenient disease to test some trendy new therapy, instead of focusing on the optimal therapeutic approach for a given disorder. It is hoped that Friedmann's book will serve as a fitting reminder of the daunting problems ahead before the development of gene therapy can go full term.