Late in 1990 the first trial gene therapy successfully transferred a gene into the cells of a 4-year-old girl suffering with severe combined immunodeficiency. The new gene produced an enzyme, adenosine deaminase, that dramatically improved her immune system’s function.
Since that pioneering event and especially now that the human genome has been finally sequenced, gene therapy has grown in scope – and notoriety. The escalating use of, and interest in, genes as disease indicators and as therapeutics seems inevitable. It is generally accepted that, at some point in the future, genetic diseases and possibly some degenerative or infectious conditions could be treated or cured by replacing missing, defective or damaged DNA in human cells.
Tales of trials
But for all the potential benefits and breakthroughs, the last few years have not fared gene therapy well. Questions of safety, accompanied by vitriolic press coverage, have raised the specter of its public rejection.
The use of virus vectors, particularly, has posed a number of questions about the safety of the technique. The primary concern is that viruses might mutate back into pathogenic forms, either spontaneously or aided by other viruses in the patient’s cells. Some scientists believe that the adenovirus vector used to transfer genes into 18-year-old Jesse Gelsinger was the cause of his much publicized death in 1999 during a gene therapy trial at the University of Pennsylvania.
Of course, the media likes a good story. Since Mr Gelsinger’s death, gene therapy has been in the spotlight. The discovery that a large number of adverse events, including deaths, in other trials had not been immediately reported to the relevant authorities also received extensive press coverage. Hundreds of gene therapy experiments failed stated one typical headline.
The media gave the Gelsinger death story some legs which in turn led to a bout of bad press that was not justified, says Dr James Merritt, Vice President of Clinical Affairs at Introgen. Introgen’s INGN 201 gene therapy candidate, which also uses an adenovirus vector, is the most advanced tumor suppression gene therapy currently in development, undergoing Phase III trials for the treatment of head and neck cancer. This trial has so far progressed smoothly and without the need for modifications to clinical study protocol, Dr Merritt notes.
The adeno affair
The adenovirus is the most researched and popular gene transfer vector. According to Dr Kathryn Zoon of the FDA, the Center for Biologicals Evaluation and Research received 55 IND applications for new gene therapies in 1999, of which 17 were for therapies using adenovirus vectors. The number of adenovirus vector trials has been rising steadily since 1993, when the first IND was submitted.
In a presentation given to of the Recombinant DNA Advisory Committee, Dr Zoon concluded that any doubts about the safety of this type of vector could have a significant effect on a large number of research programs, both currently in clinical trials and still in preclinical development.
Dr Merritt does not believe that the adenovirus is dangerous. But he does acknowledge that simply putting it under suspicion, along with the media hype, could jeopardize the future development of gene therapies. He therefore welcomes the swift action by the FDA to tighten its gene therapy regulation.
The FDA and the NIH, in March 2000, announced two initiatives designed to better ensure the safety of patients who take part in gene therapy trials. The FDA’s plan requires sponsors of gene therapy trials to routinely submit their monitoring plans to the agency. The FDA will provide surveillance and inspections to trial sites, when deemed necessary, to assess whether monitoring plans are being followed. This is a good thing, says Dr Merritt. We have to accept that gene therapy is different and the only way to comfort the public is to provide a great deal of disclosure in order to allay concern.
Promising trial result data for gene therapies could have a positive impact on both physician and patient opinion, driving strong uptake for gene therapies, says Jane Richardson, Healthcare Analyst at Datamonitor. A lot of this is about access to measured, unbiased information – as the public becomes better informed about gene therapies, and more general topics such as the Human Genome Project, then we may well see strong ‘pull’ for gene therapies.
Communication is key
Disclosure and transparency are increasingly important in medical research; companies must allow for adequate communication as well as R&D resources. In the US and increasingly in Europe, the general public is well informed about scientific and medical issues, but extremely vulnerable to forming unbalanced opinions, especially if bombarded by negative reports.
Resistance has not been an issue with those undergoing the clinical trials – they have been supporting the work. But the public, in general, do not trust their governments anymore. So companies may want to consider some form of public education program in order to increase confidence, Dr Merritt advises. Indeed, a number of biotech companies in the US are starting to set up ethical boards in an attempt to manage the interface between ground-breaking research and the public.
The field has been criticized for too much hype and too few successes, states W. French Anderson of the University of Southern California, commenting in the August 2000 issue of Nature Medicine. Companies involved in gene therapy must not blame the media for their seemingly sensational and skeptical attitudes. Nor must they blame the public for what it reads. Instead they must identify potentially controversial issues associated with these novel therapies early in the development stage in order to minimize the effects of inevitable negative publicity. Only with frank, open disclosure and discussion can French Anderson be vindicated: Gene therapy seems to be turning the corner after a very bad year.
