FEATURE ARTICLE
Gene Therapy
Investigators have been searching for ways to add corrective genes to cells harboring defective genes. A better strategy might be to correct the defects
Eric Kmiec
Clinical Trials
In the clinic, gene therapy has enjoyed few successes and many failures. But within these failures lessons have been learned. In some cases, scientific rigor was sacrificed in order to bow to financial pressures to rush gene therapy into clinical trials. In other cases, the goals were too lofty, and the expectations were unrealistically high.
Limited success in animal models all too often leads directly to clinical trials. But a mouse is not a small human with four legs, and the positive results in mice do not necessarily portend a positive outcome in people.
Even at their best, the results of trials with human gene therapy are equivocal. For example, let's consider a gene therapy trial to treat familial hypercholesterolemia (FH). People with this inherited condition have dangerously high blood levels of cholesterol, in spite of their body weight or diet. The condition results from a defective gene that encodes a receptor found on the membranes of liver cells specific for low- density lipoprotein (LDL), what many call "bad cholesterol." Normally LDL enters liver cells via this receptor, after which the liver clears the body of LDL. But people with FH have too few functioning receptor molecules and cannot remove LDL from their blood. As a result, blood serum levels of LDL are too high in people with this condition, and many FH patients develop coronary artery disease.
In animal models, investigators demonstrated some success when corrective copies of the receptor gene were transferred into liver cells via a retroviral vector. Blood levels of LDL in the treated animals were significantly reduced and remained so for over six months. These experiments were done carefully, in several animal models and with rigorous controls. All the models produced similar, encouraging results. Based on these results and the fact that patients with this disease have few good treatment alternatives, a human gene-therapy trial for FH was approved.
The experience of one 28-year-old woman represents one of the better outcomes of this clinical trial. The patient lacked any detectable functioning LDL receptor because she lacked the gene for it. At the start of the trial, she had 482 milligrams of LDL in each deciliter (mg/dl) of blood, well over twice the normal level of 160 to 210 mg/dl. Her liver cells were then treated with a retroviral vector containing the LDL-receptor gene. Within a few days, her serum cholesterol dropped by 180 mg/dl to about 300 mg/dl. With additional cholesterol-lowering drugs, her LDL blood levels stabilized at around 356 mg/dl and remained there for about two and a half years. These levels, although lower than they were originally, are still higher than they ought to be.
Herein lies the quandary of human gene therapy: It "sort of" works. This trial demonstrated the feasibility and safety of gene therapy for treating FH. But the results hardly constitute a ringing endorsement for this approach as the definitive therapy. In fact, it would be difficult to name a clinical trial to date that does, a situation that prompted review of the approval process for clinical trials.
Decisions on clinical applications of gene-therapy approaches fall under the auspices of the federal government. Originally, the Recombinant DNA Advisory Committee (RAC) was charged with the duty of making suggestions for approval or disapproval to the director of the National Institutes of Health (NIH). The RAC was empowered to consider somatic gene-therapy protocols only; that is, the RAC considered protocols that did not involve the so-called germ line cells, such as eggs and sperm. In addition to submitting protocols to the RAC, investigators submitted new gene-therapy protocols to the Food and Drug Administration for Investigational New Drug (IND) approval. More than 100 protocols have been approved by the RAC to date.
In 1996, Dr. Harold Varmus, the director of the NIH, amended the procedure because of rising concerns over the rate of failures among approved clinical trial protocols. The fallout of this effort has been an enhanced oversight role for the NIH through three mechanisms. First, the office of Recombinant DNA Activities Advisory Committee (OAC) evaluates protocols. Next, gene-therapy conferences are held to promote public discussion of scientific merit and ethical aspects of proposals for human clinical trials. Finally, the public is informed about the progress of ongoing trials. The gene- therapy policy conferences have already helped to improve the oversight of the approval process. They also encourage continued review of the ethical aspects of each trial. Although in most cases, increasing government involvement is viewed as an invasion into scientific enterprises, gene therapy will stand to benefit by such heightened control.
In spite of the increased government scrutiny of previous gene-therapy protocols, the pressures to bring gene therapy to the clinic do not seem to abate. This is in part because of the formation of ventures aimed at commercializing products and techniques. Financial pressures and constraints often force biotechnology companies to forgo basic research in favor of application-driven development. Unfortunately, this means that promising but technically difficult approaches may never be adequately developed for lack of research funding.
Increases in public funds for research may well be part of the answer to improving the technology, since it is the basic level of investigation that will in the end broaden understanding of gene-therapy techniques and increase the probability of clinical success. What is clearly needed is the development of molecular analysis and rigorous testing at the level of basic science, with an eye towards application in clinically appropriate targets. Only then will gene therapy have a hope of fulfilling its promise.
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