EUROSCOPE. Gene therapy makes a slow comeback

In late November, Reuters reported a milestone in medical history: a gene therapy drug could go on sale in Germany next year, after winning the approval of European regulators two years ago. The drug, Glybera, by a Dutch firm called UniQure — currently being scrutinised by Germany’s federal joint committee — would be the first commercial use of gene therapy in the Western world (China has had a gene therapy drug for a specific form of cancer in the market since 2004). This marks a potential turning point in an area of medicine that has been the subject of highs and lows over more than two decades of clinical trials.

Gene therapy — which can involve a number of things, including replacing a malfunctioning gene or introducing a new gene with the ability to fight a disease — has been in conceptual development for far longer. Its origins could be said to go back as early as the 1920s, well before the discovery of the structure of DNA, when a British scientist, Frederick Griffith, put forward what he described as the “transforming principle”; he successfully converted a non-virulent strain of bacteria into a virulent one, after injecting mice with both.

From the late 1960s, when the concept of gene therapy began to involve, it took several decades for the first clinical trial to take place in 1990. A young girl in the US with a genetic defect that had left her with a severely weakened immune system was successfully injected with her own white blood cells containing a corrected form of the malfunctioning gene.

However, the boost gene therapy got following that first successful trial was soon tarnished, in the view of the public, by a tragedy in 1999; an 18-year-old American boy, who had a mild version of a liver condition, which meant his body couldn’t process ammonia, died during a gene therapy treatment. This was after a massive response by his immune system to the vector — or carrier — used to introduce the corrected gene.

The episode raised a number of issues — including that of informed consent of those participating in clinical trials as well as the fact that identifying and correcting a defective gene was far from the only challenge facing gene therapy. Selecting the appropriate vector was also vital and not without risks.

Despite predictions that gene therapy would be lastingly damaged by the tragedy, research and trials continued — with many promising results for a range of conditions ranging from immune system conditions to cancer, cystic fibrosis, Parkinson’s disease and hemophilia.

The renewed confidence in gene therapy is highlighted by the fact that the world’s largest pharmaceutical companies have also entered the market (earlier this week, Pfizer announced collaboration with Spark Therapeutics, a Philadelphia based company on the development of a hemophilia B treatment).

Over 1,700 approved gene therapy trials have taken place in the past two decades, estimated an article on the history of gene therapy in Gene magazine last year — with many successes and a few hits. Among the latter were trials conducted in France in 2001 on Severe Combined Immunodeficiency, a condition where the immune system is so crippled that in one case it required a boy to live in a germ-free bubble. Several infants involved in the trial subsequently developed leukemia, though other clinical trials for gene therapy since have been successful.

There have been some understandable public concerns about gene therapy and its impact — on the one hand it offers that tantalising potential of curing some of the most lethal conditions while on the other, tampering with genetic makeup is something that has long conjured up fears in the public imagination of genetic engineering and exacerbating discrimination against those with disabilities and disease.

However, it is important to note that at this stage clinical trials and gene therapy itself are limited to work on somatic cells — and not germ cells — meaning that genetic changes won’t be passed on to future generations.

There are other major questions, of course — the few tragedies have highlighted the ongoing challenges facing researchers, particularly around a suitable and safe vector. The complexity of the procedures involved (and their risks) also raises significant questions about what constitutes informed consent, and the extent to which participants or their families could ever fully comprehend the risks involved, particularly when situations are very desperate (as is often the case with gene therapy, which is used just in cases where there are no alternative treatments).

Another focal point of concern has been cost — treatments at the moment tend to be very costly: the new drug Glybera is said to be going on sale for €53,000 a phial or €1.1 million for a treatment according to Reuters (a small discount would be applied if in Germany). It estimates only around 200 people across Europe would be eligible.

However, cost isn’t something that should stand in the way of gene therapy — while Glybera would treat a relatively rare condition, there are many therapies for far more common conditions in the works, for which the costs could be more quickly recouped, enabling it to be available at lower price points.

Another factor that cannot be discounted is the huge saving to individuals and healthcare systems if a gene therapy is successful, particularly compared to the ongoing treatment of a condition spread across a person’s lifetime.

Aside from vastly improving the lives of those with debilitating conditions it could also save people from horrific choices — in some cases parents who discover a significant anomaly in the womb might not have to face the terrible choice of keeping a foetus and watching a child suffer, and termination.

As gene therapy and our understanding of genetics gets more advanced, the ethical questions will undoubtedly become more complex, too. In particular, the ever-so-fine line between a malfunctioning gene or defect and an undesirable trait will become even finer.

This is particularly true as gene therapy increasingly moves beyond correcting a defective gene to investing cells with a gene with a power that it wouldn’t ordinarily have (say to combat cancer).

But these are not reasons to reject it — gene therapy and the move towards commercialisation is another example of what patient, meticulous research in a carefully regulated and ethically vetted field can achieve over the decades.