“As Aristotle and every serious theorist of human nature has understood, human beings are by nature cultural animals…”
It is interesting to paraphrase F. Fukuyama: the individual is born of a genetic union and evolution has developed the intelligence, and social and cultural capabilities of the species. Genetics is, however, the cause of many diseases. The inevitability, whether it be predictable or purely random, of genetic diseases is now being overturned by gene therapy. This therapy raises questions especially as we have moved from tragic impotence to direct intervention in just a few decades. The transition has been fast and brutal, the first results are in and there are new risks.
Correct or rewrite
Gene therapy is an experimental technique that uses genes to treat or prevent a disease. This incredible odyssey began with the discovery of DNA by Miescher in 1869, the double helix by Watson and Crick in 1953, then continued with the sequencing of the human genome in February 2001, and recently the discovery of CRISPR. Indeed, without excessive simplification, it can be said that living organisms have perfected their genome over the course of their evolution. Consequently, there are often several genes for the same function and conversely several functions for the same gene.
Many techniques can be used to modify the genetic abnormality that causes a disease. It is possible to decrease or switch off the expression of a gene without altering the genetic capital of the individual. To approach it from another angle, you can increase the activity of a gene that supplements the deficient gene. Or you can modify the genetic capital by using a vector that will insert a gene into the genome of cells of various tissues — most often a virus. Finally, it has become possible to rewrite the genetic code, thanks to CRISPR-Cas9, a system derived from bacteria, which suppresses or replaces one gene with another on the DNA at a specific location.
Globalisation and the three global zones of human gene therapy
In Europe there is a myriad of legislation on gene therapy. 24 European countries, including France, prohibit any intervention on the germline (the cells that combine with those of the other sex to create an embryo). The Council of Europe is calling for a ban on genetic engineering for the germline or to modify the genome of future generations. However, the United Kingdom has recently authorised a modification of the germline via mitochondrial donation.
The United States has a complex regulatory system that makes it very difficult to modify the germline, but does not prohibit it. There are also funding restrictions on embryo research that could have a major effect on the underlying basic science necessary to reach the regulatory approval stage.
And then the third world is simply not regulated. Some countries have not considered this possibility, while others have only ambiguous recommendations or regulations (China, India, Russia, Japan…).
Looking at the clinical trials reported up to 2015, the United States undertook 66.81% of gene therapy clinical trials; all other countries have modest percentages: 9.45% in the United Kingdom; 3.95% in Germany; and about 2% each in Switzerland, France, China and Japan.
The risks of gene therapy
Like any effective therapy, gene therapy presents risks.
The case of Jesse Gelsinger is an example of this; at the age of 18, he was controlling his genetic metabolic disorder with diet and medication. He entered a clinical trial at the University of Pennsylvania in 1999 to test a virus vector of a normal gene for the deficient enzyme. The result was disastrous. Gelsinger suffered a chain reaction that the tests had not predicted – jaundice, a blood clotting disorder, kidney failure, lung failure and brain death. Several mistakes were made when he was included in the trial, but his case remains a high-profile warning of these new risks.
Another example is Spinal Muscular Atrophy (SMA), which is one of the most deadly genetic diseases in infants. The motor neuron degenerates making muscular function impossible and consequently affecting movement, posture and breathing. The advent of Spinraza changed the prognosis of this disease by increasing the production of the protein necessary for the survival of motor neurons without altering the diseased gene. At the same time, AveXis applied to the FDA for approval of a new way of treating SMA, this time using gene therapy. The treatment, Zolgensma, raises questions. The clinical trials of Zolgensma focused on very small groups for short periods of time. The phase 1 trial of Avexis was conducted with only 15 infants; the phase 3 trial increased it by 20 infants. This technique entails two types of risks: the introduction of new genetic material and the vector virus. The replacement of one gene by another from the outside could affect functions other than those for which the gene is replaced, as demonstrated by the tragic experience of Gelsinger — a hypothesis that should alert regulators.
Calculating the risks
The various protagonists of gene therapy agree on one fact: the evidence for efficacy in the trials is strong because the results are quick and easy to measure, but the long-term consequences, individual or at species level, are unprecedented. When a gene therapy, whatever it is, gives children a chance of survival, the equation is simple. When it comes to non-fatal or already treatable genetic conditions, the benefit and risk assessment is difficult. Is it better to continue gene therapy that does not replace the gene but improves the patient’s condition, or is it reasonable to choose a more radical therapy with harder to identify risks? In this debate transparency and peer-reviewed scientific publications are paramount. But patients and especially parents, in the case of children, seem to me to have an essential role to play. Some gene therapies will be failures, others will survive. It is rational that patients should be protected as much as possible, but the most serious cases should be able to access innovative treatments sooner rather than later.
Authorisations for gene therapy are multiplying, which is why the classical pharmaco-economic model has to take the unique nature of this therapy into account. It’s about slowing down clinical use whenever there is major uncertainty, and being even more efficient at the point where benefit and risk are in the balance.
 “Francis Fukuyama, “Biotechnology and the Threat of a Posthuman Future.” The Chronicle of Higher Education (22 March 2002): B7 — B10.”
This post is also available in: FR (FR)