Gene therapy finally becomes a reality

The promises made about gene therapy in the 1990s gave way to caution and scepticism due to repeated failures and the occurrence of serious adverse events. But researchers were able to learn from these setbacks, and are now developing effective and safe protocols for managing a variety of diseases. These treatments have yet to appear on the market in the form of drugs enabling large numbers of patients to be treated.

Twenty-two years: this is how long it has taken to go from the first gene therapy trial in humans to approval of a drug for the European market. This tells us how difficult the road has been!

To better understand this long journey, one needs to go back to the 1950s: at this time, scientists are already raising the idea of altering the genetic make-up of human cells to alleviate diseases. However, technical capabilities and knowledge of the genome are still too limited to allow the transition from concept to practical application. But then, with the development of biotechnologies in the following decades, it finally becomes possible to undertake DNA manipulations of ever-increasing complexity. Scientists learn more about the function of genes and their roles in diseases. These years also enable them to find systems (known as vectors) for transferring therapeutic genes into cells, particularly those based on the use of viruses.

© Inserm, M. Depardieu

Together, these advances enable American researcher Steven Rosenberg to attempt a first gene therapy trial in humans in 1990, a trial based on injecting genetically modified T lymphocytes into patients with cancer. The start of a big adventure.

Soon, there is a proliferation of trials for a large number of indications: cancers, monogenic diseases (especially immunological and haematological), cardiovascular diseases, etc. “Important advances in genetics and human biology, such as the sequencing of the human genome and the ability to isolate haematopoetic stem cells, helped to generate the excitement that characterised this period,” recalls Anne Galy, Research Director at Généthon, Evry (Inserm Unit 951). The field of application of this treatment strategy and the expected effects then appear so spectacular that this approach leads to quite a boom.... which unfortunately collapses rather quickly—the results just do not come.


Initial success in the 2000s

Following an attempt by a Milanese team to carry out the first transplant of genetically modified stem cells in immunodeficient patients in 1995, it is only in the 2000s that the first reproducible therapeutic successes will be seen in children with severe combined inmunodeficiencies (SCID X1 and ADA-SCID).

The life expectancy of these patients is extremely limited—because their bodies do not produce T lymphocytes, they are unable to fight infection. Earlier work enabled the genes responsible for these disorders to be discovered, and helped improve not only the vectors for delivering functional copies of these genes, but also the clinical protocols for delivery. A first trial is carried out in Paris by the teams of Salima Hacein-Bey Abina, Marina Cavazzana and Alain Fischer (Inserm Unit 768, Necker Hospital), and others in Milan and London: physicians remove immune system stem cells from the bone marrow of the children, modify them genetically with the help of a vector carrying a copy of the therapeutic gene, and then reinject them into the patients’ bloodstream.

© Inserm, M. Depardieu

Although eight of the nine "bubble children” treated in France are alive and enjoying a normal education more than ten years after the pioneering trial, the success of this world first is marred by the occurrence of leukaemia in several of the children treated. The vector used to carry the “drug” gene, a retrovirus, triggered the expression of tumour genes in their bodies. In addition to these serious adverse effects, there has been a death in a patient given gene therapy for a rare liver disease (ornithine transcarbamylase deficiency). This death is also attributed to the vector employed, an adenovirus showing uncontrolled activity in various organs. “These events cast a chill. And although they do not call into question the interest of gene therapy for treating patients, they give fresh impetus to the search for much safer vectors,” reflects Anne Galy.

Vectors, the key to success

In fact, researchers are going back to the bench to study in detail the functioning of viruses that can be used as vectors, and to find the most suitable ones. The technical advances made during this phase will then enable modification of any part of the genetic make-up of these viruses: they can thus be made as harmless as possible, and more silent in relation to the host immune system, and equipped with more specific envelopes. New tools are thus being created in virology laboratories, at Institut Pasteur and Inserm (a team led by François-Loïc Cosset, Inserm Unit 1111).

Thus there are now non-replicating, integrating or non-integrating vectors, and viral or non-viral vectors, suited to a variety of indications. Integrating vectors such as retroviruses and lentiviruses allow the insertion of a therapeutic gene in the host DNA, thus guaranteeing its persistence in the daughter cells after cell division. Non-integrating vectors (adenoviruses, AAV), on the other hand, help to avoid random integration of the gene into the host DNA, but they disappear when the cell dies. They are therefore suitable for the modification of resting cells such as neurons or retinal cells. Other trials are even attempted using naked DNA, directly injected into the body.

© Inserm, P. Latron

“This variety of potential approaches enabled a definite improvement in the results of gene therapy from 2007 on. Several trials conducted around the world since that time have brought major benefits to patients with a variety of genetic disorders, usually disorders that are rare and extremely disabling.” Such is the case for Leber’s congenital amaurosis, a type of visual deterioration leading to blindness; leucodystrophy, a group of neurodegenerative diseases; several types of serious immunodeficiencies, and even haemophilia B. Trials conducted from 2007 to 2013 show that gene transfer therapy halts the advance of these progressive diseases.

French teams, including teams attached to Inserm, have often been pioneers in this area. A Clinical Investigation Centre for Biotherapy has been established at Necker Hospital (Paris). By collaborating with this structure, Nathalie Cartier and Patrick Aubourg (Inserm Unit 986, Kremlin-Bicêtre) have shown for the first time the possibility of halting the progression of a neurodegenerative disease in some patients, namely adrenoleukodystrophy, using gene therapy. In addition, thanks to a treatment perfected by the teams of Philippe Leboulch (Inserm Unit 962/CEA, Fontenay-aux-Roses) and at Clinical Investigation Centre 1416 (Necker, Paris) a patient with beta thalassaemia who used to undergo blood transfusions weekly has not needed any for the last five years.

In the cancer field, results are still tenuous, but research is very active due the size of the population involved and the resulting interest of industries. American teams have already shown the efficacy of modified T lymphocytes in the treatment of incurable leukaemias and metastatic melanomas. These genetically modified cells recognise and destroy malignant cells, bringing new hope of recovery to patients.


From trial to drug

© Inserm/Aubourg, Patrick

At the moment, over 1,800 gene therapy trials are underway, 65% in oncology, 10% in the cardiovascular area, 10% for monogenic diseases (where the results are often the most spectacular), and the remainder for other widely variable indications such as infectious diseases (tetanus, AIDS), neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, etc.) or ophthalmology (retinitis pigmentosa, glaucoma, age-related macular degeneration, etc.). Despite this profusion, only two gene therapy drugs are currently available. The first of these (Gencidine), for the treatment of head and neck tumours, has been marketed in China since 2004. The second (Glybera) has been available in Europe since the end of 2012, to treat a hereditary lipoprotein lipase deficiency.

Gene therapy can therefore overcome regulatory and industrial obstacles to provide new innovative drugs! The European Commission has recently allocated millions of Euro to this sector (Horizon 2020 Health Programme). And although the industrial and biotechnological landscape remains relatively underdeveloped in France, metropolitan France has acquired several useful instruments of scientific, organisational and ethical relevance, including the French Society of Cell and Gene Therapy (SFTCG). France is thus becoming part of an international dynamic and effort aimed at seeing these therapies emerge.

©Inserm/Guénet, François

“We are entering a new phase, where the challenge is to go beyond proof of principle, and transform the trial,” admits Anne Galy. Thus, France is now home to a non-profit pharmaceutical body devoted to producing gene therapy drugs, Généthon BioProd (Evry). “We work to make gene therapy available to patients, with standardised procedures, especially for the production of viral vectors, and multi-centre clinical development for rare diseases,” explains the researcher. The standardisation of viral gene therapy drugs is a particularly central point in the work conducted by Philippe Moullier (Inserm Unit 1089, Nantes).This is a real challenge, since there are few registered drugs for innovative therapies, and therefore few examples to follow in leading the way for the pharmaceutical development of this type of drug.” One of the next challenges for gene therapy is therefore that of the regulatory and industrial constraints. A challenge that proves that the technique has now reached maturity.


Further information:
To find out more about gene therapy, its different techniques and its achievements, see our information pack
Read also:
- The biography of Alain Fischer and the portrait of Marina Cavazzana and feature on Génopole d’Evry on the Histoire de l’Inserm (History of Inserm) website
- Médecine du futur: comment se feront les greffes dans 50 ans? (Medicine in the future: how will transplants be done 50 years from now? by Marina Cavazzana Calvo, on the Huffington Post website

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