Gene therapy is back

In 1999, 18-year-old Jesse Gelsinger died due to a severe immune response triggered by genetically modified viruses injected into his body to cure an inherited genetic defect. This incident rocked the field like nothing else and has hampered investigation of gene therapy for many years.

Currently, the come back of this promising therapy option seems very likely due to novel approaches regarding safety and efficiency of the gene carrying transport vehicles.

For many years, Jörn Aldag has worked meticulously on Glybera. Four attempts were needed to convince the European Medicines Agency (EMA) regarding the safety and efficacy of the novel gene therapy. In 2012, Aldag made it and got green light from the EMA to market the very first gene therapy in Europe. Since November 2014, Glybera – which is supposed to be a cure for the rare metabolic defect lipoprotein lipase deficiency – has been available on the German market. Although the incredible price of more than one million Euro, German health insurances agreed to reimburse the costs for Glybera. Aldag’s success arouses huge interest and might have a dynamic effect on the whole industry.

From the very beginning of genetics, scientist around the globe have been dreaming of replacing mutated genetic information against normal genes to cure hereditary defects and diseases, almost instantaneously. But, smuggling a fully functional gene into a cell requires a secure transport vehicle. Viruses – for million years experts in capturing human cells – are considered as the perfect gene shuttles. However, the very tiny gene carriers are not without danger: they are noticed as foreign stuctures in the human body, and, at the same time, are not very selective when integrating their genetic information into the host genome.


How dangerous this can be shows the story of Jesse Gelsinger. Gelsinger suffered from ornithine transcarbamylase deficiency (OTCD), an inherited metabolic disorder that prevents the body from breaking down ammonia. After the injection of trillion modified adeno viruses, Gelsinger suffered from an anaphylactic shock and died some days ago. He was only 18 years old. His dead led to the provisional cancellation of gene therapies around the world. But the immune system is not the only pitfall, the random incorporation of the virus genome into the host genome which can trigger fatal insertion mutations is another severe problem. In five children suffering from the rare „severe combined immune deficiency X1“ (SCID-X1) such a random insertion mutation led to leukaemia – one child died.

Urgent demand for new viruses
After these serious incidents, it became clear that only safe transport vehicles could rescue gene therapy. And rescue came finally from the rarely pathogenic adeno associated viruses (AAV). Most people infect themselves some day in their life with AAV without getting sick. As the immune system knows the invader, the risk of an excessive immune response is greatly decreased. Additionally, AVV exist of different serotypes which have preferences for specific cell types. As each serotype only infects a particular cell type, less viruses will be needed for a successful effect thus leading to fewer side effects.

Turning point
In 2008, the Children’s Hospital in Philadelphia marked the beginning of the eagerly awaited turning point in gene therapy. Children with „Leber Congenital Amaurosis“ (LCA) – a hereditary disease leading to blindness – were treated successfully using an AAV gene therapy. AAV, carrying a healthy – non-mutated – variant of the gene RPE65, were injected directly into the retina of the affected children. The gene therapy was successful. Study leaders Katherine High and Jean Bennet established in 2013 Spark Therapeutics and gathered 83 million USD venture capital. In January 2015, the company went public and yielded another 160 million USD. Phase 3 study data from the novel gene therapy are awaited at the end of this year, market approval is targeted for 2016. Spark’s next goal, a gene therapy against hemophilia, is already planned and has flushed the pharma industry. Pfizer not only heard the warning shot, but took it seriously as well. Almost 300 million USD injected the pharma giant into Spark’s experimental gene therapy against hemophilia which shall be tested in humans still within this year.

A gene therapy against parkinson disease is the dream of another US-start-up company – Voyager Therapeutics. The modified gene shuttle carries a protein supposed to boost the production of dopamin – the messenger substance missing in parkinson patients – will be directly injected into the brain. Whether this concept could really be a cure for parkinson disease remains to be seen. But french pharma company Sanofi seems to be confident, in February 2015 they signed an agreement with Voyager and paid 845 million USD to participate in the development of this novel gene therapy concept.

Aiming on common diseases
However, something is different in the new gene therapeutic approaches – the focus is not only on orphan diseases but on common diseases like cancer or coronary heart disease as well. Both already part of the major health problems in the western world. A glance inside the „The Journal of Gene Medicine“ shows: 64.2 % of all gene therapy studies are aiming on the treatment of cancer, 7.8 % are testing therapies against cardiovascular diseases. A nose ahead are American scientists. From 2,100 gene therapy studies 63 % involve US-researchers. The second place goes with 9.6 % to Great Britain and Germany follows with 3.9 % on the third place (

How a gene therapeutic approach against cancer might look like, shows the latest project of the University of Pennsylvania. The scientists use synthetic chimeric antigen receptors (CAR) which are transferred into special immune cells. These receptors recognize specific surface structures located on cancer cells and bind to them. The subsequent activation of the immune system is supposed to initiate the destruction of discovered cancer cells. This novel and innovative concept seems highly promising: from 120 children already treated, 24 were still free of any symptoms at the end of 2013.

A „heart for heart patients“ has Celladon, located in California. Celladon’s gene therapy is aiming on SERCA enzymes. Enzymes which are responsible for controlling calcium levels in cells and which activity seems to be decreased in diseases like cardiac insufficiency and other typical heart diseases. A gene therapy using AAV vectors loaded with SERCA2-genes and injected directly into heart muscle cells should have been already successful. The U.S. Food and Drug Administration (FDA) recently ennobled the gene therapy as „Breakthrough Therapy.“ There are many interesting concepts how to cure gene defects in the future. In the absence of setbacks, some of these novel approaches have good chances for success.

Simone Hörrlein, MSc (TUM), Life Scientist & Scientific Editor

Simone Hörrlein, MSc (TUM)
Life Scientist & Scientific Editor
Blütenweg 2
85649 Brunnthal


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