A second chance for gene therapy



Credit: Mayo Clinic
Credit: Mayo Clinic


We all have listened about gene therapy, and for those who are old enough not in a good way, at all. Gene therapy became the most promising clinical therapy in the 1990s and this technology was meant to transform medicine. In essence, the concept of gene therapy is pretty simple: the introduction of an exogenous DNA into a cell. The reason why we would want to introduce such DNA is because it encodes a protein which may be deficient or whose function may be impaired on that particular cell. We do know that a big proportion of diseases are the consequence of defective proteins which fail on their role within the cell, or within the whole organism and this, in turn is a consequence of a genetic condition, which can be either inherited or acquired de novo, meaning that it just appears spontaneously on the individual. The idea is then, to replace the defective protein with a fully functional one by inserting the correct gene into the cell. In order to do this, we will need a carrier or vector that can transport the DNA into the cell.

The transference of DNA into the cell can be done with two different approaches: the use of non-viral or viral gene delivering vectors. Examples of non-viral vectors are plasmids or cationic and neutral lipid-based vectors 1. Their advantage is the lack of an immune response from the host as well as the lack of a limitation in the length of DNA that can be transferred. Unfortunately, the drawback is the efficiency that these vectors can achieve in introducing the DNA into the targeted cell making them a poor clinical tool, at least for now (because a lot of ongoing research can change this in the short term). Perhaps a better approach looks then the use of viral vectors and the reason is obvious: viruses have been design to infect (among others) mammalian cells, and they can be extremely efficient in doing so. The problem is obvious too: their infective power and immune response can represent a devastating side effect. So far, approximately 70% of gene therapy clinical trials carried out have used modified viruses including lentiviruses, retroviruses, adenoviruses and adeno-associated viruses (AAV) (1). Other secondary effect associated with viral vectors is carcinogenesis and that was indeed one reason why clinical trials in gene therapy had to be halted last decade. In 2000, a gene therapy clinical trial in the Necker Hospital in Paris was carried out including 11 patients with X-linked SCID disease in order to restore expression of the missing IL-2 receptor  (IL2RG) gene to explanted CD34+ hematopoietic cells. After transplanting the cells back, 10 patients could be cured. The problem was that they were using a potent retrovirus with the capacity to activate adjacent genes eventually leading to some patients developing leukaemia 2. The second hit to gene therapy happened earlier, in 1999 when the 18 years old volunteer Jesse Gelsinger died as a consequence of a massive immune response leading to organ failure and brain dead. Jesse got enrolled in a clinical trial trying to cure a disease consequence of a deficiency in the enzyme ornithine transcarbamylase (OTC) that is part of the metabolic pathway leading to urea excretion in urine, after the breakdown of the waste product ammonia. Patients with deficiency in OTC will abnormally accumulate ammonia.

It has been therefore a rough ride for gene therapy, but the progress accumulated in the latter years could change the tides for this technology. Specifically, the development of weaker retroviruses that can be self-inactivating has led recently to the repetition of a clinical trial in 9 patients suffering from X-linked SCID. In the study, 8 out of 9 children have survived and no leukaemia has been reported after 33 month of follow-up, so far. This is relevant, although not conclusive as previous patients started to show cancer symptoms after 33 month so monitor of the children will be critical during the coming month 3.

A second achievement has been the use of adeno-associated viruses (AAV), especially in cardiovascular gene transfer. The reason is these viruses have not been linked to any human disease and moreover they do not express any viral genes resulting in a low immune response when compared to most other viral vectors 4. This is quite interesting and promising, given that a biotechnology company called Celladon has performed to date a phase 2a trial in which they enrolled 39 individuals in a double bind randomized, placebo controlled trial. The objective was to see whether SERCA2a calcium pump gene transfer into patients with a defective gene could improve progression of heart failure. (SERCA2a is involved into Ca2+ reuptake from the cytosol back into the sarcoplasmic reticulum). Their results showed that high dosage administration of the gene resulted in a durable reduced recurrent hospitalization, with a risk reduction of 82% through 3 years of treatment along with a good safety profile. Now, they are involved in a bigger clinical trial including 250 patients after which, if successful, their therapy could be approved to treat patients suffering from heart failure.

In summary, the latest results and developments do suggest that gene therapy can be (for the second time) considered a promising technology with the potential of curing hundreds of genetic diseases with largely clinical unmet needs.



  1. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG: Non-viral vectors for gene-based therapy. Nat Rev Genet 2014; 15: 541-555.
  2. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G et al: Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288: 669-672.
  3. Hacein-Bey-Abina S, Pai SY, Gaspar HB et al: A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. The New England journal of medicine 2014; 371: 1407-1417
  4. Tilemann L, Ishikawa K, Weber T, Hajjar RJ: Gene therapy for heart failure. Circ Res 2012; 110: 777-793.

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