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In this section you can find answers to frequently asked questions about Gene Therapy.

Biomedical research currently receives much attention from business, scientists and the media. Major 'breakthroughs' are reported daily and scientific developments are moving fast. Gene therapy is a promising technique in the world of life sciences. But is gene therapy hype or does it already exist right now?

1. What is the basis of gene therapy?
2. Does it run in the family?
3. How does the new gene reach its proper destination?
4. Why is gene therapy an object of discussion?
5. What does the future offer us?

1. What is the basis of gene therapy?

Proteins have a lot of important functions in our body. For example, they function as building blocks, they transfer messages and break down waste materials. The blueprints of proteins are written in our genetic material, the DNA.

We call these blue prints 'genes'. When something's wrong with a blue print, or gene, properly functioning proteins cannot be produced. They work less, or not at all. This can have far reaching effects. Illnesses like haemophilia (an hereditary disorder of blood clotting) and cystic fibrosis are examples. The idea with gene therapy is that when genes contain certain faults, we should be able to do something about it. When we replace or repair the gene, this should make things right.

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2. Does it run in the family?

You inherit many things from your parents including some of your features such as eye colour and hair colour, it is often said that these things 'run in the family'. When we look at inherited characteristics such as these it's not only genes that play a role, but also a persons lifestyle choices. For example a person can have a lot of talent for playing the piano. But if this person never takes lessons, it would be very hard for them to become the second Beethoven.

This is the same for a lot of diseases and disorders. In most cases it's not only your genes that determine whether or not you will become ill. It also depends on what you eat, how much exercise you have, where you live and what you go through in general. Many genetic conditions are what we call, multifactorial, meaning there are many different things both genetic and environmental that affect a person’s chances or risk of being affected. However for some diseases it is certain that you will get them, when you have a faulty gene for a certain protein. It is diseases like this that scientists hope to cure with gene therapy.

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3. How does the new gene reach its proper destination?

But how do we get the new gene to the right destination in the cells' DNA?  For example, in CF one of the faulty genes is in the lungs. In order for the gene to work, the replacement gene needs to get to the lungs. To do so, we need a vehicle: the gene cannot travel there on its own. Viruses are often used as a transportation vehicle. Viruses naturally deliver their own genes in cells, which can sometimes make you ill.

Cripled viruses
The viruses that are used for gene therapy are made harmless by scientists. They replace the viral genes that cause disease with the genes that need to be delivered. These modified viruses do not make you ill, but they are able to deliver the gene to the right place in the DNA.

Back to basics
In practice, this has been a bit more complicated than was originally thought. In one research project, investigating gene therapy for a severe immune disease, the gene was sometimes delivered to the wrong spot. This resulted in three patients developing leukaemia. Two of whom fortunately recovered and for the rest of the patients on the trial the therapy worked well.

They can now live normal, healthy lives without medication. Nevertheless, the risk of developing leukaemia was so great that research into gene therapy was set back quite a few years. Scientists had to pay more attention to the basics of the therapy in order to make it safer for future patients.

Knowledge and possibilities increase
In recent years better modified viruses were investigated, viruses which were more stable and able to transport and deliver genes more precisely. Scientists now claim they have safer transportation methods for certain diseases.

People are now yearning for the results of new research programmes. The first results that can give perspectives on a cure, are expected for haemophilia, cystic fibrosis, some immune diseases, metabolic disorders, eye diseases and also cancer.

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4. Why is gene therapy an object of discussion?

Some people think that genetic material should not be modified under any circumstances, even if this research has the potential to find a cure for many long term and potentially fatal conditions. For those who stand to benefit from the results of gene therapy research it means that their health could be improved dramatically. For many of the conditions being researched for gene therapy there are no treatments at present.

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 5. What does the future offer us?

At the moment gene therapy has the potential to be very useful when a disease is caused by an error in one gene e.g. conditions such as Cystic Fibrosis and Chronic Granulomatous Disease. However, a lot of genetic disorders exist as a result of errors in multiple genes (sometimes hundreds of genes) and for other genetic conditions, the chance of becoming ill also depends on a person's lifestyle. In those cases gene therapy is very complicated, if not impossible, because it only works to correct one faulty gene.

Bone marrow stem cells
Other research groups focus on adding genetic material to bone marrow stem cells in order to make transplantation more safe. These stem cells, which reside in the bone marrow, are uniquely capable of generating an entirely new blood cell production and immune system when transplanted. Bone marrow stem cells are close to ideal targets for gene therapy:

  • Inherited diseases that affect blood cell production and the immune system together are among the most common inherited diseases of humans
  • Bone marrow stem cells can be easily obtained and transplanted
  • Bone marrow stem cells and their progency come everywhere in the body, thereby delivering their products, which means that also diseases that do not directly affect blood cells may be approached by stem cell gene therapy

Bone marrow stem cells are rare and occur in a frequency of 1 per 100,000. Although purification of stem cells in experimental settings has been possible, in practice they are not enriched further than approximately 100-fold. This means that the vehicle for gene transfer should be highly efficient and preferably selective for stem cells.

Efficient vehicles for gene transfer are certain classes of viruses, the retroviruses, which are capable of delivering healthy genes to the genome of diseased cells. Researchers are focused on increasing the efficiency and improving the safety of these vehicles, which is a prerequisite for clinical gene therapy. To develop gene therapy, other hurdles are addressed as well, such as:

  • The quality of the repaired blood stem cells, in other words, are these cells still capable to provide a life long active blood cell and immune system?
  • The possible immune reactions against the transgene product
  • Engraftment and production of gene modified cells in case the transgene product does not confer a natural selective advantage

What the future will bring us is hard to say. Expectations are high. The results so far are very promising, developments are coming quickly. Gene therapy offers hope for novel treatment of a variety of acquired and inherited diseases.

However, much research, development and trials are needed to translate the basic principles of gene transfer into practical and safe treatment regimens.

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Landmark studies

While gene therapy holds much promise, there have been a few unfortunate cases of serious adverse events, and these have had an inevitable effect on progress in this area. This page give a chronological overview of landmark events from drop-backs to successes in gene therapy research.

1. April 2008: Success for inherited blindness

Results of world's first gene therapy for inherited blindness show sight improvement. UK researchers from the UCL Institute of Ophthalmology and Moorfields Eye Hospital NIHR Biomedical Research Centre announced results from the world’s first clinical trial to test a revolutionary gene therapy treatment for a type of inherited blindness.
The results, published in the New England Journal of Medicine, show that the experimental treatment is safe and can improve sight. The findings are a landmark for gene therapy technology and could have a significant impact on future treatments for eye disease. See Press release.

2. November 2007: Adverse event inflammatory arthritis study

An adverse event led to a clinical trial hold in July 2007. The U.S. Food and Drug Administration (FDA) removed the hold following the agency's review of the safety data on all 127 subjects and all data from a fatal serious adverse event.

Gene medicine found safe 
The data obtained during the investigation indicated that the investigated gene medicine did not contribute to the patient's death, which was due to a fungal infection (histoplasmosis). The subject was on other medications as well, which were known to be immunosuppressive and a risk factor for histoplasma infection.

3. October 2007: Results for Parkinson’s disease

On October 17, American researchers reported successful results from a phase I gene therapy trial for Parkinson’s disease. In the trial 12 patients had gene medicine infused into a specific part of their brains.

Towards a phase 2 Trial 
At the time of the announcement, 3 years after treatment, the first patient was dramatically improved, and 9 of the other patients showed on average 37% improvement. The company developing this therapy, together with its partners, are now working towards a phase 2 randomized controlled trial.

4. October 2006: Results for Parkinson’s disease


In October 2006, there were two promising announcements of success in treating Parkinson’s disease by gene therapy in phase I trials.
On October 16, the organizations involved announced that CERE-120, a gene therapy product they are developing for Parkinson’s disease, was well tolerated and appeared to reduce symptoms by approximately 40% in a phase 1 study with 12 patients with advanced disease.
The companies are planning a phase 2 randomized controlled trial involving approximately 50 patients.

5. September 2006: Partial success for metastatic skin cancer (melanoma)


Much excitement was caused by the report of successful immunotherapy treatment of two patients with metastatic melanoma in September 2006. Researchers were able to engineer tumor recognition in the patients own immune cells.
For up to one year, this resulted in the retreat of metastatic melanoma lesions in two patients; a dramatic improvement for patients who had only been expected to live for 3 to 6 months. However 15 other patients did not respond to the treatment. Further work is underway to improve response rates and refine the approach.


6. April 2006: Partial success for Chronic granulomatous disease (CGD)


In April 2006 one of two patients died from a severe bacterial infection two years after an experimental gene therapy treatment. It appears that the patient’s death was not due to a side effect of the gene therapy treatment, rather to a return over time of the CGD symptoms she was successfully treated for two years earlier.
In this trial, precursor immune cells from the patients blood were genetically altered in the laboratory and given back to the patient. The team behind the trial is currently investigating the reason for the loss of correction of the disease.

7. 2003- 2004 Chinese Gendicine for head and neck cancer

Gendicine, a gene medicine developed as a treatment of cancer, was approved for clinical use by the Chinese State Food and Drug Administration in October 2003.

This was followed by a license for its commercial production in spring 2004; however, this went ahead without data from a standard phase III trial, and it seems that the approval was made on the basis of tumor shrinkage, rather than extension of patient lifetime. There has been quite some concern from gene therapy researchers elsewhere in the world as to the quality of the trials performed and thereby the safety and efficacy of the treatment.

To date, the phase I and phase II trial results in patients with head and neck squamous cancers have only been published in Chinese language medical journals; the only English language article on the trials is a review summarizing the data, the value of which has since been questioned by several groups.

Despite these concerns, some patients have flown to China to try it, and the company stated in December 2006 that they had treated more than 4000 patients with Gendicine.

8. 2000 – 2005: Leukaemia but also success in X-linked SCID

In 2000 the morale of the gene therapy community was lifted with the first report from France of successful treatment of children suffering from a rare, lethal immune disease named X-linked severe combined immunodeficiency (SCID-X1).

The excitement gave way to alarm at the end of 2002, when two of the ten children developed a leukaemia-like symptoms. It appeared that the gene therapy procedure resulted in an increased risk tot develop leukaemia.

These first two serious adverse events fuelled a global debate over the future of gene therapy and led investigators and gene therapy societies in Europe and the USA to critically examine the risk/benefit ratio of gene therapy.

The trial was voluntarily halted while the cause of these conditions was investigated and the patients were treated for them. An ongoing UK trial using a similar approach but with a different protocol to treat SCID-X1 was allowed to continue and went on to achieve successful results, as did the treatment of a SCID-X1 child in a similar trial in Australia.

The French trial was restarted with a revised protocol using lower doses of modified cells. In January 2005 a third child developed a leukaemia-like symptoms, involving a different genetic basis; this patient and one of the earlier two patients responded well to chemotherapy treatment and are in complete remission.

Sadly, one of the three affected patients did not respond to the chemotherapy treatment for the leukaemia-like condition and died in October 2004; however, all of the other patients in the French trial have benefited from the gene therapy, with correction of their otherwise lethal immunodeficiency extending beyond 6 years for the first patients treated.

9. 1999: The Jesse Gelsinger case

The first case in which a gene therapy treatment turned out wrong, involved the death of 18-year-old Jesse Gelsinger on September 17, 1999. Jesse was treated for a rare metabolic disorder. His death was attributed to an inflammatory reaction to one of the components used in the experimental therapy.

In January 2000, the US Food and Drug Administration (FDA) put a hold on the trial and several other trials were also halted. In its final judgment on the case in February 2005 the US Department of Justice held the University of Pennsylvania responsible, ordered them to pay a $517.000 settlement, and placed research restrictions on the doctors who conducted the trials.
The doctors did not stick to the protocols of the study and withheld information about side-effects in previous studies. This was widely seen as a major blow for the gene therapy community.

Targetted diseases

Diseases targeted by gene therapy
The vast majority (82.7%) of gene therapy clinical trials to date have addressed cancer, cardiovascular disease and inherited monogenic diseases; the first two because of their enormous prevalence, impact and potentially fatal outcomes, the latter has an obvious appeal and rationale.

Interestingly, trials targeting cardiovascular disease have outnumbered trials for monogenic disease, although the greatest successes of gene therapy to date have been achieved in the latter group. The concept of replacing a well-defined defective gene with its correctly functioning counterpart has shown promising in several studies.

1. Cancer
Thus far, most of the clinical trials in gene therapy have been aimed at the treatment of cancer (65.2% of all gene therapy trials). Many different cancers have been targeted throughout the years, including lung, gynaecological, skin, urological, neurological and gastrointestinal tumors, as well as haematological malignancies and paediatric tumors. A range of different strategies has been applied to cancer gene therapy.

p53 gene 
Efficient delivery and expression of the p53 tumor-suppressor gene has been shown to cause regression of established human tumors, and to prevent the growth of human cancer cells in culture. Some clinical trials using the p53 gene have been combined with standard therapeutic approaches such as chemotherapy and radiotherapy.

Immunotherapy of cancer aims to control or eradicate tumors by intensifying the normally weak reaction of the immune system against tumors (which consist of a patients own and thus hard to recognize tissue). 
A number of different strategies have been employed, including vaccination with tumor cells engineered stimulate the immune system to attack them. 
Vaccination with recombinant viral vectors encoding for molecules that help the immune system recognize tumor cells, vaccination with immune cells expressing molecules that help other immune cells recognize tumor cells, and injection of gene medicines into tumors encoding for peptides that kill tumor cells.

Suicide genes 
A relative new approach consists of the introduction of genes that encode enzymes (often termed ‘suicide genes’) capable of converting pro-drugs into drugs that are toxic for tumor cells. 
Non-toxic prodrugs can thus be administered in high doses with no untoward effects and converted into the toxic drug where needed (i.e. in the tumor and its immediate environment). This strategy enables better utilization of conventional chemotherapy.

2. Cardiovascular diseases

Cardiovascular gene therapy has grown from 8.3% of all trials in 2004 to 9.3% in 2007, becoming the second most popular application for gene therapy. 
The expectation is that gene therapy will provide a new avenue for therapeutic applications in the growing of blood vessels, protection, regeneration and repair of heart tissue, prevention of the reoccurrence of constricted or narrowed arteries following a cardiovascular intervention, prevention of the rejection of a bypass, and risk-factor management.

New blood vessel 
The vast majority of cardiovascular gene therapy trials to date have addressed therapeutic stimulation of the growing of blood vessels in cases that the blood is restricted.
Two dominant categories of such diseases have been tested in approximately equal numbers, namely myocardial ischemia due to coronary artery disease and lower limb ischemia due to peripheral artery disease. A small number of trials have used gene medicines to treat foot ulcers resulting from diabetes.

3. Inherited monogenic diseases

The ultimate aim in treating monogenic diseases by gene therapy is the correction of the disorder by the stable transfer of the functioning gene into dividing cells (stem cells) to ensure the permanence of the correction.

Cystic fibrosis 
Up to now, 120 trials have been identified for inherited monogenic disorders, one-third of which targeted cystic fibrosis, the most common inherited genetic disease in Europe and the USA.
The average life expectancy of patients with cystic fibrosis is less than 40 years, hence the interest in this disease as a prime target for gene therapy.

Severe combined immunodeficiency syndromes (SCID) 
The second most common group of inherited diseases targeted has been the severe combined immunodeficiency syndromes, representing about 20% of the trials for monogenic diseases.
Around 20 other monogenic diseases have been treated, but as yet with no obvious therapeutic benefit.

4. Other indications

A small number of essentially phase I trials have addressed various other diseases including inflammatory bowel disease, rheumatoid arthritis, chronic renal disease, and fractures.

Infectious diseases, like Hiv
A total of 112 trials (7.2% of the total) have been performed for infectious diseases. Human immunodeficiency virus (HIV) infection is the major target in this category but trials aimed at tetanus, cytomegalovirus (CMV) infection, and adenovirus infection have been conducted.

Neurological diseases 
Neurological diseases have also been targeted by gene therapy, with 17 registered phase I and II trials aimed at a variety of diseases such as multiple sclerosis, myasthenia gravis, neurological complications of diabetes, Alzheimer’s disease, and recently Parkinson’s disease.

Ocular pathologies 
Ocular pathologies have also been tackled, with 12 trials to date focused on conditions including retinitis pigmentosa, glaucoma and age-related macular degeneration.

Transferred genes

Genes transferred into humans

Over 220 different genes have been introduced into cells in human gene therapy trials. It is impossible to discuss each gene in detail here, but, as would be expected, the gene types transferred most frequently match the most common group of diseases treated.

1. Cancer fighting genes

In around 60% of the trials the genes transferred are either genes coding for antigens used to stimulate an immune response, cytokine genes (cytokines are signalling molecules), tumor-suppressor genes or suicide genes, all of which are primarily used to combat cancer. In 5.2% of trials of genes for receptors were used for cancer gene therapy. In 1.9% of trials oncolytic viruses were transferred (rather than genes), these being aimed at destroying cancer cells.

2. Cardiovascular diseases healing growth factors

Growth factors were transferred in 7.9% of trials, almost all of these being aimed at cardiovascular diseases.

3. Metabolics

Deficiency genes were used in 7.5% of the trials in the fight against metabolic diseases.

4. Diagnostics

Marker genes, meanly to diagnose diseases, were transferred in 3.7% of trials.

5. HIV

In 4.4% of trials, replication inhibitors were used, to target HIV infection.

6. RNA interference

1.4% of trials involved the transfer of antisense or short interfering RNA, with the aim of blocking the expression of a chosen gene.


Gene medicines typically consist of the gene product and a vector. The function of the vector is to get the new gene to the right destination in the cells’ DNA. Viral vectors remain by far the most popular approach, having been used in about two-thirds of the trials performed to date.

1. Viral vectors

Crippled viruses are often used as a transportation vehicle. Crippled in this case means that the viruses that are used for gene therapy are made harmless by scientists. They replace the viral genes that cause disease with the genes that need to be delivered. Viral vectors can be the cause of adverse effects, when the patients’ immune system recognizes the viral particles and attacks it.

2. Retroviruses

One of the consequences of the serious adverse events in the French SCID trial is a decrease in the proportion of trials using retroviruses. Retroviral vectors were the first vectors used in gene therapy but are now used in only 21.7% of the trials (28% in 2004). They target dividing cells with a high degree of efficiency and provide stable gene transfer, as they integrate into the genetic material of the target cell.

The main drawback of the use of retroviruses is related to this latter property. Research prompted by the serious adverse events in the French SCID trial has shown that the insertion pattern of these viruses is not random, and their preference for the first part of genes which can be activation sites is a cause for concern, because this can increase the risk on developing cancer like leukaemia.

3. Q vectors

Self inactivating (SIN) retroviral vectors, also called Q vectors, are engineered so that activation of the target gene can only be driven by an internal starter signal once the expression cassette is integrated into the genetic material. The self-inactivation of the retroviral vector minimizes the risk that replication-competent retrovirus (RCR) will emerge.

It also reduces the likelihood that cellular coding sequences located adjacent to the vector integration site will be aberrantly expressed. These vectors should therefore avoid problems of incidental activation of endogenous cancer causing genes (oncogenes).

4. Adenoviruses

Adenoviruses are now the most commonly used vector (24.9% of all trials). Adenoviruses can carry a larger DNA load than retroviruses but their capacity is still too small to accommodate the genes required for certain clinical applications.

The main advantages of adenoviral vectors are their high efficiency of delivering genes into cells and high level of gene expression, though this is transient and declines fairly rapidly, because the gene is not integrated into the cells genetic material. They also have the advantage of being able to infect non-dividing cells.

There are, however, important safety issues regarding adenoviral vectors, the main one being the possibility of provoking a severe immune and inflammatory response, as was tragically exemplified in the case of a death in a trial for OTC deficiency.

Other viruses have been less widely used and include vaccinia virus (8.2% of trials), poxvirus (6.1%), adenoassociated virus (4.1%), and herpes simplex virus (3.2%). The use of these vectors has increased significantly as alternatives to retroviruses are being explored.

5. Non-viral vectors

The limitations of viral vectors, in particular their relatively small capacity for therapeutic DNA, and safety concerns have prompted the development of synthetic vectors not based on viral systems.

6. ‘naked’ DNA

The simplest non-viral gene delivery system uses ‘naked’ DNA, which when injected directly into certain tissues, particularly muscle, produces significant levels of gene expression, though lower than those achieved with viral vectors. The popularity of naked DNA has increased (18.3% of all trials, 14% in 2004), possibly due to the concerns with regard to use of retrovirus.

Naked DNA is the most popular non-viral system used in clinical trials, followed by lipofection,which involves cationic lipid/DNA complexes (used in 7.1% of all trials).

There have been 35 trials that used two vectors, 28 used poxvirus and vaccinia virus, 3 used adenovirus and retrovirus, 2 used adenovirus and vaccinia virus, and 2 used naked DNA and adenovirus.

Clinical trials

The first therapeutic human gene therapy clinical trial was approved in 1990 and involved two children suffering from a form of severe combined immunodeficiency (SCID). At the moment about 90-100 new trials are registered a year. Gene therapy trials have been performed in 28 countries from all continents.

1. Number of trials 1989-2007

From 1990 until 1999, the number of trials initiated climbed rapidly. During this period, some voices expressed concern regarding the potential dangers of the procedure and critics pointed to the fact that gene therapy had proved of little therapeutic benefit thus far. In 1999 the number of trials peaked with 116 trials approved.

Following the serious adverse events in 1999 and 2002 the momentum slowed as several regulatory agencies put a temporary hold on new or ongoing trials. In 2003, only 81 new trials were approved worldwide, the lowest number since 1998.

Negative press coverage has undoubtedly dampened the enthusiasm for gene therapy and restriction from regulatory bodies while the adverse events were investigated will have slowed the growth in numbers of trials approved.

However, recent successes are encouraging, and the number of trials per year has increased in 2004 (100), 2005 (112) and 2006 (116) with a decrease in 2007 (89).

2. Countries participating in gene therapy trials

Gene therapy clinical trials have been performed in 28 countries, with representatives from all five continents. The USA accounts for 63.2% of trials, Europe as a whole represents 26.6% of trials and Asia 2.7% of all trials.

Within Europe, the UK accounts for 12.1% of the world total with 178 trials, Germany 5% (74 trials), Switzerland 3.1% (46 trials), France 2.6% (39 trials), Belgium 1.5% (22 trials) and the Netherlands 1.5% (22 trials).

Eastern Europe is starting to have an impact on the gene therapy community with six trials in Poland, one in the Czech Republic and one in Russia. It is known that there are more trials taking place in Russia but data are unavailable.

Twentyseven trials have been reported from Australia, 17 from Japan and 19 from Canada.
Other countries where gene therapy trials have been performed are Italy (16 trials), China (12), Israel (7), Spain (6), Norway (4) and South Korea (13 trials), Finland and Sweden (both 3 trials), Austria, Singapore, New Zealand, and Denmark (2 trials each), and one trial each in Egypt, Mexico and Taiwan. Thirteen of the trials are reported as 'multi-countries' although a large proportion of the trials initiated in one country have centres in several other countries.