Biomedical research

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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 
  2. Cardiovascular diseases 
  3. Inherited monogenic diseases 
  4. Other indications

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.


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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.


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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.


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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.


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