gene therapy

Medical technique for curing or alleviating inherited diseases or defects that are due to a gene malfunction, certain infections, and some types of cancer, in which a replacement of the faulty DNA is introduced into the body. The biggest challenge is to ensure that the replacement gene can enter the cells and insert itself into the genome without disrupting other genes.

The first human to undergo gene therapy, in 1990, was one of the so-called ‘bubble babies’ – a four-year-old American girl suffering from a rare enzyme (ADA) deficiency that cripples the immune system. Unable to fight off infection, such children are nursed in a germ-free bubble; they usually die in early childhood. See also severe combined immune deficiency.

Cystic fibrosis is the most common inherited disorder and the one most keenly targeted by genetic engineers; the treatment has been pioneered in patients in the USA and UK. Gene therapy is not the final answer to inherited disease; it may cure the patient but it cannot prevent him or her from passing on the genetic defect to any children. However, it does hold out the promise of a cure for various other conditions, including some forms of heart disease and some cancers; US researchers have successfully used a gene gun to target specific tumour cells.

Trials By the end of 1990s, although hundreds of people had been treated with gene therapy, nobody had actually been cured. Even in the ADA trials, the most successful to date, the children were still receiving injections of synthetic ADA, possibly the major factor in their improvement. The death of US teenager Jesse Gelsinger during a trial in 1999 (for ornithine transcarboxylase deficiency, OTCD) presented a serious setback to further trials.

An apparent breakthrough followed in 2000, when scientists at the Hospital Necker, Paris, France used gene therapy to correct a gene disorder in the bone marrow of two infants suffering from the life-threatening disease severe combined immunodeficiency (SCID). This success prompted a series of gene therapy trials in the USA, France, and the UK. Although initially a success, the two infants developed leukaemia in October 2002 and January 2003 respectively; this setback stopped 30 gene therapy trials in the USA in January 2003, but these continued in the UK, on the grounds that without the treatment the affected patients had almost no chance of living beyond their first year of life. In 2006, it was reported that the leukaemia cases were due to the therapeutic gene acting as an oncogene and not, as was previously thought, its insertion disrupting a different, vital gene.

Other diseases for which gene therapeutic approaches have been tried include cystic fibrosis and lung cancer.

Vectors Retroviruses are being used as vectors but as these cannot be used to target specific chromosomal sites experiments are being conducted using both adenovirus and adeno-associated virus (AAV). Using adenovirus, the cystic fibrosis defect in humans has been successfully corrected within the nasal cavity. AAV is particularly advantageous because it integrates its gene cargo at specific sites, and causes no known human illnesses.

Some biotechnology firms are avoiding the use of viruses altogether; for example, by basing research on the fact that DNA injected directly into the body can be taken up by some cells and expressed. The use of liposome vectors to deliver new or altered DNA to cells is safe but imprecise, as they deliver their cargo to target cells and nontarget cells alike. Disabled virus vectors are more precise but there is a danger they will be reactivated and are therefore unsafe. Research began 1995 into a safe and precise vector involving a cluster of genes called a locus control region (LCR), whereby the therapeutic gene is attached to the LCR and is only activated by the LCR when it encounters proteins unique to the target cell type.

In February 2003, the Biological Response Modifiers Advisory Committee (BRMAC) of the US Food and Drug Administration (FDA) met to discuss measures and safeguards to allow retrovirus gene therapy trials to be carried out for the treatment of life-threatening diseases. As of 2006, the FDA had not given approval for the sale of any human gene therapy product, and all gene therapy in the USA continued to be carried out on a purely experimental basis.