Gene therapy in mice restores sense of smell

Scientists have restored the sense of smell in mice using a gene therapy designed to repair the cilia - hair- like formations on nasal cells that are important in olfaction.

The study, published in Nature Medicine, was carried out on mice with a genetic disorder preventing their cilia from properly forming. Receptors that bind scent molecules are located on cilia in the upper passages of the nose, explaining why a lack of cilia results in a loss in the ability to smell.

The mutations and cellular mechanisms that contribute to such problems in humans - 'ciliopathies' - have been well studied, reports Nature News, but Dr Jeffrey Martens, pharmacologist and study leader at the University of Michigan, USA, explained: 'There's been very little work done in the area of therapeutics'.

The disruption in cilia formation in this experiment was caused by a mutant gene which codes for a protein known as intraflagellar transport 88 (IFT88). This gene defect is associated with poor feeding abilities and a short life span in mice and is fatal in humans.

The scientists were able to insert normal IFT88 genes into the mouse cells by injecting them with a virus containing the correct DNA sequence. The virus, normally responsible for the common cold, went on to insert the DNA into the cells of the mice, repairing the original defect.

After two weeks, the mice demonstrated a dramatic increase in bodyweight, signalling their feeding had improved, and tests showed that the neurons were firing correctly when exposed to the strong smell of banana oil.

'It is a proof of concept that has shown we can get that gene back into these cells, produce the right protein, produce cilia and function as expected', said Professor Philip Beales, a researcher at the Institute of Child Health, University College London who also contributed to the study.

Poorly formed cilia are associated with many disorders, including polycystic kidney disease, eye problems and rare inherited disorders such as Alström syndrome, Bardet-Biedl syndrome, primary ciliary dyskinesia and nephronopthisis. The researchers are hopeful that their work may eventually lead to treatments for patients affected by these diseases.

However, others are doubtful of any near-term applications. Gene therapy would only benefit selective cases caused by genetic defects. An inability to smell, known as 'anosmia', can also be caused by a range of other factors, from chronic sinus problems to head trauma.

Speaking to Nature News, Professor Joseph Gleeson, a neurogeneticist at the University of California, San Diego, added that olfactory neurons are replaced regularly, unlike other neuron systems, and so the benefits may not translate into the clinic. He also highlighted the potential risks of gene therapy, including viral vectors spreading to unintended cells and immune responses, and stressed that the side effects should be considered against the relative benefits of regaining a sense of smell.