High-dose gene therapy appears toxic in monkeys and piglets

Animals given high doses of gene-carrying viruses in a new gene-therapy trial showed signs of severe toxicity.

The viral vector –called AAV9 – was previously successfully used in babies with a severe form of spinal muscular atrophy. Viruses are used in gene therapy because they are able to enter human (and animal) cells and insert a piece of DNA into the patient's chromosome. AAV9 has been widely used and was considered harmless.

The researchers injected young monkeys and piglets with high doses of AAV9 which carried therapeutic genes into the cells of the spinal cord. The animals developed severe damage to the liver and motor neurons within few days post-treatment, and some had to be euthanised.

The author of the study, Dr James Wilson, said: 'What is remarkable is we have not seen it before…If you push the dose of anything high enough, you are going to see toxicity.'

Dr Terence Flotte, a pioneer in human gene therapy and editor of the journal which published the findings, cautioned that these results may not apply to humans. It was not established if the specific virus variant, the human DNA it was carrying or contamination was responsible for the toxicity.

The stock prices of several gene therapy companies have fallen after the publication. However, Dr Flotte warns against 'overreaction' of the research community and suggests that the clinical trials should not halt. The gene therapy may have high therapeutic potential.

'The one and only guiding principle in critical moments like this should be the welfare of patients with the diseases being treated with these therapies,' said the journal's editors, who advocate for full transparency regarding all relevant data and for reproduction of these findings by different labs.

In previous trials, the use of one-dose gene therapy to treat babies born with spinal muscular atrophy led to remarkable success. Most babies showed substantial improvement in motor function and survival. Children with this disorder usually die before the age of two, which has to be taken into account by clinicians weighing the risks and benefits of potential therapies.

The current study highlights the need for careful monitoring of side effects and further research.

'Let's study this, let's not ignore it,' counsels Dr Flotte. 'If the gene therapy research community makes patient welfare as the sole priority, it will ultimately be beneficial to us all.'