Image via Flickr / John Voo

A new animal study involving virally-delivered gene therapies has indicated that high treatment doses might not be as safe as previous human trials have suggested. This comes after a recent gene therapy trial demonstrated significant benefits for human infants born with a fatal neuromuscular condition. The new research was published in Human Gene Therapy earlier this week.

The paper outlines an experiment that involved injecting three juvenile nonhuman primates (14 months old) and three piglets (all <30 days old) with multiple copies of adeno-associated virus 9 (AAV9). The viral vectors had been modified to contain a human Survival of Motor Neuron gene at a similar dose to that used in the previously mentioned human trial.

The human trial saw 15 babies with a severe form of spinal muscular atrophy being treated with an AAV9 vector containing the SMN gene, which is missing in the disease. Patients born with the disease typically die by age 2; most of the participants of the trial, on the other hand, can now sit up. Two of the participants are able to walk. The success has been seen by many as the first indication that virally delivered gene therapies can be used in vivo to treat patients with severe diseases successfully.

Despite using the same viral vector and a similar dose to the human trial, the animal study identified symptoms of severe toxicity in the subjects. One of the primates was euthanized within 4 days of injection after developing acute liver failure and shock, while the other two experiences transaminase elevations that were resolved without fatality. None of the piglets were found to experience hepatic complications, but all three had to be euthanized after developing proprioceptive deficits and ataxia.

The team noted that, unlike previous AAV studies, the side effects do not appear to have developed as a result of an immune response to the vectors themselves.

Because of the very small number of subjects used in this trial, it is difficult to say how representative the observed results are. However, the research team, led by James Wilson, MD, PhD, is urging clinicians hoping to treat patients with high-dose gene therapy to consider other options.

Despite the potential risks, Dr. Wilson, as well as others in the field, are also keen to avoid halting on-going gene therapy trials. In a response piece, Terence Flotte, MD, wrote, “Even though the commercial interests are legitimate, the editors of this journal suggest that 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. From that perspective, it is crucial that the members of our field neither ignore, nor overreact to these findings. If we were to err on the side of overreaction and suddenly halt all systemic AAV9, we may be depriving patients and families of truly life-saving therapy.”

Dr. Flotte’s article also highlights some of the reasons that the animal study saw such severe side effects, such as the use of a human gene in non-human hosts and the possibility of a contamination within the treatment. To erase the possibility of some of these theories, it is likely that Dr. Wilson’s lab will be asked to demonstrate reproducibility of their results.

In response to the initial paper’s publication, the stock prices of various gene therapies all dropped.