Four years after an experimental treatment for a rare disease, the child underwent surgery for cancer, the first case caused by a virus widely used as a vector, but he is now doing well.

The question of whether gene therapy using adeno-associated viruses (AAVs) can cause tumors has been the subject of intense debate over recent decades. Until now, our understanding of their mechanisms and the data collected over the years from thousands of patients had appeared reassuring. In fact, AAVs are the most commonly used vectors for “in vivo” therapies precisely because they usually deliver their package, containing the therapeutic gene, near the patient’s DNA without integrating into it, thereby avoiding disruptions. Will the risk-benefit balance now change, after the first documented case of a tumor linked to their use in a clinical trial?

Everything suggests the answer is no. Nevertheless, what happened will likely lead to some course corrections aimed at further reducing the probability of therapy-induced carcinogenesis and strengthening long-term patient monitoring to detect rare, though not impossible, events. To better understand the implications of this discovery, it is useful to begin with the story of the young patient involved.

Adam Brennan was born six years ago with a severe form of mucopolysaccharidosis type I, also known as Hurler syndrome, a neurodegenerative disorder caused by a mutation in the gene coding for an enzyme (IDUA) needed to metabolize certain sugars. As these substances accumulate in cells, they cause intellectual disability and many other problems, shortening life expectancy.

To correct the genetic defect, the infant first underwent a stem cell transplant, which failed. At that point, his parents had to choose between a second transplant (carrying a 10–15% chance of death) and an experimental gene therapy. They chose the latter, and at thirteen months Adam received an injection of adeno-associated viruses engineered with the therapeutic gene at the Children’s Hospital of Philadelphia.

The treatment could not free him from a series of problems affecting his heart, skeleton, and eyes, but it preserved his brain function, allowing him to keep pace with, and even surpass, his peers. He learned sign language, learned to read, and began watching mathematics videos.

During a routine checkup at age five, an MRI revealed a mass in his brain the size of a golf ball. The tumor was immediately removed surgically, and while investigators sought to clarify the possible connection between its appearance and the gene therapy, in January of this year the Food and Drug Administration (FDA) suspended this and another similar trial, both sponsored by Regenxbio.

The answer came on May 13 with an article published in the New England Journal of Medicine by Lindsey George and colleagues. Tests revealed that the viral vectors had inserted part of their contents into the genome of Adam’s brain cells, precisely near a gene capable of triggering tumor proliferation (PLAG1).

According to George, who presented the case at the annual meeting of the American Society of Gene & Cell Therapy, several factors may have contributed to the problem:

1. The virus used has an affinity for the cells lining the brain’s ventricles, and this is exactly where the tumor developed.
2. Because of Adam’s young age, his cells were probably still actively dividing.
3. The therapeutic package contained a powerful promoter chosen to stimulate IDUA gene activity, but once integrated, it activated the proto-oncogene.
4. The child had recently undergone a cell transplant, so his immune system may have been too weak to suppress tumor growth.

Ultimately, both Science and STAT agree: the case is not a cause for alarm. The risk of tumors was already explicitly stated in the informed consent forms signed by the parents and, so far, this is the only documented case among six thousand people treated with AAVs. Hundreds of trials have been conducted, and several therapies have already been approved for diseases such as spinal muscular atrophy and Duchenne muscular dystrophy.

The gene therapy Adam received is not a cure, and its effects may fade over time, but without it the child’s condition would almost certainly be far worse. The first people to affirm this are his parents themselves: for them, it was worth it.

In the past, some studies in mice and dogs had identified integration events leading to tumor formation, but adeno-associated viruses have always appeared safer than other viruses used in “ex vivo” therapies, where cells are modified outside the body before being reintroduced. In those cases, integration into the patient’s genome is the rule rather than the exception.

According to experts, there is therefore no reason to abandon AAV vectors. However, what happened confirms the need to carefully weigh risks and benefits in every clinical trial.

A second lesson concerns the choice of promoters: researchers must strike a delicate balance between the need to ensure strong expression of the therapeutic gene across multiple cell types (when required by the disease) and the cancer risk that may arise in rare unlucky cases when integration occurs at a dangerous site in the genome.

There is also a third lesson: we must ask whether all patients undergoing gene therapy are monitored long enough to detect possible tumors that could emerge years later. In the United States, a 15-year follow-up is currently required, but the tests vary depending on the experimental treatment received, and for approved therapies, routine monitoring may eventually stop.

For now, Adam’s trial remains suspended, and the FDA has requested more data before reconsidering approval of the other Regenxbio treatment being tested for a similar disease (mucopolysaccharidosis type II, or Hunter syndrome).

(Originally published in Italian by Osservatorio Terapie Avanzate)