Gene therapy has made some recent progress—is it enough?

Gene therapy has had a long and bumpy history. Although researchers have made some notable and recent progress, past failures—including some deaths—have fueled mistrust and controversy.

Despite these issues, experts say there could be a bright future ahead if gene therapy can be shown to work for difficult and rare genetic diseases. But even if gene therapy is developed successfully, researchers say that, given the past troubles, education and outreach efforts may be needed to improve people’s perception of the treatments. In the meantime, gene therapy will likely remain subject to an ongoing debate about whether its risks outweigh its rewards.

Where we’re at

Gene therapy is shorthand for a suite of techniques that attempt to treat diseases by modifying a patient’s DNA. This process can involve removing a piece of DNA that causes a disease, introducing a new gene to fight a disease or various other methods of altering gene activity. The types of cells targeted and how changes in DNA are engineered can vary considerably.

Gene therapy is often considered an option to treat difficult and rare diseases, even though it could theoretically also be used to treat less rare issues such as AIDS. As it stands, almost all gene therapy treatments make use of different types of viruses as what are called "vectors," meaning transportation methods to move genes around. But there are other vectors beyond viruses—for instance, fatty spheres called liposomes (like the ones used for mRNA COVID vaccines).

In some cases, gene therapy involves using a vector to add a functional gene to the genome of a person who has a faulty copy that is causing a genetic disease. Gene therapy can also introduce a completely different gene that helps cells work normally. These treatments are referred to in general as "gene transfer." Another form of gene therapy is gene editing, which functions similarly but uses more advanced techniques to make targeted changes to a patient’s genome.

A relatively recent technology called CRISPR can be used for gene editing. (The inventors of CRISPR won the 2020 Nobel Prize for chemistry.) CRISPR enables us to make precise edits to a genome by adapting a natural gene-editing system that allows bacteria to defend themselves against viruses. Though there’s a lot of enthusiasm about the technique, its use in gene therapy links it to the long and somewhat fraught history of that field.

History lessons

Harry Malech, chief of the Genetic Immunotherapy Section with the National Institutes of Health, recently penned a paper providing some historical perspective on gene therapy by focusing on its use to treat blood disorders, including immune deficiencies.

According to Malech, there were several pieces of research from the 1950s onward that advanced the technology that now enables gene therapy. But the field seemed poised to take off with a trial at Necker Hospital in Paris in 1999. Alain Fischer, a French professor of pediatric immunology, and his team tried to cure a disease called severe combined immunodeficiency. In the trial, children were given a treatment based on retroviruses, which were used as vectors to carry a replacement for the malfunctioning genes responsible for the cohort’s immune deficiencies.

Things looked promising at first, as the children showed signs of getting better. However, two of the 10 children in the trial developed Leukemia after a few months, and one eventually died. This prompted the FDA to cancel 27 gene therapy trials in the US. In academic circles, the incident caused concern about gene therapy’s safety.

Around the same time, an 18-year-old American named Jesse Gelsinger joined a University of Pennsylvania trial to treat Ornithine transcarbamylase deficiency, a rare genetic disease that causes a buildup of ammonia in the blood. On September 14, he was injected with the treatment, a normal ornithine transcarbamylase gene that the researchers had encased in an attenuated cold virus. Four days later, Gelsinger died due to an immune response to the vector.

There have been newer issues as well. This year, Swiss-American pharmaceutical company Novartis announced that two people who received its Zolgensma treatment for some forms of spinal muscular atrophy have died of liver complications apparently linked to the treatment.

Recently, a gene therapy trial to treat an extremely rare form of epilepsy appeared to cause fluid to build up in the brain of two infants in the trial. One of the infants—for whom the treatment, valeriasen, was named—died from the side effect. These have all been cases where researchers were operating under strict ethical and safety guidelines; in a strange and notable case, Chinese biophysics researcher He Jiankui was sentenced to three years in prison for producing genetically altered babies.

Given this complex history, it’s unsurprising that people’s opinions are mixed regarding gene therapy. Martin Donnelley, co-director of the Cystic Fibrosis Airway Research Group at Adelaide University, recently studied public perceptions about gene therapy. He told Ars that the Gelsinger case was a setback for the field. “And since then, I think the public perception of gene therapy has taken a bit of a beating.”

Broadly speaking, the team found that the public’s concerns are shaped by several factors, including moral or ethical issues, the severity of the disease being treated, and the mode of delivery of the gene therapy. But in general, perceptions were positive in cases where gene therapy was used for medical reasons, like to treat fatal diseases. People were also more likely to support gene therapy when they understood what it was.

People were less supportive of therapies that could augment or enhance a person—like making people smarter, for instance. Donnelley said that there are several reasons why people might mistrust this sci-fi-like application of gene therapy. These include factors like faith beliefs, moral concerns, and a distrust in the process. The COVID-19 pandemic also spread a bit of an “anti-science” sentiment among some people as well, he said. “(i)f a child is sick and going to die, and [gene therapy is] something that could help cure them, then that's OK. But it's not OK to just make ourselves into one of the characters from a Marvel movie,” he said.