What Happened to Gene Therapy?

What Happened to Gene Therapy?

Mutant genes play a role in countless diseases, from cancer to cardiovascular disease. One day, millions of people may owe their lives to gene therapy. But why don't we hear about it anymore?

Article Contents

The Scientific Breakthrough Myth

When it comes to scientific breakthroughs, Hollywood has taught us to imagine the lone scientist working late at night, hunched over a microscope. Suddenly, a test tube starts fizzing and he's got his winning formula.

Cartoon of Rick and Morty making a scientific breakthrough

Scientists lovingly call this the Breakthrough Myth.

The unsexy reality is it often takes researchers many years to develop new treatments and introduce them into medicine.

When the first bone marrow transplant was performed in 1957, the survival rate was less than 1%. It was 30 years before immune suppressing drugs emerged, bringing the survival rate up to anywhere between 35% and 90% depending on the donor.

Cartoon of the first bone marrow transplant having terrible survival rates

New therapies can start with appalling efficacy rates.

Chemotherapy was another slow-to-emerge treatment that has improved with age like a supposedly fine wine. During post-World War I autopsies, doctors found that soldiers poisoned with mustard gas had too few white blood cells.

Even though the gas was a harmful toxin, it prompted researchers to investigate if it could reduce the excess white blood cells in leukaemia patients.

The first chemotherapies using mustard gas were introduced in the 1940s. However, problems with resistance and toxicity emerged, and it was several more decades before survival rates reached meaningful levels.

And gene therapy—first dreamed up 60 years ago—is turning out to be no different.

What is Gene Therapy?

To understand how gene therapy works, we need a quick primer in genetics.

Your genome—that is, your complete set of DNA—lives in every single cell of your body. Each cell contains 30,000-100,000 genes (it's still an open question) bundled up into 46 chromosomes.


The only exception to this rule are egg and sperm cells, which have 23 chromosomes each. When they merge during reproduction, the embryo then has half its mother's and half its father's chromosomes.

Genes code for more than 100,000 different proteins that make up your body, from insulin to haemoglobin. Genetic diseases occur when mutant genes no longer code for a protein, and your body experiences a critical shortage.

Gene therapy works by replacing disease genes with their healthy counterparts. It gives patients the vital code needed to produce the missing proteins.

The First Gene Therapy

Ashi DeSilva was born with adenosine deaminase (ADA) deficiency. She inherited faulty copies of the ADA genes from both her parents, and so was unable to produce it herself. It meant she lacked a key immune response that provides protection from most bacteria, viruses and fungi.

"Ashi had her first infection at just two days old. By the time she was walking, she was constantly hacking and dripping with coughs and colds." - Ricki Lewis, The Forever Fix: Gene Therapy and The Boy Who Saved It
The Forever Fix: Gene Therapy and The Boy Who Saved It by Ricki Lewis

The Forever Fix: Gene Therapy and The Boy Who Saved It by Ricki Lewis

Most infants with ADA deficiency don't survive past their second birthday. Ashi was lucky: after her diagnosis she was put on enzyme replacement therapy—a treatment developed in the 1980s in which ADA is taken from cows for infusion into the patient's bloodstream.

Although expensive and only partially effective, the enzyme therapy helped keep Ashi alive until 1990, by which time she was four years old.

When her white blood cell count started falling again, a gene therapy trial—the very first of its kind in humans—looked like her best hope. Being in the right place at the right time, Ashi became the first human being ever to receive gene therapy.

How Gene Therapy Works

Here's how doctors carried out the experimental gene therapy on Ashi DeSilva.

1. Healthy genes are inserted into a vector

Doctors took ADA genes from a healthy volunteer and inserted them into a vector—a carrier vessel to transport the genes into Ashi's cells. In this case, they used an engineered retrovirus.

Why a virus? Viruses are very basic biological machines, made up of a squiggle of DNA inside a protective shell. They're not even living organisms by most counts. Nonetheless, viruses possess a trait helpful to gene therapy: they hijack body cells to reproduce themselves. Some even insert their own DNA into your genome to become a part of you forever.

For the purposes of gene therapy, the viral DNA is removed. The residual capsule, with its biological entry codes to your cells, acts as a transport vector for the healthy gene payload.

Besides curing horrible diseases, this is the coolest part of gene therapy because we're actually hijacking the hijacker.

2. The patient's white blood cells are replicated

At the same time, doctors took a sample of white blood cells from Ashi and placed them in a culture to replicate. These cells were targeted because they're responsible for producing the protein ADA.

3. The cell culture is mixed with the vector

When Ashi's doctors introduced the virus into the culture, nature took over. The viral particles were taken up by the white blood cells, introducing the replacement ADA genes into the cell cytoplasm.

Not all gene therapies occur this way. Sometimes the insertion takes place within the body. But when it's done outside the body like this, it's called ex vivo (ex = outside, vivo = life).

4. The white blood cells are returned to the patient

Finally, a pint or so of murky fluid containing around 10 million of Ashi's genetically modified white blood cells was returned to her bloodstream. The infusion took just 28 minutes.

The gene therapy was a success. Ashi had no side effects, and her condition continued to improve over 11 gene infusions during the next two years.

Thanks to this genetic modification, she began making her own antibodies to protect against infections, her treated cells outlived the ADA-deficient ones, and they went on to replicate with the new ADA genes. Today, Ashi is alive and well. She's a 30-something married woman with a Masters in Public Policy.

The results of this ground-breaking trial prompted researchers to treat newborn babies with ADA deficiency in the same way. They even took white blood cells straight out of the umbilical cord, enabling the infants to produce their own ADA from the start of their lives.

When Gene Therapy Goes Wrong

Ashi's case was a resounding success for gene therapy. Despite the experimental complication that she was being treated with the cow enzyme at the same time, gene therapy was looking extremely promising.

So it was a shock to the research community when, later that decade, a gene therapy trial resulted in the sudden death of 18-year-old Jesse Gelsinger.

The Case of Jesse Gelsinger

Jesse suffered from a rare metabolic disorder called ornithine transcarbamylase (OTC) deficiency, which meant he couldn't digest protein. Most babies born with this disease suffer from the excessive build-up of ammonia and die soon after birth. But Jesse had only a partial deficiency. He he was able to make some OTC himself, and could manage his condition with medication and a strict no-protein diet.

When Jesse enrolled in a gene therapy clinical trial in 1999, he was hoping to help babies born with the fatal form of his disease. Researchers were exploring alternative viral vectors, destined for his liver cells, to test their safety.

But the trial was doomed. As a direct result of the viral infusion, Jesse had a massive immune response with fever, blood clots, and inflammation throughout his body. Multiple organ failure ensued, and four days later, he died.

Jesse's doctors were shocked. What had gone wrong? Why hadn't they seen this reaction before? Naturally, Jesse's family wanted answers.

The FDA launched an investigation and concluded multiple factors in the death of Jesse Gelsinger, which would lead to far stricter controls over the execution of clinical trials. Here's what went wrong.

Breech of Safety Protocols. As a result of his partial OTC deficiency, Jesse had unusually high ammonia levels. This should have excluded him from the trial, yet the researchers entered him nonetheless.

Lack of Reporting. Prior to that fateful day, two other gene therapy patients had suffered serious side effects. And in animal studies, three monkeys had died from a clotting disorder and liver inflammation after being injected, all of which went unreported.

Massive Viral Load. As the eighteenth and final patient in the safety trial, Jesse received the highest dose of the virus: 3.8x1013 (380,000,000,000,000) viral particles. This was orders of magnitude greater than was required for treatment.

Risky Viral Vector. The study used an adenovirus (as opposed to a retrovirus) as the vector, known for stimulating an immune response even when inactive. Adenoviruses are particularly risky for OTC-deficient patients, especially when they reach the liver, which is exactly where Jesse's treatment was targeted.

The risk factors combined to have a lethal effect: Jesse was 1 of 4,000 gene therapy patients to die as a result of the type and dose of virus used.

Gene Therapy Trials Today

After that fateful clinical trial in 1999, gene therapy has continued to forge ahead, but with better protocols in place to protect volunteers.

The US performs two-thirds of gene therapy trials in the world today, followed by the UK and Germany. Nearly 30 years after the initial trial involving Ashi DeSilva, gene therapy is still an experimental technique requiring greater refinement and proof of safety in its various forms.

Gene therapy could be used to treat a wide range of diseases. Most are now targeted at cancer because of its widespread incidence. The second most popular target is monogenic disease, that is, any disease caused by a single-gene mutation, like cystic fibrosis.

Therapies for cardiovascular disease, infectious disease, and inflammatory disease come after those.

Two different vector systems are used in gene therapy today: viral and non-viral. Retrovirus and adenovirus are still among the top used in viral vectors.

Non-viral vectors include chemical and physical systems like cationic liposomes, particle bombardment, electroporation, and ultrasound. These are less efficient but their availability and cost-effectiveness make them extremely useful.

In fact, the largest challenge faced in gene therapy is not the process of modifying genes—but delivering those genes to the patient's cells.

Different cells are responsible for different jobs, and only a subset may be involved in disease (for example: Ashi's white blood cells, or Jesse's liver cells). Gene therapy need only target the affected cells.

However, when a virus is introduced, the body responds as a whole with an immune response, which can be life-threatening. There are other problems too, including dose-related toxicity, pre-existing neutralising antibodies, and insufficient gene expression.

Researchers are now working to re-engineer viruses to ensure the safety and efficacy of gene therapy in the future. Despite its troubled history, gene therapy is a promising treatment for numerous disabling and incurable diseases. Investment is gene therapy research is growing and regulators are creating rapid access paths, providing hope for doctors and patients.

While Jesse Gelsinger lost his life to gene therapy, thousands—even millions—may one day owe their lives to it.

Becky Casale Bio

Becky Casale is the creator of Science Me. She's studying for a BSc and raising two small humans so parts of her DNA can live a bit longer.