Gene therapy is a hot area of development in the biotech industry right now, with many treatments in development and a number of recent approvals. However, the path to get to this stage has not always been a smooth one.

Gene therapy has been one of biotech’s biggest success stories of the 21st century. Genetic diseases were once seen as incurable, etched in stone (or rather, in nucleotides) within the genomes of those unfortunate enough to receive them in life’s genetic lottery. Already, gene therapies have begun to change that view.

Type ‘gene therapy’ into google and you’ll find a near constant stream of positive news from the last few years, with therapy after therapy receiving regulatory approval, succeeding in trials, or raising vast sums to enter development. And with nearly 400 clinical trials currently underway, we may finally be witnessing the long-awaited arrival of the gene therapy revolution.


Gene therapy - google search

Gene therapy - google search

The field has had a long and often bumpy road to get to this point, with both triumph and tragedy along the way. Let’s take a look back at gene therapy’s evolution from futuristic idea to tangible treatment, and what is still to come.

The early years

In 1972, a seminal paper titled ‘Gene therapy for human genetic disease?’ was published in Science by U.S scientists Theodore Friedmann and Richard Roblin, who outlined the immense potential of incorporating functional DNA into patients’ cells for treating people with genetic disorders. However, they urged caution in the development of the technology, pointing out several key bottlenecks in scientific understanding that still needed to be addressed.

For the foreseeable future… we oppose any further attempts at gene therapy in human patients because (i) our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate; (ii) our understanding of the details of the relation between the molecular defect and the disease state is rudimentary for essentially all genetic diseases; and (iii) we have no information on the short-range and long-term side effects of gene therapy.”

Following 18 years of further research, in 1990 the first approved gene therapy trial was launched. A four-year-old girl named Ashanthi DeSilva underwent a 12-day treatment for a rare genetic disease known as severe combined immunodeficiency. DeSilva lacked a key enzyme called adenosine deaminase (ADA), which left her immune system crippled and put her at constant risk of contracting an infection that could kill her.

A viral vector was used to introduce a functional copy of the ADA gene into DeSilva’s T-cells, markedly improving her immune system function and allowing her to live a normal life for the first time, without having to be isolated to avoid infection.

Gene therapy feature - viral vectors

The success of DeSilva’s case was a major milestone, and numerous further trials were enthusiastically launched throughout the 1990s. The atmosphere of optimism didn’t last though,  and nine years later gene therapy encountered a devastating setback — the first reported death of a patient during a clinical trial.

In 1999, 18-year-old Jesse Gelsinger had signed up for an experimental gene therapy trial at the University of Pennsylvania. He had a genetic condition known as ornithine transcarbamylase deficiency. The disease, caused by a mutated OTC gene, compromised his liver’s ability to break down toxic ammonia, which then accumulates in the blood. The trial was designed to introduce a working copy of the OTC gene into his liver cells using an adenovirus (a modified common cold virus) as a vector. Four days after being injected, Gelsinger was declared dead, having suffered a catastrophic immune reaction to the treatment.

Gelsinger’s death shocked the entire field and drew significant media and regulatory attention. The US FDA criticized the design of the trial, suspended the university’s entire gene therapy program (one of the largest in the world at the time), and launched investigations into 69 other gene therapy trials taking place across the country. The safety of viral vectors came under high levels of scrutiny, and the need for much-improved vectors became one of the key lessons learned. Gene therapy was seen to have moved too far too fast. A slower, more cautious approach was urged.

When the field finally rebounded, it did so gradually. China became the first nation to approve a gene therapy — Gendicine — for head and neck cancer in 2003, followed by Russia’s approval of Neovasculgen for peripheral artery disease in 2011. Europe’s moment came in 2012, when the European Commission granted approval to UniQure’s Glybera for treating the ultra-rare inherited disease lipoprotein lipase deficiency.

While initially celebrated as a breakthrough moment for gene therapy in the EU, Glybera was largely a commercial failure.It was the most expensive drug in the world at over €1M per patient and was ultimately withdrawn in 2017 after reaching very few people.

From bust to boom

Since the first wave of gene therapy approvals in 2003-2012, the pace has rapidly picked up. Half a dozen gene therapies have arrived in the EU over the last few years, most recently Zynteglo for beta-thalassemia in June. The US has experienced a similar boom, and the FDA expects an approval rate of 10-20 cell and gene therapies every year by 2025.

Much of gene therapy’s recent success can be attributed to considerable advances in the viral vector technologies used to deliver the genetic material to patients’ cells.

Following the early failure of gene therapy trials with retroviral vectors and highly immunogenic adenovirus vectors in the late 90s and early 2000s, huge gaps have been closed concerning virus biology, vector dynamics, immune interaction, and vector safety,” Christian Thirion, founder and CTO of Sirion Biotech, a German viral vector developer, told me.


In particular, a class of viral vectors called adeno-associated viruses (AAVs) has emerged as a leading platform for new gene therapies.

AAVs are the new superstars in the gene therapy sector,” said Thirion. Wild-type AAVs don’t elicit disease in humans and result in long-term gene expression for up to 10 years. They can be engineered and targeted towards specific cell or tissue types. All these features make them ideal tools for modern gene therapy applications, and the rise in interest in this technology has been steep.”

Targeting the eye has become particularly attractive, as its anatomy is well suited to gene therapy approaches. The 2018 EU approval of Luxturna, an AAV-based therapy for patients with a genetic mutation that causes progressive vision loss, was the first approval of any gene therapy for the eye, but there are several others well on their way.

Luxturna’s approval was a significant milestone for the industry, our company and others who are looking to offer new therapies in ophthalmology,” said Bernard Gilly, CEO of Paris-based Gensight Biologics, which specialises in gene therapy approaches for retinal and neurodegenerative diseases.

Gene therapy - luxturna

Gene therapy - luxturna

Gensight aims to file for EMA approval of its first gene therapy in December 2019. In Europe, Nightstar Therapeutics and Horama are also working on gene therapies for blindness, taking advantage of the eye’s inherent suitability to the technology.

The eye is a closed system; once injected in the eyeball, the vectors have very little opportunity to leak outside and as a result vectors will stay within the eye and be able to unload their DNA cargo into a maximum number of targeted cells. Furthermore, neurons are not renewed and once a neuron is expressing the gene of interest it is likely to do so for a very long period of time,” Gilly explained.

A CRISPR future?

The idea of simply ‘editing out’ genetic diseases has been one of the most widely discussed possible applications of the revolutionary CRISPR gene editing technology. This technique has immense potential and could broaden the concept of genetic treatment beyond conventional gene therapy approaches.

A number of key players have emerged in the race to develop the first CRISPR-based therapy, including Editas Medicine and Intellia Therapeutics in the US, and Swiss CRISPR Therapeutics.

Many traditional gene therapies introduce a functional copy of a gene into a cell, but do not reduce or stop expression of the original diseased gene,” a spokesperson for CRISPR Therapeutics told me.

On the other hand, gene editing approaches can alter the DNA to precisely disrupt, delete or repair the original diseased gene. As a result, gene editing has the potential to address a vast array of genetic disorders.”

In partnership with Vertex Pharmaceuticals, CRISPR Therapeutics made history in 2018, launching the first company-backed human CRISPR trial for beta-thalassemia and sickle cell disease. The company is also developing several CRISPR-based cell therapies for cancer and regenerative medicine.

“There has been a rapid technology cycle to make this platform a reality and to allow us to begin bringing the first CRISPR-based medicines to patients. We have laid a careful groundwork with our preclinical research and are very optimistic about what the next phase means for science and for patients.”

Gene therapy has overcome immense challenges to become a medical reality, and its evolution is still far from over. Increasingly powerful and elegant molecular tools will continue to expand our ability to correct genetic disorders, offering fresh hope to patients around the world.

Hurdles still remain, especially around the question of how to fairly price these often costly treatments, but it’s clear that after nearly 50 years of effort, gene therapy’s transformative potential is finally being realized.

Farhan Mitha

Farhan Mitha

Farhan Mitha is a science communicator based in the UK, with a background in biology and science policy. When he’s not writing about science he’s performing stand-up comedy and then complaining about the gig minutes later on his twitter account @FarhanMitha.

Images via Shutterstock, E. Resko and Sirion Biotech