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The rollercoaster ride of gene therapy

Where there is a symptom there is hopefully a treatment. For example, if I have a headache, I reach straight for the paracetamol (acetaminophen) – which at most costs me 50p. However, for many individuals and families born with rare genetic conditions, an effective therapy that improves their quality of life is not within such reach. In fact, even if such an advanced and experimental therapy was available – there is no guarantee that these individuals will receive it.

From 1997’s Gattaca to 2011’s Rise of the Planet of the Apes, gene therapy has long been depicted as an unnatural and unethical practice that leads to a range of negative consequences. While these fears are a clear representation of the insecurities of society, for many, gene therapy represents a hope for a better life. Last year, the number of clinical trials in the UK alone (despite the pandemic) increased by 20%. With this continuing global appeal and the ongoing advancements in genetic engineering technologies, the future of gene therapy looks promising. 

In this blog, we explore the history and current landscape of gene therapy, as well as the emerging concerns regarding equity of access of such technologies.

Gene therapy – a quick definition

The European Medicines Agency defines gene therapy as a medicine that works by inserting ‘recombinant’ genes into the body that can lead to a therapeutic, prophylactic or diagnostic effect. Meanwhile, the FDA defines gene therapy as a technique that seeks to modify or manipulate the expression of a gene or alter the biological properties of living cells to treat or cure disease.

The target cell type of gene therapy is currently divided into two large groups: gene therapy of the germline and gene therapy of somatic cells. The key difference between these two groups is that germline modifications can be passed onto the next generation. Germline editing is associated with a host of safety and ethical concerns, which will require further consideration and discussion in the coming years. Current legislation allows gene therapy only on somatic cells. This was reinforced at a recent international commission established by the US National Academy of Medicine, the US National Academy of Sciences and the UK’s Royal Society on the clinical use of human germline genome editing. There was an international consensus that the technology for germline editing is not presently ready for clinical application. Meanwhile, the NIH have released a paper discussing the Somatic Cell Genome Editing Consortium and their plans to develop and benchmark gene editing approaches. The products of this Consortium are set to accelerate the progression of gene editing therapies over the next ten years and beyond.

The early days

The path to gene therapy has not been smooth. It was first conceptualised by Theodore Friedmann and Richard Roblin who authored a paper in Science in 1972 titled: “Gene Therapy for Human Genetic Disease?” The pair highlighted the value of incorporating exogenous DNA into patient’s cells to improve some human genetic diseases in the future. However, they emphasised that until our understanding improves, and several bottlenecks are overcome, then further attempts in human patients should be seized.

After another 18 years of research, the NIH undertook the first approved gene therapy clinical trial. The trial involved Ashanti DeSilva (Figure 1), a four-year-old child with a severe combined immunodeficiency caused by a mutation in the gene encoding for the adenosine deaminase enzyme. The researchers used a viral vector to introduce a functional copy of the gene into DeSilva’s immune cells. DeSilva’s immune system was partially restored, and the production of the enzyme was temporarily stimulated. While the effects were successful, they were temporary. Nonetheless, this story was a major breakthrough in the field and generated a lot of optimism – leading to the launch of several other trials throughout the 1990s.

Figure 1: Ashanti De Silva, born in 1986 – the first patient to be treated with gene therapy. (Van De Silva)

Unfortunately, this positive tone didn’t last as the field suffered a major setback in 1999 when the first death was reported. Jesse Gelsinger (Figure 2) was an 18-year-old who suffered from an X-linked genetic disease known as ornithine transcarbamylase deficiency. The condition impacted his liver’s ability to break down toxic ammonia. While this disease is usually fatal at birth, Gelsinger had a milder form of the disease due to somatic mosaicism. The clinical trial was run by the University of Pennsylvania and involved injecting the correct gene into his liver cells using an adenovirus. Four days after receiving the treatment, Gelsinger died following a massive immune reaction triggered by the use of a viral vector. This event shocked the entire community and drew significant media attention. The FDA later slammed the trial and concluded that several rules of conduct were broken. It was apparent that the field had moved too fast and consequently, all gene therapy trials in the United States were halted.

Figure 2: Jesse Gelsinger, born in 1981 – the first person publicly identified as having died in a clinical trial for gene therapy in 1999. (

A booming market 

While the Gelsinger case was a major setback for the field, it reminded researchers of the risks involved in such experimental work. As a result, the field rebounded slowly and cautiously. The first gene therapy – Gendicine – was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. This is a recombinant adenovirus engineered to express wildtype p53 for patients with tumours which have mutated TP53 genes. In 2012, the European Medicines Agency for the first-time recommended approval of a gene therapy product in the EU. The therapy – Alipogene tiparvovec (Glybera) – was used to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis. While this was initially celebrated as a breakthrough for gene therapy in the EU, it was largely a commercial failure. In 2017, the therapy was withdrawn after being prescribed only to a single patient outside of a clinical trial.

Nonetheless, over the last decade, with increased understanding of molecular medicine and the development of more specific and efficient vectors, a wave of gene therapies has emerged and the pace has rapidly picked up. For example, despite the success of AAV-based gene therapies, up to 50% of patients can be excluded from treatment due to pre-existing immunity to the viral capsids. Technological advances, such as the modification of AAV capsids that can evade neutralising antibodies, alongside immunosuppression regimens have now enabled researchers to circumvent this immune obstacle.

One of the most notable approvals is that of onasemnogene abeparvovec (Zolgensma), which was approved by the FDA in 2019 and EU in 2020. This therapy is for the treatment of spinal muscular atrophy. The list price of Zolgensma was set at US$2.125 million per dose, making it the most expensive drug ever.

The future is CRISPR

The power of gene editing technologies has enabled a new modality for treatment based upon the precise modification of human genome sequences. In particular, the emergence of CRISPR-Cas9 gene editing (Figure 3), which won Dr Jennifer Doudna and Professor Emmanuelle Charpentier the Nobel Prize in 2020, holds immense potential that could broaden genetic therapeutics beyond conventional gene therapy approaches. In the field of gene therapy, CRISPR enables the correction of a particular gene defect rather than the replacement of a gene. Several key players have emerged in this space, including Editas Medicine, Intellia Therapeutics and CRISPR Therapeutics, which aim to create CRISPR-based therapies.

Figure 3: Simple schematic of CRISPR/Cas9. (

Tremendous efforts in recent years have been made in the development of ex vivo gene therapy based on CRISPR-Cas9. One significant investigatory CRISPR gene-edited therapy is CTX001, which is being tested in people suffering from beta-thalassemia and sickle cell disease. This therapy involves engineering haematopoietic stem cells ex vivo. While the trial is still ongoing, the first individual to receive the treatment – Victoria Gray (a sickle cell disease sufferer, Figure 4) – has seen improvements in her symptoms. In vivo CRISPR-Cas gene therapy is only in its initial stage. Last year, a person with a rare eye condition that causes blindness known as Leber’s congenital amaurosis 10, was the first person to receive a CRISPR-Cas9 gene therapy administered directly into their body. Typically, cells are removed and edited outside of the body then infused back into the patient. In this trial – the BRILLIANCE trial – components of the gene-editing system were injected directly into the eye to delete a mutation in the CEP290 gene that is responsible for the disease. The trial is expected to end in 2024.

Figure 4: Victoria Gray – first individual to receive a CRISPR-based gene therapy for sickle cell disease. (Meredith Rizzo/NPR)

Alongside the continued expansion of CRISPR-Cas systems, other gene-editing technologies are emerging that aim to improve specificity, accuracy, efficiency and applicability to different disease classes. For example, base and prime editing are enabling the precise alteration of genomic sequences in the absence of DNA breaks. In addition, RNA-targeted editing technologies allow for reversible modifications of gene expression, which could potentially increase efficiency and safety. Finally, epigenome editing technologies have the advantage of tunability and reversibility as well as the potential for sustained outcomes. It is clear that the rapid pace of emerging technological innovations will not only transform how we currently approach gene therapy but also broaden their applicability to a range of human diseases.

Out of reach

A cure could be made for a rare disease tomorrow – but without access to these therapies, their benefits are limited. To date, the FDA have approved 20 cellular and gene therapy products, with only 11 in Europe. The main driver for negative marketing authorisation is evidence of insufficient clinical efficacy and also safety issues. However, a positive outcome does not necessarily ensure immediate availability to patients. After regulatory approval in Europe, health technologies are assessed for their value with pricing and reimbursement negotiations. This aspect is particularly important in the case of gene therapy, where there is a significant budget impact. Even today, when few gene therapies exist, families are having to directly turn to pharma or insurance companies or even GoFundMe pages in order to afford these life-saving treatments. For example, a family and a group of over 700 volunteers known as Maisie’s Army recently ran a successful social media campaign to convince an insurer to overturn its decision to deny 20-month-old Maisie Green (Figure 5) access to Zoglensma to treat her for spinal muscular atrophy. Fuelled by the success of Maisie’s story, the group has continued to help other kids get access to this drug.

Figure 5: Maisie Green (Ciji Green)

It is important to note, that we often consider these treatments in the context of high-income countries (HICs), like the United States and UK. While access to gene therapies in these countries is challenging, the outlook for low- and middle-income countries (LMICs) is even more bleak. Despite an estimated 81% of gene therapy trials addressing a global health priority in LMICs, opportunities for individuals in these countries to participate in clinical trials are often limited. Therefore, global access of these therapies represents another obstacle to access, particularly the associated logistical and ethical challenges. Nonetheless, it is hoped that as pricing goes down and more competition comes in, access will increase overtime.

Unfortunately, for many patients requiring these therapies – time is not on their hands. Therefore, waiting for the approval process and for negotiations to be made may not be an option. Today, many patients rely on access to investigational therapies through clinical trials. However, even in this context, the individual may not meet the strict clinical trial criteria. In these cases, a pathway known as expanded access (compassionate use) may be an option. This process involves appealing to the company to get access to the investigational product outside of a clinical trial setting. While these companies are not obliged to consider these appeals, there is a clear ethical obligation for them to at least think proactively about whether or not they should consider it.   


The field of genetic therapeutics is just starting. After 50 years of effort, the potential of gene therapies is only just being realised. The currently approved therapies are not only life-changing for affected patients, but they have also laid a foundation for which treatments for many other conditions can be developed. Gene therapy is one of the most exciting areas of biotechnology that is having an actual real-time clinical impact. At the same time, these therapies come with a host of social, ethical and legal challenges that must be addressed. I don’t think I can sit here and write that access to these therapies will be available to everyone – when access to something as basic as fresh water is still not the case in 2021. However, the improvement of patient access to gene therapies can only be achieved with recognition and understanding of all the barriers and challenges that exist. Starting these conversations and opening them up to the wider community will enable us to establish strategies that will ensure that the benefits of gene therapies reach as many patients as possible.

Check out our interview with bioethicist Carolyn Chapman as she discusses the turbulent history of gene therapy, the potential of advanced gene editing technologies, rogue scientists and the conversations that must be had before genomics becomes more integrated into society.


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  • Carvalho M, Sepodes B, Martins AP. Patient access to gene therapy medicinal products: a comprehensive review. BMJ Innovations. 2021 Jan 1;7(1).

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CRISPR / Equity / Gene Therapy