In 1989, the discovery of the gene that is defective in the childhood disease cystic fibrosis brought about the hope of treating this, and similarly devastating genetic diseases, by targeting the defective gene itself. We call this approach gene therapy.

Diseases such as cystic fibrosis are known as ‘rare’ diseases, but whilst individually a rare disease can affect just a handful of people, collectively the numbers are much more alarming. For instance, in the UK alone, up to 3.5 million people will be affected by a rare disease at some point in their lives.

Up to 80% of these rare diseases are genetic in origin and, with recent advances in genetic sequencing technologies, the rate of successful diagnoses has increased dramatically. Unfortunately, for the overwhelming majority of these patients, there is still no treatment.

Since that first disease-gene discovery 30 years ago, researchers have been testing different approaches to gene therapy. These have included limiting or switching off expression of the gene, replacing it with a healthy copy, or increasing the activity of an alternative gene that can compensate for the deficient one. Success relies on being able to carry out targeted alterations of DNA sequences, but also on the ability to get the gene to the right organ – the problem of gene delivery.

For many years gene therapy trials had limited success, resulting in adverse reactions, most notably the case of Jesse Gelsinger, an 18-year-old with a rare liver disorder, who died from multiorgan failure following gene therapy in 1999.

Any new treatment or drug comes with a risk of adverse events. However, in the case of an individual rare disease, standard trial designs often cannot be easily optimised to obtain adequate safety and efficacy data, due to the small numbers of patients available. As a result, alternative designs have had to be developed. Thanks to legislative incentives for developing orphan drugs to target rare diseases, there has been substantial progress over the past 20 years.

Excitingly, a string of recent success stories has returned some hope to the field. These have included the first US Food and Drug Administration (FDA)-approved gene therapies for an inherited eye condition (RPE65-mediated retinal dystrophy), and a severe neuromuscular condition (spinal muscular atrophy; SMA), and phase 3 gene therapy trials for a severe skin-blistering condition (epidermolysis bullosa).

Another important recent development has been the advent of a new powerful technique for gene editing, known as CRISPR. This technique allows researchers to edit DNA much more cheaply, accurately and simply than ever before. It has quickly led to a series of clinical trials to test safety and efficacy of CRISPR-mediated gene therapies for debilitating genetic diseases.

CRISPR relies on the use of proteins used by bacterial cells to fight viruses. For effective gene delivery it is often coupled with the use of adeno-associated viruses (AAVs). These viruses have been modified to function as delivery agents. They have been used over the years in gene therapy trials, including, for example, the recent successful SMA trial.

However, since CRISPR technology is relatively easy to implement, it can also be abused. Last year, news of an unregulated, unethical use of CRISPR technology to edit the DNA of otherwise healthy human embryos threatened to slow down the excitement and progress of CRISPR-based gene therapies. Altering genes in human embryos means that offspring will inherit the changes, potentially leading to unpredictable effects on future generations. In reaction to the news, some of the scientific community released a statement asking for a global moratorium on all clinical uses of human germline editing.¹

Yet, the technology is immensely valuable in disease research and for the treatment of many serious inherited conditions, a distinction highlighted in the statement. Unlike the controversial germline gene editing, CRISPR-based human clinical trials have thus far been limited to somatic cells. In other words, as with any experimental drug or treatment, they have no consequence for future generations.

For example, earlier this year, CRISPR Therapeutics and Vertex Pharmaceuticals announced the first dosing of a patient with a severe haemoglobinopathy using a gene-edited cell therapy, called CTX001, in a phase I/II trial.² This trial involves gene editing the cells outside the body, then reintroducing them into the patient. The first in vivo (i.e. editing inside the body) CRISPR-based therapeutic, EDIT-101, is also being investigated. Editas Medicine Inc. published their preclinical data on EDIT-101, which will be administered to patients with a genetic form of blindness.³

As with any new therapeutic development, there will be elements of uncertainty. However, for families living each day with the real burden of genetic disease, this uncertainty will need to be balanced against the potential benefits and, ultimately, patient choice.

Following decades of development, there lies ahead an exciting path towards finally realising those initial hopes of gene therapy as a promising treatment option for families affected by a rare disease.

Yalda Jamshidi, Reader in Genomic Medicine and Head of Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London

REFERENCES

1. Lander E et al. 2019 Nature 567 165–168.
2. CRISPR Therapeutics & Vertex Pharmaceuticals 2019 http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-progress-clinical.
3. Maeder ML et al. 2019 Nature Medicine 25 229–233.