DNA acts as a blueprint, providing all the information needed for building our proteins. Variations in DNA affect us all, but luckily most changes in our DNA are benign. A recent breakthrough study analysed the protein-coding ‘blueprints’ of more than 60,000 different people and identified a huge range of genetic variants that don’t cause any disease. You can read more about that study here.

However, some variants in our DNA can mutate, disrupt or delete important genes, leading to a disease or disorder. Many genetic disorders result in a wide variety of symptoms, often with serious health consequences. Many genetic disorders are also rare. Because of this, very few rare genetic disorders have treatment options that are curative, or even effective. Gene therapy has the promise of being a one-time, disease modifying treatment. If there is a broken gene, we can provide a working copy of that gene and fix the problem in the cells at a fundamental level.

But how do we get that gene to the appropriate cells?

Gene therapy relies, mainly, on the use of viruses (also called viral ‘vectors’) to deliver the genes into the cells of patients. Viral-based gene therapy is often regarded as a ‘one-time treatment’ because repeated administrations are not effective. This has stimulated significant effort to develop non-viral gene therapy vectors for conditions that will require repeat delivery.

A flurry of gene therapy clinical trials in the late 1990’s and early 2000’s, driven by the progress of the Human Genome Project, used viruses to deliver genes to patients. Despite some initially promising results, the death of a patient and several cases of leukaemia revealed major problems with the types of viral vectors being used, setting the field back.

The development of safer viral vectors has been a major reason for the resurgence of gene therapy in recent years. New, improved lentiviral and adenoviral vectors have been shown to be safe and effective in preclinical and clinical settings. The emergence of adeno-associated virus (AAV) as a delivery system for gene therapy has proved to be a valuable tool for the field.

In one of the most striking recent success stories, AAV was used to deliver a gene therapy to treat children with Spinal Muscular Atrophy type 1 (SMA1). SMA1 type 1 is a progressive and severe motor neuron disease caused by mutations in a single gene, SMN1. Children either die or require mechanical ventilation by 2 years of age. Delivery of a functional copy of the SMN1 gene to a group of 15 children resulted in profound improvements. As of 2019, all the children in this first trial are still alive, all are breathing without a ventilator, two can even walk, emphasising the impact of the therapy as a truly disease-modifying treatment. You can read the 2017 published study here.

Gene therapy has now been shown to be effective tackling several, very different disease indications. To treat haemophilia, the delivery of Factor XIII or Factor IX as a gene therapy has been shown to significantly reduce bleeding in patients, the requirement for Factor XIII or IX infusions, and the number subsequent hospital visits. Gene therapy to treat children with epidermolysis bullosa, a severe and previously untreatable skin condition, was able to reconstruct 80 percent of a boy’s skin, including his arms, legs, and back; a profound improvement to the condition. Luxturna has been approved as the first ever gene therapy to treat a genetic disorder that causes blindness. A single injection in each eye (delivering the RPE65 gene) can improve vision in patients for more than three years.

These are just some examples. Many other gene therapy clinical trials are underway, and many of these target rare diseases (some very rare), where there are few current treatment options. You can go to the clinicaltrials.gov site to see how many gene therapy studies are currently active.

With so many different disease indications, targeting the appropriate cells and regulating expression of the gene therapy (the ‘transgene’) is essential. Cutting edge research has provided the field with viral vectors and genetic regulatory elements that provide more specificity, targeting gene therapies towards the most appropriate cells in the body and regulating gene expression to ensure levels are not too high, or too low. This might mean, for example, that a gene therapy could be engineered to target and ‘switch on’ in brain cells but not in liver cells.

The viral and genetic toolkit available to researchers, and the success of recent patient trials mean that gene therapy is now a clinical reality. The SMA1 trial prompted the FDA to approve and ‘fast track’ that drug, now called Zolgensma, to the market. Luxturna, for retinal dystrophy, has also been approved and is on the market.

The next few years will be crucial to see how gene therapy is adopted into the clinical realm. Different healthcare systems will need to find ways to deal with these novel drugs, because it will undoubtedly be an expensive treatment option. However, it has the promise of being a one-time fix, unlike most conventional drugs. Cost-benefit ratios are likely to be at the forefront of developments, in addition to the clinical impact as we find out how effective and long-lived these therapies can be.