Gene therapy: Editing the Blueprint of Life

Gene therapy is subject to many of the platitudes that are endemic to medical communication – ‘ground-breaking’, ‘miracle cure’, unprecedented’ – the list goes on. It is, as always, more nuanced than that, and below we will highlight some of gene therapy’s successes, its missteps, and what its future may look like.

To the uninitiated, we will refrain from spending too much time explaining gene therapy, as it is one of those concepts that is so esoteric in its finer details, yet when viewed from 30,000 feet, it is eminently easy to comprehend.

At its most uncomplicated, gene therapy is the process by which one’s genetic make-up is amended to either banish a disease or at least lessen its impact (we can broach the more thorny issues of non-disease traits later).

Gene therapy achieves its goals via a number of methods, the foremost being the use of viruses as vectors to deliver a payload of functioning genetic material to a patient’s cells.

Viruses have evolved from time immemorial to be sniper-like in their ability to inveigle themselves into the human genome and cause disease. By defanging the viral genome and removing the disease-causing properties, scientists are able to harness the virus’s exceptional transport method to deliver corrected – or entirely new – forms of genetic material.

Gene therapy’s potential is boundless, and is most vividly demonstrated in the case of sickle cell anaemia (SCA), a particularly nasty inherited disease affecting millions of people in the developing world. This single-gene mutation can result in severe health effects and is often fatal. Its single mutation status makes it a good candidate for gene therapy.

There are several ongoing trials that have successfully edited the mutated section of the patient’s genome using a form of gene therapy (or gene editing in this instance) known as CRISPR-Cas9.

Published in the New England Journal of Medicine, 2021 (Frangour H, et al) scientists successfully treated a 19 year-old female and 33 old female with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), respectively. The therapy has corrected the errant gene or, in one case, delivered another gene that assists in haemoglobin production, thereby reducing the impact of SCA. Follow-up of these patients is ongoing, though initial results appear promising.¹

Gene therapy has also made inroads in cancer, most notably using CAR-T cell therapy. CAR-T cell therapy is performed ex vivo, meaning cells are extracted from a patient, edited in the lab, and then introduced back into the body with a newly-acquired ability to better recognise and attack cancer cells.

In 2010, researchers published a study where they used CAR-T cell therapy in a patient with lymphoma. The effect has been enduring with the patient still in remission today.²

There are other conditions that have met with some success with the application of gene therapy, including retinal diseases and spinal muscular atrophy (SMA). There are thousands more diseases characterised by mutations in single genes.

Health is generally the first port of call for innovations such as gene therapy, but it would be remiss to not discuss its future (and, arguably current) ethical implications.

In 2018, Chinese scientist He Jiankui announced he had successfully edited a pair of twins’ embryos to reduce susceptibility to HIV. This sent shockwaves around the medical community, and the world in general. He’s actions raises all sorts of ethical issues, including the impossibility of obtaining consent from these future children and their progeny, and their progeny, all the way down.

We can debate whether He’s conduct is virtuous, reckless, or somewhere in between, but it’s undeniable that the horse has bolted and embryonic editing is with us – if a little slowed due to his actions.

Finally, it’s worth meditating on what embryonic editing can mean for non-disease traits such as eye colour, height, or intelligence. It’s not outrageous to imagine a future where parents of means are locked in an arms race to create their perfect child, further exacerbating inequities already present.

We ought to be prepared for such eventualities by establishing ethical frameworks that will help us navigate these morally choppy waters.

References:

• Frangoul H, Altshuler D, Cappellini D, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med 2021; 384:252-260.
• Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875-3886.
• Cyranoski D. What CRISPR-baby prison sentences mean for research. Nature. January 3, 2020. Accessed March 10, 2022.