The role of gene therapy in curing rare diseases

There’s optimism that gene therapy could cure many of the 5,000-plus known rare diseases caused by single-gene disorders, but the associated costs and risks are formidable


A life-saving gene therapy with a reported ‘list price’ of £1.79m per dose became available on the National Health Service in March after NHS England struck a confidential pricing deal with Novartis for what’s said to be the world’s most expensive drug. 

Zolgensma treats spinal muscular atrophy (SMA), a rare and often fatal genetic disease that causes muscle weakness, progressive movement loss and paralysis. Severely affected babies have a life expectancy of two years. 

What makes this therapy so exciting is that it’s delivered in a single dose. Containing a replica of the missing SMN1 gene, it helps babies to breathe without the help of a ventilator, sit up on their own and crawl. By contrast, many traditional drugs for rare diseases need to be taken permanently, often several times a week. Some have painful side effects. Moreover, they treat only the symptoms. 

More than three-quarters of the approximately 7,000 rare diseases known to science are linked with just one faulty or missing gene, according to the US National Center for Advancing Translational Sciences. The hope is that many such disorders can be cured with one-off treatments. 

But the typical costs incurred in producing gene therapies are astronomical. The University of California’s Innovative Genomics Institute estimates that developing one treatment can require an investment of up to $5bn (£3.7bn) – more than five times the R&D cost of the average conventional drug – which puts Zolgensma’s price tag into perspective. SMA is thought to affect up to 10,000 babies annually worldwide, but the drug is unlikely to be affordable in many countries outside England, where about 80 babies are born with the disorder each year. 

Because people like me were under-treated for haemophilia as children, we developed significant physical disabilities. Yet children are still being treated suboptimally today, with the same inevitable bad outcomes

Patients with lipoprotein lipase deficiency, an inherited disorder affecting about one person in a million and causing severe pancreatitis, have already been denied the drug Glybera. In 2012, it became the first gene therapy to be approved in the EU, but was withdrawn in 2017 because it was unprofitable, even with a price tag of $1m.   

Cost isn’t the only problem. In the high-risk game of pharma roulette, there are many more losers than winners. The 50-year history of gene therapy has been marked by failure and controversy. For instance, of several hundred trials that were started before 2002, not a single one was completed successfully, according to research published in Value in Health, the journal of the US Professional Society for Health Economics and Outcomes. 

In 1999, studies in the field were nearly ended in the US after the death of Jesse Gelsinger, an 18-year-old high-school student in Tuscon, Arizona. He had a rare metabolic disorder called ornithine transcarbamylase deficiency syndrome, which causes ammonia to reach dangerous levels in the body. Having managed his condition on a low-protein diet and nearly 50 pills a day, Gelsinger joined a gene therapy trial. Previous participants had experienced flu-like symptoms after taking the treatment, but he developed an intense inflammatory response that proved fatal. 

Gelsinger’s tragic case illustrates some of the risks of gene therapy. Genes cannot be inserted directly into patients’ cells, so they are usually delivered using a vector. The most common vectors are viruses with the original ‘bad’ genes substituted by ‘healthy’ ones. Such treatments could target the wrong cells and lead to other illnesses, such as cancer; generate infections if the virus recovers its disease-causing abilities; or prompt the patient’s immune system to overreact in attacking the virus. 

Nonetheless, there is increasing optimism that gene therapy will become part of mainstream care. In October, the first patient to undergo such treatment at Great Ormond Street Hospital for Children (GOSH) celebrated his 21st birthday. Rhys Evans, from Cardiff, was born with severe combined immunodeficiency, a rare condition leaving him vulnerable to even the smallest infection. He was a year old when his parents made the brave decision to write him into medical history. Evans is one of more than 100 young patients to have received gene therapy at GOSH, a leading international research centre. Without it, many would have died before their second birthday. 

Paul Gissen, professor of metabolic medicine and head of the genetics and genomic medicine department at GOSH, says: “The original research was sponsored by academic grants from bodies such as the Medical Research Council and charities. The success of these has led to an explosion of industry-sponsored trials by companies such as Alexis and Spark Therapeutics.” 

More than 120 clinical trials testing cell and gene therapy – 10% of the global total – are ongoing in the UK. Any success stories arising from these will inevitably raise the hopes of the 500,000-plus Britons who are thought to be living with a genetic disorder. 

Laurence Woollard, 32, has haemophilia A, caused by defects to the F8 gene. Haemophilia, which impairs the blood’s ability to clot, can cause arthritis and joint damage as well as painful internal bleeding. He has extensive joint damage even though he injects himself up to five times a week with synthetic Factor VIII, the clotting protein encoded by F8. 

“In England, we have one of the cheapest Factor VIII products in the developed world,” says Woollard, who is the founder and director of On the Pulse, a consultancy providing guidance on the management of rare diseases. “Because people like me were under-treated for haemophilia as children, we developed significant physical disabilities. Yet children are still being treated suboptimally today, with the same inevitable bad outcomes.”

Gene therapy could free Woollard from a lifetime of painful maintenance therapy and even save the NHS money in the long term, despite speculation that the cost of treating haemophilia this way could exceed £1.8m per patient. Research published in 2017 estimated that the combined annual cost of looking after people with severe haemophilia in France, Germany, Italy, Spain and the UK was €1.4bn (£1.2bn), equating to an average of just under €200,000 per patient.

Health economists are proposing alternative payment models for gene therapy. One suggestion is that the health service or insurer should pay annuities to meet the costs, as long as the treatment works, until these have been met in full. 

The UK continues to invest heavily in the field. In March, for instance, the Medical Research Council, the LifeArc charity and the Biotechnology and Biological Sciences Research Council announced an £18m programme to create “gene therapy innovation hubs” at NHS Blood and Transplant in Bristol, the University of Sheffield and King’s College London.

But Woollard and others with haemophilia fear that increasing optimism about gene therapy may encourage people to join trials without fully understanding the risks. The current process through which a patient gives informed consent is inadequate, they say, arguing that it should involve an independent adviser, not a one-off discussion with a researcher. 

That’s a radical proposal, but not nearly as revolutionary as gene therapy itself, which could transform the treatment not only of many rare conditions, but also of several other diseases, including some cancers. As James Watson, one of the scientists who discovered the molecular structure of DNA, put it: “We used to think that our fate was in the stars. But now we know that, in large measure, our fate is in our genes.”