Gene therapy: tweaking nature's errors

Gene therapy is arguably the most exciting area of biotechnology, thanks to a string of clinical breakthroughs, and the possibilities the technique offers. It is already helping sufferers of incurable diseases like sickle cell disease who previously lived in excruciating pain, and those with Duchenne Muscular Dystrophy for whom a short life expectancy may soon be a thing of the past.

The aim is tackle diseases by replacing or fixing a single faulty gene, the section of DNA which stores information that determines everyone’s unique characteristics. They are the body’s blueprints for making proteins that determine bodily functions. Variants in genes, known as mutations, alter the blueprint, causing the production of faulty proteins that lead to disorders and disease.

The discovery of double-stranded DNA in the 1950s paved the way for gene therapy in the 1980s with the first approved therapy procedure carried out on a four-year-old with severe combined immunodeficiency (SCID), a group of rare, genetic abnormalities of the immune system. The attempt was successful, and the patient is now in her 30s and healthy. Fast forward to today, and gene therapies are making continuous inroads into severe and often fatal diseases, with some 2,400 therapy drugs currently in development, and a quarter of them in clinical trials.¹

The US Food and Drug Administration (FDA) has already approved over 12 gene therapies. These include Vyjuvek, a cream developed by Krystal Biotech to combat epidermiolysis bullosa, a genetic condition that results in painful blisters and open wounds.² Then there is Luxturna, for the treatment of an inherited form of vision loss, Roctavian for haemophilia, Zolgensma for spinal muscular atrophy and Adstiladrin for the treatment of bladder cancer, and more. 

In Europe, gene therapy treatments have been approved for diseases like metachromatic leukodystrophy (MLD), a fatal, rare genetic disorder caused by a missing enzyme that leads to unhealthy build-up of fatty substances in areas such as the brain, spinal cord and peripheral nerves. Patients with the disease are normally diagnosed in childhood, suffering motor and cognitive deficits and are likely to die at a young age.

Before gene therapy, the only treatment available for MLD was a bone marrow transplant. “It doesn’t work, it slows things down a bit but has a bad outcome,” laments Vivienne Clark, Chair of the MLD Support Association UK. MLD was chosen for gene therapy because it has one specific error. Now after 20 years of research, gene therapy treatment for MLD patients now means limited side effects, no ongoing problems and no need to take medication.

New and improved treatments

Newer approaches are fuelled by the discovery of CRISPR-Cas9, a bacterial immune defence system that can detect the DNA sequences of invading viruses and destroy its genome, a discovery that won the Nobel Prize in 2020 and allows precise repair of the gene within the cell. “We’re seeing many more companies use CRISPR in different and creative ways with the potential to reach a much larger number of patients,” explains Mike Lehmicke, senior vice president for science and industry affairs at the Alliance for Regenerative Medicine, an international advocacy organisation. 

CRISPR stands for clustered regularly interspaced palindromic repeats; they are sequences in a bacterial genome that give protection against invading viruses. The CRISPR-Cas9 system consists of two molecules – an enzyme called Cas9 that can act as molecular scissors and cut DNA at specific points, and a piece of guide RNA that binds to DNA and ‘shows’ Cas9 where to cut. Recent results from a clinical trial using CRISPR-Cas9 showed gene therapy as a potential treatment for sickle cell disease, where the red blood cells are unusually shaped and can cause blockages in blood vessels that lead to severe pain.

Lofty prices

Gene therapy still faces hurdles to scale, notably cost and accessibility. In the US, costs can range from USD400,000 to over USD2 million, due to the expense of development, manufacture and the costs associated with clinical trials as well as the small patient populations. Prices are similarly high elsewhere in the world. Many of the therapies are made from scratch each time, which requires costly components and more testing for each batch.

Such eye-watering price tags place these therapies out of reach of many who would need them and leaves low- and middle-income countries completely excluded. This has prompted discussions on improving access, particularly as some relevant diseases are more common in poorer parts of the world.

And cost isn’t the only issue: as an advanced, frontier treatment, gene therapy, it is also only administered at specialist sites of which there are five in Europe and one in the UK.

Gene therapy advocates argue that the promise of a cure justifies the expense and can save millions of pounds compared to no treatment at all for diseases that levy significant economic burden on families, carers and the health system. “We need to look at it in terms of the costs of looking after patients with complex needs over 10-12 years,” suggested Clark, referring to MLD. “Multiple hospital admissions and visits, the need for nursing care at home both day and night, the specialist equipment with regular replacements as the child grows, the cost of medicines and clinician care.”

Lehmicke agrees: “A therapy costing millions of dollars up front may seem a lot, but lifetime costs for a disease may reach to USD25 million. Looking at the bigger picture changes the mathematics.” And while the cost is clearly huge, it may not be as high as first appears as list prices are considered a starting point for negotiations between the manufacturers and payers. England’s NHS, for example, negotiated a significant confidential discount for Libmeldy.

Still, health systems need alternative payment models to take account of the unique economics of gene therapy. One approach is to tie reimbursement to a specific, measurable health outcome, in effect guaranteeing the cost savings promised by a cure. A second is a warranty model where the payer is refunded an amount by the developer if the therapy does not work. Instalment models alleviate a single upfront cost into multiple tranches.

“I think we will start seeing these drugs move into bigger populations, that’s where we really need to start thinking about the budget impact, that’s where these payment models will need to evolve,” says Dr Alex Vadas, Managing Director and Partner in L.E.K Consulting, a life sciences consulting firm.

Scaling up

The gene therapy supply chain also needs to mature in terms of materials and reagents that facilitate their functioning. Processes and technologies are predominantly based on early development work which may have been designed for academic settings and not built for commercial scale. “Many of the gene therapies are made from scratch each time, and most are between 200 and 500 litres at most,” explains Vadas. “There’s a game of trying to scale up into larger volumes. It’s all about higher yield and lower costs”.

Manufacturing is also mostly confined to the US and the UK, introducing considerations for transportation and storage logistics which include temperature deviations and minimising vibrations. The real-time and patient-specific nature of manufacturing means that significant effort is needed to manage the supply chains. “Capacity needs to be built on a geographical basis. More investment is needed, but there has been a bit of financing slow down,” says Lehmicke. Companies are springing up to help the bottleneck of production, including ElevateBio, VintaBio and Vector BioMed. 

The workforce is another bottleneck. The rapid pace of growth is making it harder to staff with a skilled workforce and gaps are currently seen in manufacturing, analytical development, testing and quality control, with the manufacturing gap expected to widen the most. An industry survey showed the majority of companies have unfilled positions and two thirds of them take up to three months to fill an open position. Skilled labour demand is projected to double by 2026, creating concerns within the industry.

Positively, gene therapy drugs, which can be thought of as designer drugs based on a modular set of technologies such as DNA and RNA, have a much shorter time from discovery to clinical trial compared to small molecule drugs which require optimisation with the drug target. “People are going from an idea on paper into a clinical trial in two and a half years, the R&D to create these drugs is much faster,” says Vadas.

The gene and cell therapy market is expected to reach USD42.56 billion by 2030. This depends on gene therapy gaining acceptance as a short, one-off treatment, leading to lifelong benefits, to justify its pricing. Long-term safety studies are also needed, as the impact of permanently modifying a patient’s genetics is still unknown, and price-setters may need new methodologies to balance R&D investment and patient access.