Given it could soon revolutionise medicine, gene therapy has a surprisingly short history. Watson and Crick demonstrated the molecular structure of DNA in 1953 and scientists speculated it could cure genetic disorders by the early 1960s. But in reality, these principles have only practically been applied over the last few decades. Now used to combat everything from haemophilia and immune deficiencies to blindness, genes have the ability to upend our assumptions about incurable illnesses – along the way transforming our understanding of life’s building blocks. No wonder the global market for cell and gene therapies (CGT) is already worth $7.5bn, with one recent study expecting it to enjoy CAGR of nearly 20% through 2030.

Yet, amid all this potential, the practicalities of getting new CGTs from labs to patients is far from simple. In large part, this is simply down to the complex nature of the therapies themselves, involving as they do the subtle manipulation of cells and genes. The individualised nature of this work – some genetic mutations only impact tiny numbers of people – also makes manufacturing difficult.

Yet, beyond these technical hurdles, probably the most consistent issue encompasses manufacturers themselves. With so much money at stake, it makes sense that companies are reluctant to work together towards common goals, with the resultant cobweb of regulations often proving too much for industry minnows. “Companies in the CGT space are protective of their proprietary methods in manufacturing, by necessity,” says Courtney Silverthorn, associate vice president for research partnerships at the Foundation for the National Institutes of Health (FNIH).

At the same time, however, Silverthorn is working to introduce collaboration to this most introverted of sectors. Bringing together some of the biggest pharmaceutical companies on earth, as well as major non-commercial interests like NIH, the new Bespoke Gene Therapy Consortium (BGTC) aims to regulate CGTs, giving scientists and regulators alike a common set of guidelines around new genetic treatments. More than that, the BGTC hopes to streamline manufacturing, making it easy for even small companies to get innovative products to market quickly. Nor are Silverthorn and her colleagues necessarily interested purely in genes and cells. On the contrary, the same principles of teamwork could soon be applied to other corners of medicine too, with equally dramatic consequences.

Lean, gene-fighting machines

Though it’s usually described with that tight threeletter acronym, gene therapy in fact covers a bewildering array of treatments. One, for instance, replaces a disease-causing gene with a healthy copy. Another involves ‘deactivating’ a malicious gene, while a third introduces new or modified genes into a patient’s body, helping them combat a particular ailment. There’s similar variety when it comes to how scientists think about ‘vectors’ – the technical term for the vehicles by which therapeutic genes enter the body. That’s true, for example, of bacteria, which can be tweaked to carry genes into human tissue. Viruses can perform similar functions, while the plasmid DNA of certain microorganisms can be adapted too.

Combined with complementary research around cell therapy – and a market that’s predicted to see 52 distinct CGTs launch in 2024 alone – it’s no wonder experts are so exhilarated about what’s coming. “I am most excited about the impact of these medicines on the treatment of so many diseases, including those that have been difficult, or impossible, to treat,” is how Professor Kelvin Lee, director at the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), puts it. Yet, as he adds, the speed and scale of change can also cause problems, with both cell and gene therapies requiring “improved analytical tools to characterise the process and the product,” to say nothing of a bigger manufacturing workforce.

Silverthorn highlights another problem with the contemporary CGT market: scalability. “At the high end,” she explains, “physical scale-up eventually becomes a limiting factor. At the low end, however, the traditional business model for drug development falls apart.” As Silverthorn concedes, this is true, to a certain extent, when fighting other rare diseases. Yet, because the regulatory and manufacturing costs for small molecule drugs are “substantially more achievable” than for CGTs, the latter have traditionally been too pricey for all but a handful of patients. Certainly, this point is bolstered by the numbers, with work by the Institute for Clinical and Economic Review finding that a single dose of a gene therapy has an average cost between $1m and $2m. The challenge of applying a small molecule drug development paradigm to CGT means that companies have typically been loathe to share techniques, with Silverthorn noting that because of high development costs, specialised manufacturing processes are guarded as closely as the delivery vectors themselves.

“I am most excited about the impact of these medicines on the treatment of so many diseases, including those that have been difficult, or impossible, to treat.”
Professor Kelvin Lee, director at NIIMBL

Group therapies

Spend a few minutes studying the BGTC and it’s hard not to be impressed. This is especially true when you consider who’s involved. Bringing together 11 NIH institutes and centres, as well as commercial players as varied as Biogen, Novartis and Takeda, this is clearly a major undertaking. The same is true in terms of financing, with the BGTC altogether offering around $100m to CGT research. But beyond these headline figures, how exactly will the project support the manufacturing of new cell and gene therapies?

For Silverthorn, it’s fundamentally a question of standardisation. Right now, there are so many different variables around testing, even before human trials can take place, that smaller firms (to say nothing of nonprofits) find it hard to cope. But by developing what Silverthorn calls “a standard set” of quality and preclinical testing requirements, understood and accepted across the sector, she suggests “we can eliminate the cost and time of unnecessary testing and reduce the cost of manufacturing”. “The BGTC,” she continues, “has the highest number of private sector partners out of any of the Foundation’s current partnerships, which speaks volumes about the industry’s desire for better standards and regulatory clarity.” Even better, successful applications to the FDA for human testing will be made publicly available, making it easier for other manufacturers to follow in their wake.

There are clear practical advantages to this approach – especially to the most vulnerable patients. It could mean, after all, that individuals with the rarest genetic disorders might be able to receive treatment before the traditional three-stage development cycle is completed. That’d surely be a godsend to sufferers of numerous diseases, notably Huntingtons, whose genetic cause was first pinpointed in 1993, but where medical progress has lagged. More than that, Lee explains that these ideas could be applied right across the CGT sector. “By developing a platform that is productive, reliable, robust, and well-understood,” he says, “one can imagine using the same platform over and over to produce medicines to treat different genetic diseases by only changing out the ‘gene of interest’, the result being greater regulatory confidence in the approach.”

“I think we are right on the cusp of CGT having a major impact for patients, on par with where antibody-based therapies were 30 years ago.”
Courtney Silverthorn, AVP for research partnerships at the FNIH

Manufacturing isn’t the only area that could be shaped by the BGTC. Upstream of production comes R&D, with Silverthorn claiming that collaborative research on the basic biology of adeno-associated viruses (AAVs) could inform how vectors from these viruses are made in future. That’s shadowed, she continues, by bolstering the efficiency of AAVs, for example lowering their viral loads while still retaining their effectiveness. Given all this, it’s no wonder that Lee is optimistic about the future of the BGTC. “There will always be organisations that will protect their own innovations,” he concedes. “But convergence on manufacturing platforms can ‘lift all boats’ – as was experienced with the biopharmaceutical industry’s growth after convergence on an antibody manufacturing platform.”

Other sectors, other vectors

That last point is worth dwelling on. For if it’s clear that the sector has already witnessed success around the manufacture of antibodies – in 2020, Eli Lilly and Amgen announced a manufacturing partnership, drastically increasing the global supply of Covid-19 therapies – there’s no reason the same principles can’t be applied even more widely. As Silverthorn stresses, the collaborative Accelerating Medicines Partnership model epitomised by the BGTC has worked well in other areas of medicine, including Parkinson’s, Alzheimer’s and schizophrenia, with more projects currently in development. Nor is this especially surprising; with personalised medicine set to become a $922bn industry by 2030, siloed manufacturers focused on large-scale production may struggle to cope.

Not, of course, that old-school manufacturing seems destined to vanish altogether. In Silverthorn’s telling, the point of public-private partnerships like the BGTC is to “supplant, rather than replace” the sector’s current production format – a claim supported by the facts. In the United States, a subsidiary of Roche recently announced plans for a $575m gene therapy innovation centre in Philadelphia. On the West Coast, German giant Bayer has earmarked $200m for a bespoke cell therapy plant in Berkeley. In whatever form it comes, though, both Silverthorn and Lee agree that the future for CGTs looks very bright indeed. As Silverthorn puts it: “I think we are right on the cusp of CGT having a major impact for patients, on par with where antibody-based therapies were 30 years ago.” Considering the field itself is little more 30 years old, that’s a remarkable thing to hear.