Gene editing: beyond the hype

Genome editing is an exciting but still nascent field, and companies in the area face as many obstacles as they do opportunities. Sangamo CEO Sandy Macrae told us how his company is being cautious about the hype and finding ways to be financially viable in an emerging space.

‘Cutting edge’ is, for once, a truly apt description when it comes to gene editing – both because the field is pushing medicine into areas we might never have dreamed possible, and because these technologies involve literally cutting DNA at a specific point in the genome.

This has, of course, garnered immense excitement – Doctors Emmanuelle Charpentier and Jennifer Doudna were named winners of the Nobel Prize for chemistry in recognition of their discovery of CRISPR/Cas9 gene editing technology.

Since that discovery, a flurry of gene-editing focused biopharma companies have launched – including Intellia Therapeutics, CRISPR Therapeutics, Caribou Biosciences and Mammoth Biosciences – and the first drug therapies based on the technology are now in human testing for diseases like cancer.

California-based Sangamo Therapeutics is one such company that believes in the powerful potential of in vivo genome editing and regulation, together known as genome engineering, and has built up a sizable preclinical pipeline of genome regulation treatments for diseases such as Huntington’s disease and Amyotrophic lateral sclerosis (ALS).

But when I spoke to CEO Sandy Macrae during the JP Morgan Health Care Conference 2021, he stressed that companies cannot be successful in the area unless they are “wise” about the hype, and understand that focusing purely on in vivo editing is unlikely to be financially viable for some time.

Zinc fingers

Macrae had previously worked at GSK and Takeda before he was recruited by Sangamo.

“They wanted someone who had lots of experience in drug development, was a molecular biologist, and was stubborn enough to take on CRISPR!” he jokes.

Since Macrae joined the company just four years ago, Sangamo has more than tripled its staff and raised $1.6 billion in funding. It has also built its own manufacturing site and launched partnerships with six big pharma companies.

This growth reflects the continued and increasing interest in gene therapy – and with stock prices rising for editing companies across the board, Macrae says there has never been a more interesting time to be in genomic medicine.

“When I started in 2016 it was still a very academic field without much industrial interest. Then over the next two or three years, gene therapy was accepted as something that companies got involved in, and several biotechs have been bought up by big pharma.”

And Macrae notes that we still don’t even know the full potential for the field.

“At the moment it’s mostly being applied to ultra-rare diseases. That can be incredibly effective, but it doesn’t allow for a sustainable business model. That’s why companies like ours have decided to move into larger unmet medical needs such as transplant, multiple sclerosis, or inflammatory bowel disease.”

The company’s primary technology is its zinc finger (ZF) platform. ZFPs can be engineered to make zinc finger nucleases, or ZFNs, which are proteins that can be used to edit genomes by knocking select genes in or out to specifically modify DNA sequences.

ZFPs can also be engineered to make ZFP transcription-factors, or ZFP-TFs, which are proteins that can be used to regulate genomes by selectively increasing or decreasing gene expression.

“Zinc fingers are the most common control gene in the body,” Macrae explains. “We can place them near the promoter of a gene and repress or upregulate it.”

The exact mechanism depends on the disease in question. For example, the company is working on repressing promoter genes in tauopathies in collaboration with Biogen, but its partnership with Novartis is focused on upregulating genes related to autism, both leveraging the ZFP-TF platform.

The genomic medicine journey

Genome editing and regulation are still in their early stages, though, and Macrae says the field’s evolution is likely to come in waves.

“First of all it will be used for ultra-rare monogenic disease. Then it'll be used for common monogenic disease, then polygenic disease or diseases where there's a genetic component. And ultimately we will be able to add genetic influences to diseases that don't have a genetic cause. Hypertension is one example – there are probably 20-30 genes that control your hypertension, and perhaps one day we'll be able to identify which ones we can turn up or down.

“That's some way off, but it could be a whole new way of treating people.”

That said, Macrae notes that the industry needs to be cautious about this hype.

“We have to be thoughtful and prudent, because the worst thing that could happen is that gene editing is used in the wrong kind of patient, where there's a risk without a benefit. That would just slow the whole field down.

“This is still a new area of medicine, and every company is realising that we don't always know as much about some of these rare diseases as we thought we did. We’ve never had treatments for these conditions before, and now that we do we often find that we need to know a lot more about the physiology and the pathology of the disease than we imagined.

“Many companies in this area tell wonderful stories about preclinical potential, but once you’re in a clinical trial it doesn’t matter how clever your science is – what matters is whether the patient gets better, and because of that you really need to understand the potential risk.”

Gene editing, he says, still has to go through a long journey to truly reach this potential.

“That involves collecting as much safety data and uncovering as much about the benefit-risk profile as we can,” Macrae says. “The benefit-risk for a child that's going to die without treatment is unquestioned. The benefit for lowering your cholesterol, when there are other tools you can use, is more uncertain. We shouldn't go there until we have enough data to be sure that it’s safe.

“Maybe in 50 years’ time we’ll be using gene editing for things like that – but while many patients might benefit from gene editing for lowering cholesterol, it’s not going to replace statins for anyone but those with life threatening mutations for a long time.”

On top of this, there are the well-documented manufacturing challenges that come with such a new field.

“I think we’ve all learnt that we need to spend more time earlier on in developing the industrial processes,” Macrae says.

“The call I get most often from headhunters is, ‘Do you know anyone that can do manufacturing in cell therapy?’ The field has grown so rapidly that there are very few people with experience in it. There is also a shortage of manufacturing sites.”

This is part of the reason Sangamo has built its own manufacturing site in California and is building a European site in France.

“Owning your own fate in manufacturing is really important,” says Macrae. “The process of gene editing needs lots of care and attention, and we’re at an early stage of the science where we don’t know all the answers. That's why it’s so important to have your own people in-house who know how to do it well.”

Pragmatic genomics

As such, while Sangamo strongly believes in the potential of in vivo genome editing and regulation, Macrae says that early on the company made a “pragmatic” decision that it shouldn’t depend on the field becoming financially viable anytime soon, and required a near-term strategy that would bring in revenue and benefit patients.

That is why the company is also working on gene therapy and ex vivo gene-edited cell therapy.

“If you’re working in gene editing, you can also work in gene therapy, because you already know a lot about delivery, vectors, molecular biology etc.,” Macrae explains. “So it seemed like a sensible decision for us to work on that while gene editing is still an evolving field.”

The company’s gene therapy pipeline now includes treatments for PKU, Fabry disease and hemophilia A (in partnership with Pfizer).

The next ‘easiest’ area for the company to take on with its existing capabilities was ex vivo gene-edited cell therapy.

In this area, Macrae says he is most excited about the company’s CAR-Treg platform, from its acquisition of French company TxCell.

“Tregs travel to the site of the inflammation and release mediators to calm it. We can put our localising CAR onto the Treg, which takes it specifically where we want it to go. For example, for multiple sclerosis you can use a CAR that takes the Treg to the myelin sheath.”

“You don't need to know the cause of the disease, you just need to know where the disease is.”

Sangamo still anticipates, though, a time when in vivo genome editing and regulation is just as key to the business as these other two pillars – and in fact Macrae anticipates that over time, Sangamo will shift its development focus to genome engineering as the field and science mature.

“Gene therapy can ultimately only take you into the liver,” he explains. “There are 7,000 liver diseases, and only 10-20 of them that are big enough to run large clinical trials. Most of them are rare mutations.”

“Everyone is going to the liver and doing the same disease, and what was already a small population gets sliced and diced between several companies. We therefore don’t see it as a long-term sustainable opportunity.”

“We have the advantage of also being able to edit cells in vivo, and eventually we will be able to do fundamental once-and-done editing in other tissues. It’s just a matter of getting the field there.”

About the interviewee

Sandy Macrae has served as Sangamo’s president and chief executive officer and as a member of the Board of Directors since June 2016. He has twenty years of experience in the pharmaceutical industry most recently serving as the global medical officer of Takeda Pharmaceuticals. From 2001 to 2012, Dr Macrae held roles of increasing responsibility at GlaxoSmithKline, including senior vice president, Emerging Markets Research and Development (R&D).

About the author

George Underwood is pharmaphorum’s Deep Dive magazine editor. He has been reporting on the pharma and healthcare industries for seven years and has worked at a number of leading publications in the UK.