Rewriting genetic medicine | Business

‘We’re now essentially reforging these really interesting DNA-targeting technologies to something that looks a lot more like a therapeutic,’ says Benjamin Oakes, chief executive of Scribe Therapeutics – a US-based genetic medicine company that is tailoring Crispr editing technology to develop both genetic and epigenetic treatments.

Oakes co-founded Scribe in 2017 alongside three former colleagues from the University of California, Berkeley. These included Oakes’ postgraduate advisors – molecular biologist David Savage and Nobel-prizewinning Crispr pioneer Jennifer Doudna – and Brett Staahl, a former postdoc in the Doudna lab.

Having previously worked on DNA-targeting using zinc finger proteins, Oakes joined Doudna’s research group in 2014, inspired by the ‘sea change’ in genome targeting that her Crispr tools stood to usher in. Following the completion of his studies, Oakes was determined to find ways to harness the technology in the medical space.

‘The ultimate vision that we had at the start of Scribe was genetic medicine should be for everybody, because we all could benefit from it,’ says Oakes. ‘And then the question is, how do you get there?’ The answer, Oakes explains, would involve years of painstaking work to gradually improve Crispr–Cas genetic editing systems’ potency and specificity – transforming them from naturally evolved components of bacterial immunity into finely tuned therapeutic tools. ‘I’m not going to get another Nature Biotech paper, because I improve the potency of a molecule 10% every six months for seven years. But when you do that, you get a very different molecule by the end,’ notes Oakes.

A cornerstone of Scribe’s platform is the CasX enzyme family. According to Oakes, these ‘super rare, super interesting’ proteins perfectly fit the bill ‘in terms of being functional, but also highly specific, and being small enough to fit in any delivery system’. From 2019 to 2021, Scribe spent three years evolving the CasX proteins into what it now dubs its X-Editor, which Oakes describes as ‘the industry leading genome editor’ that demonstrates high uptake into liver cells, while minimising off-target effects.

At that point, Scribe raised $100 million (£74 million) in investment to build on the X-Editing platform and take steps towards its goal of ‘making genetic medicine accessible to everybody’. Aiming to make an impact for as many people as possible, the company has turned its focus towards cardiovascular disease, the leading cause of death globally.

This year, the company will launch a phase 1 human trial of an epigenetic editor for tackling ‘bad’ low-density lipoprotein cholesterol (LDL-C) – a major contributor to atherosclerotic cardiovascular disease (ASCVD). In doing so, Scribe joins a small group of genetic medicine companies that are beginning to probe the safety of medicines based on targeted epigenetic editing in humans. Rather than introducing permanent genetic edits, these epigenetic editors add or remove chemical tags on DNA that regulate gene expression – amplifying or reducing the rate at which specific genes are transcribed into proteins.

Scribe’s STX-1150 candidate therapy aims to epigenetically silence the PCSK9 gene and so reduce the production of low-density lipoprotein cholesterol (LDL-C). The company had initially built a gene editor to target PCSK9, but developed the epigenetic editor as well, Oakes explains. ‘The epigenetic molecule ended up being, not only potentially a more broadly applicable molecule, but one that the data looked better on.’ Scribe’s editor is enhanced by the incorporation of an allosteric control loop, described in a recent preprint, which helps to further improve specificity for the target gene and reduce off-target methylation.

Preclinical studies showed that a single dose of STX-1150 in non-human primates reduced production of LDL-C by more than 50%, with the effect sustained over a monitoring period of 18 months. In May this year, Scribe received clearance from the Australian Therapeutic Goods Administration for its phase 1 trial, planned to include up to 64 participants at sites across Australia and New Zealand. In June, Scribe also received $25 million in grants to develop two further therapies.

While various drugs that lower cholesterol already exist, from antibodies that inhibit PCSK9 to cheap generic statins, Oakes points out that the high number of deaths linked to cardiovascular disease show that it still is not served well enough. In his view, this comes down to a mismatch between the durability of the drugs and the duration of the disease – while a typical statin might have an effect measured in days, the disease itself progresses over decades. That’s why he believes that an epigenetic treatment that could bring about an effect that lasts for years, or even decades, would be transformative.

According to Oakes, the company is ‘thrilled to be headed to the clinic’, and he is excited to see how the technology translates into humans. ‘ASCVD is the leading cause of death globally, [but] the genetics say it doesn’t have to be this way,’ he says. ‘Let’s make that possible.’