Building plug-and-play gene therapies

Gene therapy

Inherited genetic disorders can have an enormous impact on a patient’s life. Diseases like haemophilia and Fabry disease are debilitating and require patients to undergo regular injections, usually for life. Others can be life-threatening. Gaucher disease and other Lysosomal Storage Disorders (LSDs) affect mostly children, many of whom die at a young age. But now, significant advances in gene therapies are opening up the prospect of curative treatments for these devastating diseases.

Freeline Therapeutics is one of a new breed of biopharmaceutical companies pursuing the challenge of creating safe and effective therapies for patients with genetic disorders. The company was founded in 2015, based on work done by Professor Amit Nathwani at UCL’s Cancer Institute in collaboration with the St. Jude Children’s Research Hospital in Memphis, Tennessee.

The technology uses a virus vector to get functional copies of the missing or mutated genes directly into a patient’s cells. Newly synthesised proteins are then released into the blood. Crucially, it can achieve long-lasting effects from a one-time infusion. A 2010 clinical trial in haemophilia B patients showed promising results, as Amit recalls:

Freeline logo

“The study showed that we could get stable expression of [blood clotting] Factor IX from a single dose. That was really exciting, because it was the first time anyone had shown that.”

Redesigning the gene carrier

Nonetheless, Amit and his colleagues were disappointed to achieve expression levels of only around five per cent, much lower than had been achieved in animal studies and falling significantly short of a normal range. The team went back to the drawing board to try and design a better treatment, focusing on the ‘capsid’ or protein shell used to deliver the gene. Amit explains:

“We came to the conclusion that the capsids we were using gave us a false sense of security, because they were giving good outcomes in the laboratory. We developed a new, synthetic capsid that resulted in much better gene transfer to human liver cells.”

Data from the new approach was impressive, with Freeline’s haemophilia B gene therapy now able to normalise Factor IX levels, allowing patients to lead normal lives. It has opened the door to creating treatments for other diseases, including Fabry, and Gaucher disease. This potential pipeline attracted the interest of biotech investor Syncona. With UCLB, they launched Freeline Therapeutics in 2015, licensing three gene therapies from UCL. Richard Fagan, Director of BioPharm at UCLB, led the creation of the company with Syncona:

“Gene therapy is a highly innovative field, in which UCL has significant expertise. We were excited to partner with Syncona to commercialise these potentially life-changing technologies.”

Harnessing drug-development know-how

Initially joining Freeline as Chief Scientific Officer, and now scientific adviser to the company, Amit is clear that commercialisation was the best way to get the treatments into the clinic. It also allowed them to optimise the manufacturing method, helping to reduce some of the risks associated with gene therapy for patients.

Syncona made a substantial Series A investment of £25m in 2016, alongside the UCL Technology Fund (UCLTF), and an initial public offering on the US Nasdaq stock exchange followed in 2020, raising $158.8m. These investments have enabled the company to invest in a manufacturing facility, alongside its R&D laboratories in Stevenage. This capability means that they can produce clinical-grade products rapidly, without concerns about bottle-necks or quality, and enable the rapid progress of multiple programmes through pre-clinical and clinical phases.

“The advantage of doing this in a company setting is that we now have a whole bunch of experts working with us who have significant experience of developing drugs in industry. They brought vital know-how that enabled us to come up with very safe and effective ways of generating the vectors.”

Getting treatments into the clinic

The first patient in Freeline’s lead programme in haemophilia B was dosed in 2018. A second programme in Fabry disease entered the clinic in 2019, and a third programme in Gaucher disease is expected to start dosing patients in 2022. The speed of progress has been thrilling for Amit:

“As an academic, even with the support of the MRC, I wouldn’t have been able to take three clinical programmes into clinic in such a short period of time. I’m still very excited that patients are benefiting from some of the technology that we developed at UCL.”

Admitting to being “an impatient man”, Amit is focused on the big milestones which remain ahead, of moving into late-phase studies and progressing the gene therapies to a stage where they are market-ready and can be accessed by patients anywhere in the world. The transferable nature of the technology creates an exciting prospect. Amit is hopeful that they will be able to target other monogenetic disorders, for which there are few available therapies, as well as offer treatments to children:

“The vision is setting up the platform that allows this ‘plug and play’ approach. Now that the capsid has been validated, we have the opportunity to offer gene therapy to children, which is fantastic, because if you can start gene therapy early it reduces the prospect of permanent organ damage. So this would be a new, impactful, potentially curative avenue of hope.”

Visit Freeline