The democratisation of cell and gene therapy

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Marc Hummersone, Senior Director of Research and Development (R&D) at Astrea Bioseparations, shares insight on the challenges and opportunities in cell and gene therapy (CGT) with DDW’s Megan Thomas.

Lack of standardisation

According to Hummersone, the major challenge in the CGT space is a lack of throughput that’s due to a lack of alignment of processes. He says: “If you compare that with what’s happening within the monoclonal antibody space, for instance, everybody’s got standardised processes with standardised equipment. That’s not the case in CGT.”

Hummersone indicates that the bespoke nature of cell and gene therapy development means that it’s very difficult for purification processes to be standardised.

DNA purification

“Plasmid DNA is an incredibly important part of molecular biology”, says Hummersone. This is because ultimately, when it comes to what is going to be used for the patient, it is used as a bulk commodity, as we’ve seen more recently with things like vaccines.

It’s also the cargo that is loaded inside viral vectors, which makes it very important. He says: “What we are seeing from a molecular biology perspective is that the genetic material that we want to pack into viral vectors is becoming increasingly complicated. We are now looking at larger plasmid DNA sequences to carry more genetic material, and so we can get a more delicate endpoint with a much larger plasmid DNA sequence. That takes a lot of effort, and some very clever people to get that amount of genetic information into a single plasmid DNA. On top of that, we’ve got to make sure that it’s pure before we use it. Molecular biology is useful in many ways, but we must put an emphasis on its purity as well as its function.”

Extracellular vesicles (EV)

“Right now, exosomes represent the true cutting edge of CGT,” Hummersone continues. “They are the nano vesicles that are released by most cells, and they are really equipped to mediate the intracellular communication via the transfer of genetic information. That’s their basic role.”

Based on this basic premise applied across different areas, from regenerative medicine to diagnostics and so on and so forth, Hummersone believes that EVs represent the next generation of therapeutics.

He says: “What’s particularly interesting for me, is that EVs are involved in so many different physiological processes. So, you can target them specifically in many ways. Also, they have a huge capacity to load genetic material, and so if you couple the ability to target many different forms of tissue with a huge genetic payload, then these guys are particularly interesting when it comes to next generation of therapeutics.”

Moreover, Hummersone adds that they offer the ability to deliver that genetic material in a completely non-toxic way.

Affordability and accessibility

Of the more recently approved CGTs that are available to patients, approximately a third of the cost of those drugs is due to purification alone. Affordability and accessibility for CGTs is something that Hummersone is particularly passionate about, and he reflects on the significant impact that can be made by streamlining purification, which is a speciality of Astrea Bioseparations, particularly in the AstreAdept nano-fibre materials.

Hummersone says: “If you go back to what I’ve said previously, if we’re aligning our manufacturing processes to make those more streamlined, more efficient, and you put those together with improved purification processes, then you’ve got an ability to not only compress processes, but ultimately to compress costs, which I describe as the democratisation of CGT, making them more accessible to the patient. If you can really do that, then you’re not allowing CGT to only be accessible to the ultra-rich or the ultra-privileged, and for me, that’s a requirement for the entire industry to focus on.”

Hummersone shares that when it comes to purification, many of the processes that are being used now have been repurposed from monoclonal antibodies, and so they work, but they don’t work efficiently – the same can be said for the upstream processes for the manufacturing parts. He says: “Let’s not focus on what we can use, but on what we should use to become more efficient to deliver these CGTs and to democratise them.”

AAV purification

The question of adeno-associated virus (AAV) vectors, according to Hummersone, is interesting for several reasons. Firstly, AAV is a delicate vector. Hummersone says: “This means, as I indicated for the purification and lentivirus use, that it is not just about purifying protein, but purifying an active vector that has the capability to deliver genetic information in the way that you intend. Often, the purification processes damage the vector. So yes, you’ve got protein, but it’s not going to transfect or infect.”

He draws on the example of AAV, because while you can purify it, you also have a mixture of capsids both packed and unpacked. “The packed capsids are the ones you really want, as they contain the genetic information that’s going to be transferred to the host”, he says. “But the unpacked capsid can give rise to an immune response, which is not good for the patient. So, not only do we need the packs to be in good working order, but we need to separate the packed capsid from the unpacked capsid.”

This, he says, minimises any sort of target immune responses. As such, when it comes to AAV, you’ve got to be delicate and precise – and, ideally, fast. This is where Astrea Bioseparations’ nanofibre technology for the purification of CGT comes in, as it’s specifically made with large pores so that there is no damage to the materials being purified.

Key development milestones

Hummersone thinks the success of the current state of the industry can be linked to having targeted the correct sort of diseases that can benefit from CGTs. Looking over the last five to eight years, he reflects on the handful of FDA approvals and CGTs that really work well. “But in my mind, they’re only proof of concept”, he says. “They’ve showed that CGT can work, and if you look at the patient populations associated with those FDA approvals, they’re pretty low. I think for the top eight, it’s less than 180,000 people.”

The next big step for Hummersone is using certain CGTs to target much larger patient populations in the millions, tying into why purity is so important, as well as the upstream manufacturing. He says we need to demonstrate that we can treat patients effectively with CGT, equip bodies in a way to fight disease which we’ve now proven can be extrapolated to much larger patient sizes, and then really help people. He adds: “To come back to a previous point, we can’t do that unless we can actually democratise the CGTs, so that they are accessible to the masses. If we’re targeting a mass patient population, we’ve got to be able to make these things at a cost that works for the patient as well as the manufacturers. That’s what we’re dedicated to at Astrea Bioseparations with our technologies: to be able to purify quicker and get greater recoveries and more functional vectors.”

In conclusion, Hummersone said: “We’ve shown that this stuff can work. CGTs are real. Now, we need to move forward and really make it work for the masses.”

Biography

Marc Hummersone has over 20 years of experience with industry leaders such as AstraZeneca, GE Healthcare and Cytiva. His broad experience base lies across technologies including the development of novel chromatographic media for the purification of complex biological feed streams as well as drug discovery and development. His PhD and Post-Doctoral experience were focused on the total synthesis of complex natural products at University College, London.

 

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