Drug delivery
and minimises the risk of sharps injuries and the spread of blood-borne diseases – needle-free (or jet) injection, which penetrates cell membranes through sheer mechanical force, is particularly inefficient, and requires a very large dose.
Electroporation opens pores in cell membranes by subjecting them to an electrical field. The method requires smaller doses than needle-free injections for vaccine applications and is familiar in microbiology research and chemotherapy. In fact, Takis Biotech’s vaccine electroporator is adapted from a large electrochemotherapy tool called a cliniporator. As the electrical conditions required for a vaccine injection are far milder and more specific than those used to fight tumours, the company’s modifications have resulted in a handheld, drill-like device that incorporates four electrodes around a central hypodermic needle. By contrast, Inovio’s Cellectra handhelds are designed to be placed over the injection site after a separate needle is used to deliver DNA intradermally.
“If you do a naked DNA injection, you have a given level of expression, but if you add electroporation on top your level of expression increases by about 100 to even 1,000-fold,” explains Luigi Aurisicchio, Takis’ founder and CEO, adding that the technique also brings its own “adjuvant effect”, prompting a heightened immune response.
In short, the only notable problem with the devices is the fact they’re necessary. For all the work Takis and Inovio have done to develop portable, battery powered and easy-to-use electroporation tools, Aurisicchio admits that convincing people to use them will be difficult, particularly in the low-resource environments most in need of vaccine supplies. “DNA is very stable compared to mRNA, but you need the electroporation,” he sighs. “You need a device. It’s not the classical vaccine you can use in any physician’s office. That’s the disadvantage.”
The search for solutions Aegis Life thinks otherwise. The Entos Pharmaceuticals spinout is positioning its Fusogenix platform as a true ‘second-generation’ LNP-based gene delivery technology for getting DNA to its target without any extra tools. Whereas Pfizer and Moderna’s LNPs deliver their payloads thanks to ionisable cationic lipids that assume a positive charge (and therefore become toxic) in contact with cells, Aegis Life’s incorporate a fusion protein like those that occur naturally on viral vectors – only much smaller and stealthier. “We like LNPs,” says Jiang. “They have nice properties to encapsulate payloads and are much more flexible than viruses, but, with the positive charge on the surface, they basically barge into the cell by knocking down the door. That creates collateral damage and toxicity.” In the terms of that metaphor,
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
viral vector vaccines use fusion proteins to carefully pick the locks on cells – not causing any harm, but leaving just enough evidence to convince the immune system to upgrade its security. Contrast Aegis Life’s fusion-associated transmembrane (FAST) protein – the only known fusion protein that doesn’t cause immunogenicity: it enters cells with a skeleton key. As a result, the Fusogenix platform can be used to simultaneously deliver multiple genetic payloads (whether RNA or DNA) intramuscularly, systemically or orally – over and over again. Aegis Life has also found that, because its DNA survives and functions inside cells for two to three months – compared with the couple of days that injected mRNA takes to degrade – it can be used for single-shot vaccines without compromising the immune response. Like all the approved vaccines, Aegis Life’s first formulation, which is moving into phase II trials, targets the spike protein. Following it up the pipeline, though, is a vaccine that delivers DNA encoding for the spike, envelope and membrane proteins. As almost all coronavirus mutations affect the spike protein, vaccine delivery systems that can multiplex in this way are likely to be variant proof. “What we have, potentially, is a vaccine that only requires one dose, and that can be shipped at room temperature or in a refrigerator,” beams Jiang. “At room temperature, it will last for a month; and in a refrigerator, it will last for a year. It’s cheap, it's easy to distribute and it only requires one shot. That’s what we think the world needs right now.” Developers of other DNA vaccine candidates would make the same claim. Aegis Life is working towards a vaccine that could be delivered via a single tablet within five years, but, in partnership with Merck, Canadian start-up Symvivo already has an oral DNA vaccine delivered by bacterial vectors in clinical trials. The next race, the one that might end the pandemic – and change what it means to be vaccinated – is just getting started. ●
Takis and Inovio both use electroporation, shown here being in vitro, to zap intradermally or intramuscularly injected DNA across cell membranes.
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