The VLP Promise

Virus-like particles (VLPs) leverage the advantages of both viral and nonviral delivery systems and have the potential to revolutionize the field of cell and gene therapy. But how do they compare with other delivery systems. And what does the future look like? 

The advances made in the field of genomic medicine over the last decade have been truly astounding. Novel gene editing techniques (for example, base, prime and epigenome editing), more sophisticated approaches for gene writing and replacement, tools for reprogramming T cells and the tumor microenvironment (TME) are all propelling the sector forward. I’d love to be able to say that we can fully harness the power of these technologies to create new medicines across the full spectrum of human disease, but sadly this is not yet the case. Existing gene delivery vehicles employed to deliver these exciting new technologies in vivo either lack tissue specificity or are difficult to reprogram, have limitations in cargo capacity, and can lead to other issues, such as immunogenicity or genotoxicity.

Recent years have seen growing interest in employing non-viral technologies as delivery vesicles – primarily due to the success of mRNA COVID-19 vaccines (1). Specifically, LNPs have a couple of advantageous properties over viral delivery vehicles: namely, relatively low immunogenicity and cytotoxicity, and the ability to deliver different types of payload (for example, RNA, proteins, and, to a limited extent, DNA). The primary limitation? It can be challenging to achieve sufficient payload delivery to the cells or tissues of interest with LNPs. Despite efforts to retarget, LNPs naturally gravitate to absorption by the liver and thus delivery of extrahepatic payloads is problematic. As such, LNPs are not well suited for delivering DNA payloads. Finally, non-viral systems are characterized by transient persistence in the circulation, resulting in challenges in delivering payloads (such as DNA) that are needed for a longer time to achieve a therapeutic effect.

Among the various viral delivery systems explored for gene therapy, adenovirus and adeno-associated virus (AAV) are the most extensively studied vectors (2). Engineered AAV vectors have been modified to eliminate non-essential viral genes, such as the cap and rep genes, rendering them unable to replicate. Despite these favorable features, as genomic medicine technologies become increasingly complex, the limited cargo capacity of AAVs (4.7 kb) poses a significant challenge. Moreover, AAVs are poorly compatible with precise, cell epitope-specific retargeting and repeated dosing. They also need to be delivered at high doses leading to concerns about genotoxicity; AAV genomes can integrate into host DNA at a rate of up to 1 percent.

In contrast to AAVs, engineered adenovirus vectors exhibit broad tropism profiles, high transduction efficiency, and packaging capacity. They have also not been found to integrate into the host genome, ensuring a lower genotoxicity risk. However, the major challenges in adenovirus vector development arise from a widely pre-existing viral immunity among the general population, robust innate immune responses to its capsid proteins, and strong adaptive immune responses to synthesized viral and transgene products.

In my view, answers to this “grand challenge” of gene delivery are thankfully just around the corner. The development of virus-like particles (VLPs), which efficiently overcome cargo packaging, safety, and localization issues, hold significant promise for gene therapy. Specifically, there is a reignited interest in VLPs based on “gutless” non-replicative high-capacity engineered adenovirus vectors (HCAdVs) that lack all viral genes except for the capsid packaging signal (2). Addressing immunogenicity concerns associated with the capsid, any remaining virus-based components can be engineered and shielded from the immune system, providing a safe and stable delivery system that is uniquely equipped to carry complex gene cassettes because of a large genome packaging capacity of 36 kb (3, 4). For example, a shielded, retargeted adenovirus-based platform, harnessing the capabilities of HCAdVs, has been combined with exogenous, high-avidity adapter proteins to shield the particle from immune surveillance without affecting the infectivity of the VLP (3, 4, 5). Such VLPs can also be easily reprogrammed to target a tissue or cell of choice, where the large payload can be delivered at high efficiency thanks to the innate ability of the adenovirus capsid proteins to facilitate cellular transport and delivery of cargo into the nucleus (5).

The combination of large payload, exquisite retargeting, and immune “stealth” makes such platforms a very promising vehicle for in vivo delivery of sophisticated genomic medicine technologies. I’m hopeful that this will unlock the true potential of the advances we have witnessed in recent years, enabling us, for example, to reprogram the tumor microenvironment and deliver biological medicines to the site of action, or to reprogram human T cells in vivo. In the latter case, issues of supply chain and cost considerations can be effectively circumvented, permitting access to these medical advances for patients around the world.