Research highlights novel gene therapy delivery platform using proteolipid vehicles, enabling the efficient transport of DNA and RNA to cells.
Innovation in and expansion of the field of gene therapy depends on the development of innovative techniques that can safely and efficiently deliver genetic material to human cells. Now in a newly published paper in Cell, researchers have demonstrated the potential of a new delivery system that could accelerate gene therapy by overcoming significant challenges that have limited its clinical application.
A fusogen is a protein that helps cells fuse together by controlling and coordinating membrane fusion, and the new approach employs proteolipid vehicles (PLVs) that incorporate a viral fusogen protein, and which can deliver therapeutic DNA and RNA directly into the cytoplasm of target cells [1]. As gene therapies hold great promise for addressing genetic diseases, cancers and age-related conditions, the ability to deliver these therapies safely and effectively is of critical importance.
Longevity.Technology: Gene therapy has long been seen as a promising method to treat a wide range of conditions, from inherited genetic disorders to cancers. By altering or supplementing defective genes, it offers the possibility of treatments that go beyond traditional drug-based therapies, particularly in targeting the underlying causes of diseases. However, the challenge has always been how to get these therapeutic genes to their target cells effectively and safely. Previous delivery systems, including lipid nanoparticles (LNPs) and viral vectors, have encountered issues such as immunogenicity, limited tissue distribution and the inability to deliver large genetic payloads. The new PLV platform, developed by a team at Entos Pharmaceuticals, aims to address these limitations, providing a redosable, scalable and less immunogenic alternative.
The newly developed fusion-associated small transmembrane (FAST) protein-based proteolipid vehicles mark a significant advancement in the delivery of genetic material, combining key aspects of viral and non-viral delivery methods. Viral vectors, particularly adeno-associated viruses (AAVs), have shown efficacy in gene delivery, but their immunogenicity and restricted repeat dosing have limited their broader use in clinical settings. By contrast, LNPs, which have been used for RNA delivery – most famously in COVID-19 vaccines – are cost-effective but face hurdles in gene delivery to tissues outside the liver, and they tend to trigger immune responses after systemic administration. The integration of FAST proteins into the proteolipid vehicle helps to bypass the endocytosis barrier that LNPs typically face, enhancing gene delivery while mitigating the immune system’s reaction.
PLVs and their mechanism
At the core of this development is the FAST protein, a small viral fusogen isolated from fusogenic orthoreoviruses. Unlike traditional viral fusogens, which are large and prone to antibody neutralization, the FAST proteins used in this study are notably smaller, making them less likely to be neutralized by the immune system and thus suitable for repeated dosing; this feature represents a key advantage over current viral delivery platforms, as it permits the delivery system to be used multiple times without triggering a strong immune response.
The PLV platform combines this FAST protein with a lipid-based formulation, creating a particle capable of delivering DNA and RNA to extrahepatic tissues – organs outside the liver – including muscles, lungs and even the brain. In trials conducted on animal models, these proteolipid vehicles demonstrated broad biodistribution and low immunogenicity. Notably, gene expression was maintained without triggering significant inflammatory responses – a common issue with existing LNPs and viral vectors [1].
Application in Oisín’s follistatin gene therapy
One of the most promising applications of this platform has been demonstrated in a collaboration with Oisín Biotechnologies, whose follistatin gene therapy program is aimed at combating muscle loss, a common issue in age-related diseases. In preclinical trials, the PLVs were used to deliver plasmid DNA (pDNA) encoding follistatin (FST), a protein known to promote muscle growth and strength. The results were striking: mice treated with the PLVs exhibited increased muscle mass, grip strength and enhanced muscle function, compared to control groups. These findings not only help validate Oisín’s decision to adopt the FAST-PLV platform early in its development but also point to the broader potential of gene therapies for treating conditions like sarcopenia and frailty in an aging population.
The sustained gene expression seen in these models – up to one year in some cases – demonstrates the durability of the PLV platform, which is essential for therapies that may require long-term genetic modification or repeated dosing [1]. This durability, combined with the PLVs’ ability to deliver large genetic cargo, such as the CRISPR-Cas9 system, suggests wide-reaching implications for future gene therapies targeting a variety of tissues and conditions.
Challenges and future directions
While the new PLV platform offers significant advantages, some challenges remain. Although the system has shown efficacy in delivering genetic material to multiple tissues, further research is required to optimize tissue-specific targeting, particularly for more complex therapeutic needs like cancer treatments. Additionally, as with any novel delivery method, it will be essential to understand the long-term implications of repeated dosing, especially regarding potential immune system interactions over extended periods.
Another area for future investigation is the application of PLVs in human gene editing therapies. With their capacity to carry large genetic payloads, such as those required for CRISPR-based therapies, PLVs could enable the simultaneous delivery of Cas9 proteins and guide RNA, which would simplify the gene editing process and improve its precision.
As gene therapies continue to evolve, the importance of delivery systems like PLVs is significant; they could hold the key to unlocking the potential of these therapies by ensuring that genetic material reaches its intended target safely and efficiently, while minimizing adverse effects and immune responses. There are interesting times ahead as further refinements to this approach could bring us closer to a new era of precision medicine.
[1] https://www.cell.com/cell/fulltext/S0092-8674(24)00783-9
