Cell and gene therapies (CGTs) have long been heralded for their potential to revolutionize the treatment of complex and previously intractable diseases, offering the tantalizing prospect of long-term disease modification where conventional therapies have fallen short. However, as these advanced modalities gain traction within the healthcare ecosystem, critical safety concerns have increasingly come under scrutiny. Issues such as liver toxicity and immunogenicity have, in certain instances, tempered the initial widespread enthusiasm for the technology.
A prominent case in point is Elevidys (delandistrogene moxeparvovec), a therapy developed by Sarepta Therapeutics for Duchenne muscular dystrophy (DMD). This adeno-associated viral (AAV) vector-based treatment faced significant attention from the US Food and Drug Administration (FDA) following its association with two patient deaths linked to liver toxicity. The serious adverse events associated with Elevidys underscore the inherent risks that can accompany viral vector delivery systems, prompting a broader re-evaluation of safety protocols and delivery strategies across the field.
The concerns surrounding viral vector safety are not isolated to a single therapy. Similar safety signals, including fatalities reported in gene therapy studies conducted by major pharmaceutical companies such as Pfizer, Intellia Therapeutics, Rocket Pharmaceuticals, and Capsida Biotherapeutics, have collectively propelled a significant segment of the industry to reassess and explore alternative delivery mechanisms. This has led to a pronounced and growing interest in non-viral gene therapy approaches, which are increasingly being investigated for their potential to mitigate some of the safety challenges inherent in viral vector-based treatments.
Beyond safety, proponents of non-viral methods also highlight their potential to address manufacturing complexities and reduce the overall cost of gene therapy production. This dual benefit of enhanced safety and improved commercial viability is a powerful driver for innovation in this rapidly evolving sector. While experts acknowledge the significant potential of non-viral methods to shape the future of gene therapy, most do not anticipate them entirely supplanting viral vector-based approaches in the immediate future, suggesting a period of coexistence and specialization.
The Ascendancy of Non-Viral Delivery Systems
As gene therapies transition from experimental treatments to established therapeutic options, the industry faces the imperative to ensure these treatments are not only effective and safe but also scalable and commercially sustainable. This multifaceted challenge is driving the exploration of novel delivery platforms.
Tamas Laufer, an industry-funded PhD student at University College London (UCL) specializing in non-viral gene therapies, posits that these alternative delivery methods are poised to play a crucial role in achieving scalability and commercial sustainability. He anticipates that non-viral approaches will likely exhibit simpler manufacturing processes, facilitating larger-scale production more efficiently.
Laufer also expresses optimism regarding the potential of non-viral methods to circumvent issues of genotoxicity and immunogenicity that have been associated with viral vectors. However, he cautions that it is still too early to draw definitive conclusions, as these approaches are generally in their nascent stages of development. The ability of non-viral systems to accommodate larger genetic payloads also represents a significant advantage, particularly for therapies designed to correct large genes that are challenging or impossible to deliver using current viral vector technologies.
Ilya Yasny, a partner at LanceBio Ventures, shares this positive outlook on non-viral delivery, emphasizing their potential to overcome the inherent unpredictability and manufacturing intricacies associated with viral vectors. The drive towards these alternatives is fueled by a desire for greater control and consistency in the gene therapy manufacturing pipeline.
Judith Greciet, CEO of the Parisian gene therapy biotech PulseSight, stresses that for non-viral gene therapies to achieve widespread success, precise targeting of therapeutic agents to specific cells and tissues must remain a paramount focus. Concurrently, Venkata Indurthi, Chief Science Officer at contract development and manufacturing organization (CDMO) Aldevron, believes that accumulating robust clinical evidence is paramount to unlocking the full market potential of these non-viral modalities. Data trends indicate a growing number of pharmaceutical and biotechnology companies are indeed directing their research and development efforts toward non-viral approaches, although these endeavors largely remain in the early phases of investigation.
Lipid Nanoparticles (LNPs) Capture Investor Interest
The scientific journey of the lipid nanoparticle (LNP) delivery system traces back to the late 20th century, with foundational work by researchers Pieter Cullis, Michael Hope, and Thomas Madden at the University of British Columbia. Mimicking the structure of cell membranes, LNPs create a protective shell around nucleic acids, enabling the direct delivery of genetic material, such as messenger RNA (mRNA) or DNA, to target cells.
While LNPs have been utilized in various applications for some time, their prominence surged during the COVID-19 pandemic. Companies like Moderna and Pfizer successfully employed LNPs to encapsulate mRNA for their highly effective vaccines, SPIKEVAX and Comirnaty, respectively. As researchers continue to explore the broad therapeutic potential of this delivery method, Yasny predicts a sustained increase in LNP adoption.
"LNPs hold great potential, but are still at the beginning of the road," Yasny remarked. He further suggested, "Sophisticated, viral-like particles that can distribute effectively to target organs other than the liver could also be a game changer." This points to ongoing efforts to refine LNP targeting capabilities beyond the liver, a common site of accumulation for many current LNP formulations.
Indurthi echoes this sentiment, characterizing LNPs as "more tunable and controllable" compared to viral vectors. He acknowledges, however, that the ultimate preference for LNPs over traditional viral approaches will likely be dictated by the specific disease a therapy aims to treat and the biological characteristics of the target. Laufer also foresees the potential for LNPs to be employed in in vivo applications in the future, thereby expanding their utility within this burgeoning therapeutic area.
Although there are currently no approved traditional gene therapies utilizing LNPs, Alnylam Pharmaceuticals’ Onpattro (patisiran) marked a significant milestone as the first small interfering RNA (siRNA) delivered via an LNP to receive regulatory approval in 2018. This early success paved the way for further exploration of LNP-based nucleic acid therapeutics. Analysis from GlobalData’s Pharmaceutical Intelligence Center reveals that a substantial proportion of non-viral gene therapies currently undergoing early-stage development predominantly employ LNP-based delivery mechanisms, underscoring their current dominance in this emerging field.
The "Sleeping Beauty" Transposon System Awakens Interest
As Tamas Laufer delves deeper into the potential of non-viral gene delivery methods, he has developed a particular fascination with the Sleeping Beauty transposon system. He believes this approach holds significant promise in addressing one of the most persistent challenges in gene therapy development: the high cost of manufacturing. The Sleeping Beauty system ingeniously combines a plasmid or minicircle, which houses both a transposon protein and the gene of interest, with an mRNA encoding a transposase enzyme. These components work in concert through a "cut-and-paste" mechanism, enabling the stable integration of genetic material into the recipient’s genome. This integration can occur in both ex vivo settings, where cells are modified outside the body, and potentially in vivo.
Laufer further elaborates that precision gene editing technologies, such as CRISPR-Cas9 and transposon-based systems, offer the capability to deliver or integrate larger genetic sequences. However, he prudently notes that this enhanced capacity can be accompanied by trade-offs in delivery efficiency and expression levels, which tend to decrease as the size of the genetic sequence increases.
From Indurthi’s perspective, Sleeping Beauty systems have demonstrated notable promise, particularly in preclinical animal models. He suggests that these systems could offer a viable alternative for treating diseases that necessitate durable gene expression over extended periods. The ability to achieve stable, long-term gene expression is a critical factor for many genetic disorders where continuous therapeutic protein production is required.
Electroporation Emerges as a Viable Delivery Method
Another non-viral delivery technique gaining increasing traction within the gene therapy sector is electroporation. This method utilizes precisely controlled electrical impulses to transiently create pores in a target cell’s membrane, thereby facilitating the entry of a genetic payload. Researchers are actively investigating the application of electroporation in both in vivo and ex vivo therapeutic strategies.
A landmark development in this area occurred in 2023 when Vertex Pharmaceuticals and CRISPR Therapeutics achieved a significant regulatory milestone. They secured approval for Casgevy (exagamglogene autotemcel), the world’s first CRISPR-based gene therapy approved for sickle cell disease. Notably, the manufacturing process for Casgevy utilizes electroporation, highlighting its proven efficacy in a clinically approved therapy.
PulseSight is also strategically investing in this technology. The company is currently planning to advance its electro-transfected geographic atrophy (GA) gene therapy candidate, PST-611, into Phase II clinical trials in the summer of 2026. Judith Greciet explains that by directly administering the DNA plasmid into a patient’s ciliary muscle, this method effectively bypasses the inherent limitations associated with chemical or viral delivery systems by eliminating them entirely. A comprehensive review published in Nanoscale further supports the utility of electroporation as a method for mitigating off-target risks associated with gene delivery.
Despite the burgeoning interest and demonstrated successes, Ilya Yasny expresses a degree of skepticism regarding the widespread applicability of electroporation. He conveys a stronger preference for intravenous delivery approaches, which he believes offer greater assurance of targeted distribution to specific organs. This viewpoint suggests a divergence in expert opinion regarding the optimal delivery route for different therapeutic applications.
Viral Vectors Remain a Cornerstone of Gene Therapy
Despite the earlier safety concerns that have surfaced concerning viral vector-based gene therapies, both Tamas Laufer and Venkata Indurthi emphasize that non-viral approaches are more likely to coexist alongside their viral counterparts rather than completely displace them. This perspective suggests a future where different delivery platforms cater to distinct therapeutic needs.
Judith Greciet concurs with this outlook, positing that both viral and non-viral approaches are likely to retain specialized roles within the market, leveraging their differing advantages for specific diseases and patient populations. The choice of delivery system will ultimately be dictated by the unique biological and clinical requirements of each therapeutic intervention.
Indurthi further points out that the immunogenicity observed in viral gene therapy treatments is not always exclusively attributable to the viral vector itself. He explains that this immune response can also be triggered by the nucleic acid payload. Consequently, non-viral systems may not inherently resolve this challenge if the genetic cargo itself elicits an immune reaction. This nuanced understanding highlights the complexity of gene therapy safety and efficacy.
Looking ahead, both Yasny and Indurthi suggest that non-viral systems may indeed represent "the future" of gene therapy. However, they strongly emphasize that significant further development and rigorous validation will be essential before this transformative potential can be fully realized and broadly translated into clinical practice. The path forward involves continued innovation, robust clinical investigation, and a deeper understanding of the intricate biological interactions governing gene delivery and expression.
Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.
Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content.
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