Cell and gene therapies (CGTs) have long been heralded for their potential to transform outcomes of patients with complex, hard-to-treat diseases, with several of these medicines offering previously unattainable long-term disease modification.
As their use expands across the healthcare landscape, however, safety concerns have come into sharper focus. Issues such as liver toxicity and immunogenicity have, in some cases, tempered enthusiasm for the modality.
A prominent example is Elevidys (delandistrogene moxeparvovec), an adeno-associated viral (AAV) vector-based therapy developed by Sarepta Therapeutics for Duchenne muscular dystrophy (DMD). The treatment drew scrutiny from the US Food and Drug Administration (FDA) after being linked to two patient deaths tied to liver toxicity.
Similar safety signals, including patient deaths in gene therapy studies conducted by Pfizer, Intellia, Rocket and Capsida, have prompted parts of the field to reassess delivery strategies.
In response, some developers are increasingly exploring non-viral approaches. These alternatives are seen by some as offering potential safety advantages in certain contexts, while others point to their ability to reduce the cost and complexity of gene therapy manufacturing.
Even so, while experts interviewed by Pharmaceutical Technology suggest non-viral methods could represent the future direction of gene therapy, most do not expect them to displace viral vector-based approaches in the near term.
The non-viral movement
As gene therapies become a mainstay modality, companies must find ways to ensure their drugs are efficacious and safe, but also scalable and commercially sustainable.
According to Tamas Laufer, an industry-funded PhD student exploring the potential of non-viral gene therapies at the University College London (UCL), non-viral delivery methods could prove instrumental in addressing these final points, as they will likely be simpler to produce at scale.
Laufer is also optimistic that non-viral methods may be able to overcome issues around genotoxicity and immunogenicity sometimes associated with viral alternatives – though he warns that it’s too early to say this with confidence, as these approaches generally remain in their infancy.
Non-viral systems are also more flexible in terms of payload size, Laufer says, which could prove advantageous when designing therapies to correct large genes that are difficult or even impossible to deliver using viral vectors.
Laufer are not alone in shifting towards this approach. Ilya Yasny, a partner at LanceBio Ventures, also see strong potential in non-viral delivery - largely because it may help overcome the unpredictability and manufacturing complexity associated with viral vectors.
For non-viral gene therapies to be a success, Judith Greciet, CEO of Parisian gene therapy biotech, PulseSight, says precise targeting must be a key focal point, while Venkata Indurthi, CSO at contract development and manufacturing organisation (CDMO) Aldevron, believes that further clinical proof is key to unlocking their market promise.
Data suggests that an increasing number of pharma and biotech companies are now focusing on non-viral approaches, though efforts remain mostly in the early stages.
LNPs draw investor attention
The story of the lipid nanoparticle (LNP) began in the 20th century with scientists Pieter Cullis, Michael Hope and Thomas Madden, who invented the delivery approach alongside a team of scientists at the University of British Columbia. Similar to a cell membrane, LNPs can form a protective layer around nucleic acids, allowing the direct delivery of genetic payloads, such as mRNA or DNA, to target cells.
While LNPs have been in use for some time, they rose to prominence in the Covid-19 pandemic, when companies like Moderna and Pfizer used them to encapsulate mRNA in vaccines like SPIKEVAX and Comirnaty. As developers continue to explore the potential of this delivery method, Yasny predicts that LNPs will continue to gain prevalence.
“LNPs hold great potential, but are still at the beginning of the road,” Yasny comments. “Sophisticated, viral-like particles that can distribute effectively to target organs other than the liver could also be a game changer,” he adds.
Indurthi expresses a similar view, explaining that LNPs are “more tunable and controllable” than viral vectors, but their use over traditional viral approaches will depend on what disease a therapy is trying to treat.
Laufer also notes LNPs could be used in an in vivo context in the future – potentially extending their applications to this growing field.
While there are currently no approved LNP-based traditional gene therapies, Alnylam Pharmaceuticals’ Onpattro (patisiran) became the first silent interfering RNA (siRNA) delivered via an LNP to secure approval back in 2018.
According to GlobalData’s Pharmaceutical Intelligence Center, most of the non-viral gene therapies currently in early development employ an LNP-based delivery mechanism.
Researchers wake up to Sleeping Beauty
As Laufer advances his research into non-viral delivery methods, he has developed a particular interest in the Sleeping Beauty transposon approach, which he suggests could help address one of the most pressing challenges in gene therapy development: the high cost of manufacturing.
The method combines a plasmid or minicircle, which incorporates both a transposon protein and a gene of interest, with an mRNA encoding a transposase enzyme. Together, these elements act through a “cut-and-paste” approach – allowing the stable integration of genetic material into a recipient’s genome both in the ex vivo setting.
Alongside their potential to bring down manufacturing costs, Laufer adds that precision gene editing techniques like CRISPR-Cas9 or transposon-based systems can be used to deliver or integrate larger genetic sequences. However, he cautions that this can come with delivery efficiency and expression trade-offs, which both tend to diminish as sequences get larger.
In Indurthi’s eyes, sleeping beauty systems have shown promise, but more so in animal models. However, he does believe they offer an alternative for diseases that require durable expression.
Electro-transfection catches eyes
Another non-viral delivery method becoming increasingly common in the gene therapy sector is electro-transfection, which uses electrical impulses to temporarily open a target cell’s membrane to deliver a genetic payload. Researchers are exploring the approach in both the in vivo and ex vivo settings.
Back in 2023, Vertex and CRISPR Therapeutics made headlines when they secured an approval for pioneering CRISPR-based sickle cell disease therapy, Casgevy (exagamglogene autotemcel), which is manufactured using electroporation.
PulseSight is also betting on this technology, with the company currently planning to take its electro-transfected geographic atrophy (GA) gene therapy, PST-611, to Phase II in Summer 2026.
By directly administering the DNA plasmid into a patient’s ciliary muscle, Greciet says that this method overcomes limitations associated with chemical or viral delivery systems by removing them entirely. A review published in Nanoscale also touts this method as a way to dodge off-target risks.
Despite the growing interest, Yasny is sceptical about electroporation, as he feels more confident in intravenous approaches that are guaranteed to distribute in a targeted manner to the organs.
Viral vectors here to stay
Despite earlier safety concerns surrounding viral vector-based gene therapies, Laufer and Indurthi note that non-viral approaches are likely to coexist alongside their viral counterparts rather than replace them.
Greciet shares a similar view, noting that both approaches are likely to retain distinct roles in the market, given their differing advantages across specific diseases and patient populations.
Indurthi adds that viral gene therapy-prompted immunogenicity is not always tied to the viral vector, as this impact can be caused by the nucleic acid itself. This means, that non-viral systems will not overcome this challenge if associated with the genetic payload.
Looking ahead, Yasny and Indurthi suggest that non-viral systems could represent “the future” of gene therapy, though they emphasise that further development will be required before this potential can be fully realised.
