A record number of gene therapies achieved regulatory approval in 2024, transforming how biopharma companies treat and potentially cure certain diseases. However, the forecast for gene therapy in 2025 is uncertain. The sector is currently trying to address high manufacturing costs, scale-up difficulties, and toxicity issues.
A “one size fits all” solution to such issues is unlikely, but developments are being made across the field of delivery technologies. Could these innovations boost investment in gene therapy, and help make treatments more commercially viable?
AAV – Honing Tissue Specificity
Adeno-associated virus (AAV) has been used thus far for the majority of in vivo gene therapies. It has become a pivotal tool for many gene therapy developers, enabling safe, long-term expression of therapeutic genes in host cells, and providing cures for a variety of genetic diseases such as sickle cell disease. AAV vectors provide some control over the target tissue, as different serotypes have different tissue tropisms, but ultimately all AAV serotypes accumulate in the liver.
Some parties are developing next-generation AAV vectors that can provide enhanced tissue specificity. One such company is Dyno Therapeutics, which has developed an AI based approach to screen for capsid protein variants that offer precise delivery to tissues that are difficult to reach, such as the central nervous system. For example, bCap 1 is an AAV9 variant engineered for enhanced brain specificity, including 7 sequence edits that result in 100-fold improved transduction efficiency in the brain. These vectors are available for licensing, but Dyno also have collaborations in place to develop proprietary gene therapy vectors for the likes of Roche and Sarepta Therapeutics.
Lipid Nanoparticles (LNPs) – Reducing Immunogenicity
LNPs are synthetic particles made up of phospholipids, cholesterols, ionizable lipids, and PEGylated lipids. LNPs are generally well-tolerated as they are less immunogenic than AAV, meaning that repeated doses can be given without the body developing an immune response to the vector.
The first CRISPR-based gene therapy to enter clinical trials using LNPs was Intellia Therapeutics’ NTLA-2001, now known as Nexiguran Ziclumeran (Nex-z), in late 2020. Nex-z is a treatment for transthyretin (ATTR) amyloidosis. It is given in a single dose to inactivate the pathogenic TTR gene in patients produced primarily in the liver, using a proprietary LNP delivery system carrying an mRNA encoding Cas9 and a gRNA. LNPs work well for this therapy because they also accumulate in the liver, so Nex-z may be given systemically and still efficiently deliver its cargo to the target site.
LNPs specifically face issues with low bioavailability because they are rapidly cleared from the body. This means that high doses have to be used, making manufacturing more complex.
Cell-derived Vesicles (CDVs) – Scaling Up Production
Enter the CDV, a type of extracellular vesicle (EV) with superior productivity. Extracellular vesicles are naturally occurring molecular shuttles used for cellular transport, which achieve comparable therapeutic delivery with LNPs and reduced immunogenicity. CDVs in particular are produced by a simple and fast extrusion step, from virtually any cell type, meaning that they can be manufactured at a low cost and with a yield of up to 100 times greater than EVs. BioDrone Therapeutics are leading the way with their BioDroneTM CDV platform technology, which uses a proprietary extrusion process to generate CDVs. BioDrone are collaborating with Caravan Biologix to deliver CAR-T/CAR-NK based therapies using the BioDroneTM CDVs.
Viral delivery methods – Enhancing Potency
Lentiviral vectors are commonly used for delivering large genes into a patient thanks to their increased packaging capacity compared to AAV, and their ability to integrate into the host genome. These vectors are often used for modifying cells during ex vivo gene therapy such as CAR-T cell therapy, but the drive towards “off the shelf” cell therapies has also led to their use in vivo for delivering CAR genes.
One to watch in this space is EsoBiotec (recently acquired by AstraZeneca), and their proprietary lentiviral vector platform, ENaBL. In January 2025, EsoBiotech announced dosing of a first patient with ESO-T01, an in vivo CAR-T cell therapy that uses ENaBL to deliver a BCMA CAR to patients’ T cells inside the body. ENaBL features CD47 on the viral envelope to reduce vector phagocytosis, which increases the amount of vector available for on-target transduction, and is engineered to be devoid of MHC class I molecules, to reduce immunogenicity.
IP Opportunities
The success of gene therapy long-term will depend on innovations in manufacturing and delivery. IP is therefore an important consideration. Patent protection is available for new and non-obvious vectors/products, based on e.g. modifications that improve efficacy, such as capsid-modified AAV vectors, as well as aspects of the final drug product, such as LNP systems. Methods of producing articles like AAVs, LNPs, EVs, and CDVs can also be protected, as can aspects of the software and apparatus used.
Delivery technologies provide a ‘platform’ for the delivery of various gene therapies, presenting an excellent opportunity to commercialise this IP. Broad patent claims directed to the ‘platform’ may find utility for multiple gene therapy applications and thus enable effective licensing strategies, and the numerous examples of collaborations in this field highlight the importance of a robust IP portfolio. Lastly, brand names for such platforms may also benefit from trademark protection.
We are excited to see the impact that these developments will have on the field. To learn more about how you can protect your IP in the gene therapy field, take a look at our other blog.
