Why gene therapies must go virus-free

Gene therapies have made spectacular progress in delivering new cures for previously intractable disease, but they remain the world’s most expensive treatments. Now companies are replacing the virus in gene therapies with new delivery technologies that promise not only to overcome the limitations of viral vectors but to slash production costs too.

Moderna and Generation Bio teamed up in April to develop non-viral gene therapies for liver and immune-related conditions, in a deal that builds on Generation Bio’s lipid nanoparticle (LNP) delivery platform. The collaboration is part of a growing trend to swap virus-driven gene therapeutics for innovative nucleic acid delivery platforms that escape the high costs and technical limitations of viral vectors. Engineered lipid or protein nanoparticles, DNA-based nanocarriers, and novel physicochemical methods point the way toward redosable genetic medicines (Table 1).

Virus-based vectors — particularly those based on adeno-associated virus (AAV) and lentiviruses — have dominated the first wave of gene therapies to gain regulatory approval. But their widespread deployment in dozens of clinical trials has exposed their limitations. “One of the issues is just the biomass needed to produce, for example, AAV at the scale and in the doses needed for large indications,” says Akin Akinc, CEO of Aera Therapeutics, a company developing a protein-nanoparticle-based delivery system. AAV vectors are further limited by their 4.7-kilobase packaging capacity; poor tissue selectivity; risk of liver toxicity; and immunogenicity, which eliminates the possibility of redosing. Lentiviral vectors and, to a lesser extent, AAV vectors also elicit oncogenicity concerns arising from chromosomal integration and insertional mutagenesis. Moreover, the theoretical risk of replication-competent viruses emerging from recombination events during lentiviral production necessitates extensive testing in patients.

To provide a viable alternative, non-viral technologies need to satisfy certain well-defined requisites. They must accommodate a large payload and deliver it to specific organs, lack immunogenicity to allow redosing, and have a high safety margin and low production costs. Although most are still preclinical, the field is gaining momentum.

Continue reading the nature article

Sheridan, C. Why gene therapies must go virus-free. Nat Biotechnol 41, 737–739 (2023). https://doi.org/10.1038/s41587-023-01824-6