Why gene therapies must go virus-free

Gene therapies have made spectacular progress in delivering new cures for previously intractable disease, where virus vectors-particularly those based on adeno-associated virus (AAV) and lentiviruses, have dominated this first wave of gene therapeutics. Nevertheless, they remain the world’s most expensive treatments. Hemgenix, a genetic medicine for hemophilia, is the most expensive drug: it costs $3.5 million per patient. Moreover, the development of several clinical trials highlighted other limitations of virus-vectors in gene therapy. In particular, viral vectors are characterized by limited 4.7-kilobase packaging capacity, poor tissue selectivity, risk of liver toxicity, and immunogenicity, which eliminates the possibility of redosing. Therefore, companies are currently trying to optimize gene therapies with new nucleic acid delivery technologies that promise not only to overcome the limitations of viral vectors but to slash production costs too.

Engineered lipid or protein nanoparticles as virus – free gene therapy

A viable alternative of non-viral gene therapy is to develop lipid or protein nanoparticles able to carry genetic material into cells. To date these delivery nanoplatforms were developed by several biotechs and many have just entered preclinical phase for cure of a wide range of diseases. Novel platforms of Intergalactic (IG-002) and ReCode (DNAI1) Therapeutics are significative examples. The first drug is a nanosystem for electro-transfer based non-viral delivery of DNA for addressing retinopathies. The other is an mRNA-based therapy for the treatment of primary ciliary dyskinesia (PCD) caused by mutations in DNAI1, where lipid nanoparticles (LNPs) are nebulized, and delivered as an aerosol directly into the airway of patients. Nevertheless, these non-viral technologies still need to be optimized in order to satisfy certain well-defined requisite of gene therapy, such as the cell targeting and the release of genetic cargo to the cell nucleus within target tissues. An approach to direct delivery to different organs was developed adding selective organ targeting (SORT) lipid to the classical LNPs. These lipids bind specific serum proteins whose receptors are strongly expressed by the target cells. While the Switzerland Company Anjarium Bioscience introduced “hybridosome“. They are LNPs with exosomes, that can be readily modified externally, and they are also immunologically silent, given their ubiquity in human circulation and tissues.

The liver is an obstacle for gene therapies

Another obstacle to overcome for any systemically delivered gene therapy is the liver, which scavenges from the circulation viral and non-viral vectors alike. Therefore, companies try to engineer DNA-based nanocarriers that have no inherent liver tropism. Code Biotherapeutics’s technology of multivalency, Gensaic’s phage-derived gene therapies, Aera’s approach based on endogenous human proteins derived from retroelements and Nanite’s polymer nanoparticles are examples of nonviral delivery of genetic therapies avoiding the issue of liver trafficking from the outset. Although most of these non-viral gene therapies are still in the clinical trial phase, the field is gaining momentum. Hence, when these innovative nucleic acid delivery platforms will be able to evade the liver and reach at the same time their target organ, the whole experience of gene therapy will become similar to taking a biologic drug. It will take time and effort to deliver this vision — but it is now starting to take shape.

By Annarita D’Urso, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan


Link: https://www.nature.com/articles/s41587-023-01824-6

Doi: https://doi.org/10.1038/s41587-023-01824-6