Beyond the Liver: Decorated Carriers for Targeted In Vivo Delivery

When it comes to gene therapy development, delivery to the liver is a double-edged sword. Easily targeted by commonly used viral and non-viral vectors, the liver can serve as a depot for strong therapeutic gene expression, or become a barrier for safe and sufficient cargo delivery to other tissues. Especially in the in vivo context, reaching tissues other than the liver can be quite difficult without purposeful vector modification. To illustrate the challenges and advancements in this space, several experts presented during the 26th ASGCT Annual Meeting session, “Beyond the Liver: Decorated Carriers for Targeted In Vivo Delivery.”

During the session, speakers shared their unique approaches for conjugating delivery vehicles to hone in on a particular cell type or disease state to elicit a therapeutic response. Hamideh Parhiz, PhD, from the University of Pennsylvania, spoke about her group’s work on FAPCAR T cells, which involves using anti-CD5-conjugated LNPs carrying cargo to target T cells in order to downregulate fibroblast activation protein (FAP). A single injection of these targeted LNPs into a cardiac fibrosis mouse model successfully reduced fibrosis in the heart and improved cardiac function. Dr. Parhiz noted that in vivo administration circumvents the need to extract, expand, and edit autologous T cells ex vivo, which is time-consuming and expensive.

Semih Tareen, PhD, from Sana Biotechnology reiterated this point in his talk, adding that a patients’ own cells are sick, and many times these ex vivo efforts fail. Dr. Tareen discussed the hurdles for successful in vivo delivery and pointed to examples of engineered viral carriers for targeting immune cells. He highlighted his work with Sana Biotechnology focusing on fusosomes, or pseudotyped lentiviruses that are surrounded by a Nipah virus envelope, which improves CD8+ cell tropism.

On the protein engineering side, Jilliane Perkins, PhD, from the University of Washington described her work with the Colocalization Latching Orthogonal Cage-Key Protein (CoLOCKR) system. In this model, a cage and a key protein are expressed on the T cell surface to specifically bind target cells of interest. Furthermore, she showed that CoLOCKR could be designed to bind viral vectors and improve delivery in the bone marrow after in vivo administration.

Finally, to show how cargo can be altered directly, Anastasia Khvorova, PhD, from UMass Chan Medical School spoke about modification of siRNAs to improve therapeutic efficacy. One example of these modifications was a new type of nucleic acid chemistry, called extended nucleic acids, or exNAs. These exNAs contain an extra carbon in their phosphodiester backbone, which provided significant stability, leading to improved plasma pharmacokinetics and extrahepatic biodistribution in mice. In addition, Dr. Khvorova gave examples of lipid head engineering and altered cargo size that could improve siRNA effectiveness.

While the speakers acknowledged that many of these new carrier modifications are early stage and dependent on particular therapeutic needs, they all expressed their hope in improving delivery outside of the liver. With the aid of other vector engineering approaches, such as high-throughput screening, these collective learnings and efforts have the potential to be used in complementary ways to provide the greatest benefit to patients.

All Annual Meeting registrants can watch sessions on demand through June 23 on the virtual platform. If you didn't register, do so through June 19 to get on-demand access.

Karen Bulaklak, PhD, is a member of the ASGCT Communications Committee and editor of The Vector newsletter.

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