Gene therapy with a molecular address

Delivering genetic material to the right cells is one of the major challenges in gene therapy. PD Dr Dr Ulrike Lange and her team at the Leibniz Institute of Virology have developed an engineered adeno-associated virus (AAV) vector designed to selectively target T cells and natural killer (NK) cells — two important components of the immune system. By equipping the AAV with a molecular “address” that recognizes CD7, a molecule found on the surface of these immune cells, the researchers achieved targeted gene delivery in experimental models. The approach was published in Human Gene Therapy and could provide a new tool for studying and engineering immune cells and for developing gene- and cell-based therapies in the longer term.

Giving the delivery vehicle an “address”

Gene therapy offers a way to treat disease by changing the genetic instructions inside our cells, i.e. correcting a defect or change how a cell functions. However up to date, getting this genetic material into the right cells is a major challenge. One way researchers address this challenge is by using modified viruses as delivery vehicles. Viruses have naturally evolved to enter cells and deliver their genetic material. Researchers can harness this ability by modifying viral vectors so that they can transport genetic instructions without causing any disease that might be associated with the original virus.

Among the most widely used platforms for gene delivery are adeno-associated viruses (AAVs). These small viruses can be engineered to carry genetic material into human cells and have become an important platform of gene delivery – already applied in clinical settings. However, directing AAVs specifically to certain cell types, particularly immune cells such as T cells and NK cells, remains challenging.

This is where the work of PD Dr. Dr. Ulrike Lange’s BMFTR junior research group “Genomics of Retroviral Infections” at the LIV comes in.  In order to design a AAV-based vector to recognize these cells more selectively, they modified the AAV capsid—the protein shell surrounding the virus's genetic material. The team lead by PD Dr Dr Ulrike Lange created a hybrid capsid combining features of two AAV types, AAV6 and AAV9, and equipped it with a specific single-domain antibody. This so called nanobody recognizes CD7, a molecule found on the surface of T cells and NK cells. 

“One can think of the engineered protein on the surface as a molecular ‘address label’ helping the vector to recognize cells carrying CD7, such as T cells and NK cells, and deliver its genetic cargo to them,” explains Hendrik Jahnz, first author of the study.

Using these modified AVVs the researchers were able to successfully demonstrate the delivery of genetic material to both primary human T cells and NK cells in vitro as well as in a humanized mouse model. At the same time, the engineered vector showed reduced delivery to non-target cells compared with unmodified AAV vectors.

Boosting gene expression after delivery

The researchers also sought to improve what happens after the genetic material reaches the immune target cells. To increase the activity of the delivered gene, they introduced an intron into the vector’s genome. An intron is a section of genetic sequence that can influence how efficiently genes are processed and expressed. This modification increased expression of the delivered gene in CD7-positive T cells and NK cells. 

“What we show here is a two-part strategy: Using nanobody-engineering we modify the outside of the AAV and combine this with an optimized genetic cargo to improve expression of the delivered gene. Together, this strategy yields a more precise and efficient AAV vector for immune-cell engineering, which could inform future therapeutic approaches,” says PD Dr Dr Ulrike Lange. 

T cells and natural killer (NK) cells play a central role in protecting the body against disease. Because they can recognize and destroy abnormal cells, they are also important targets for cancer therapies and other forms of immunotherapy. Efficiently delivering genetic material specifically to these immune cells could therefore be valuable for both research and future therapeutic approaches.

The study was conducted in collaboration with Prof Dr Priti Kumar at Yale University and PROVIREX Genome Editing Therapies GmbH. Funding was provided by the National Institutes of Health (NIH) and the Investitionsförderbank Hamburg (IFB) with European Regional Development Fund (EFRE) within the TheraImmune project.

Original Publication

Jahnz H, Hamann MV, Kim H, et al. Development of a Recombinant Adeno-Associated Virus Vector for Human T Lymphocyte- and Natural Killer Cell-Targeted Gene Therapy. Human Gene Therapy. 2026;0(0). doi:10.1177/10430342261487919