Büning, Hildegard - C 1

Tailoring AAV vectors for cutaneous gene transfer and gene therapy



Gene Therapy has emerged as promising strategy for the treatment of inherited, acquired and degenerative diseases. From the portfolio of viral and non-viral gene transfer vector systems currently developed for clinical application, we chose to work on vectors based on the Adeno-Associated Virus (AAV), a non-pathogenic, replication-deficient member of the parvovirus family.

AAV vectors are widely used for long-term in vivo gene transfer into post-mitotic tissues, for which AAV serotype 2 (AAV-2) or the more recently developed serotypes have tropism. Furthermore, AAV vectors are valuable tools for transient genetic modification of proliferating cells/tissues, for gene correction approaches and in vaccine development.

Like many other viruses, AAV show a broad tropism. While this is advantageous for ex vivo gene transfer, off-target transduction following in vivo application represents a major challenge. In particular, the high vector doses required to achieve clinical benefit may increase the likelihood of side effects such as host immune responses or the occurrence of toxicities related to off-target gene expression. Additionally, using these “conventional” AAV vectors high particle-per-cell ratios are needed to overcome pre- and/or post-entry barriers in a number of cells (i.e. endothelial cells, hematopoietic progenitor/stem cells), which represent important targets in Gene Therapy.

We address these key limitations by two interrelated approaches: The in depth analysis of the host/cell-vector interactions, and the development of engineering strategies to overcome identified barriers towards efficient gene delivery, and to re-direct and restrict vector tropism towards the target cell type.

This results in the generation of specifically tailored vectors that can be used as optimized gene transfer tools for the development of novel Gene and Cell Therapy based treatment strategies related to a wide range of medical applications (i.e. Regenerative Medicine, hematology/oncology, cardiology, infectious diseases, rare genetic disorders). In addition, we exploit our capsid engineering strategy to decrease immogenicity of AAV vectors in Gene Therapy and to augment immunogenicity of AAV vector-based vaccines.

Buchholz CJ, Friedel T, and Buning H (2015). Surface-engineered viral vectors for selective and cell type-specific gene delivery. Trends in biotechnology 10.1016/j.tibtech.2015.09.008.

Buning H, Huber A, Zhang L, Meumann N, and Hacker U (2015). Engineering the aav capsid to optimize vector-host-interactions. Current opinion in pharmacology 24, 94-104.

Millet R, Jolinon N, Nguyen XN, Berger G, Cimarelli A, Greco A, Bertrand P, Odenthal M, Buning H, and Salvetti A (2015). Impact of the mrn complex on adeno-associated virus integration and replication during co-infection with herpes simplex virus type 1. J Virol JVI.00171-15 [pii]10.1128/JVI.00171-15.

Mingozzi F, and Buning H (2015). Adeno-associated viral vectors at the frontier between tolerance and immunity. Front Immunol 6, 120.

Munch RC, Muth A, Muik A, Friedel T, Schmatz J, Dreier B, Trkola A, Pluckthun A, Buning H, and Buchholz CJ (2015). Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors. Nat Commun 6, 6246.

Seyffert M, Glauser DL, Tobler K, Georgiev O, Vogel R, Vogt B, Agundez L, Linden M, Buning H, Ackermann M, and Fraefel C (2015). Adeno-associated virus type 2 rep68 can bind to consensus rep-binding sites on the herpes simplex virus 1 genome. J Virol 89, 11150-11158.

Selected publications 2014

Horner M, Kaufmann B, Cotugno G, Wiedtke E, Büning H, Grimm D, and Weber W (2014). A chemical switch for controlling viral infectivity. Chem Commun (Camb) 50, 10319-10322.

Hosel M, Lucifora J, Michler T, Holz G, Gruffaz M, Stahnke S, Zoulim F, Durantel D, Heikenwalder M, Nierhoff D, Millet R, Salvetti A, Protzer U, and Büning H (2014). Hepatitis B virus infection enhances susceptibility toward adeno-associated viral vector transduction in vitro and in vivo. Hepatology 59, 2110-2120.

Neerincx A, Jakobshagen K, Utermöhlen O, Büning H, Steimle V, and Kufer TA (2014). The n-terminal domain of nlrc5 confers transcriptional activity for mhc class I and II gene expression. J Immunol 193, 3090-3100.

Sallach J, Di Pasquale G, Larcher F, Niehoff N, Rubsam M, Huber A, Chiorini J, Almarza D, Eming SA, Ulus H, Nishimura S, Hacker UT, Hallek M, Niessen CM, and Büning H (2014). Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy. Mol Ther 22, 929-939.

Vogt A, Sievers E, Lukacs-Kornek V, Decker G, Raskopf E, Meumann N, Büning H, Sauerbruch T, Strassburg CP, Schmidt-Wolf IGH, and Gonzalez-Carmona MA (2014). Improving immunotherapy of hepatocellular carcinoma (hcc) using dendritic cells (dc) engineered to express Il-12 in vivo. Liver Int 34, 447-461.

Former Funding Period 01/2014 - 12/2016

Information from this funding period will not be updated anymore. New research related information is available here.


Prof. Dr. rer. nat. Hildegard Büning

CMMC and Institute of Exp. Hematology - Hannover Medical School

Prof. Dr. rer. nat. Hildegard Büning

Work +49 221 478 89611

Fax (Work) +49 221 478 97332

CMMC-Research Building
Robert-Koch-Str. 21
50931 Cologne

Publications

Link to PubMed