Improved targeting of human CD4+ T cells by nanobody-modified AAV2 gene therapy vectors

TY - JOUR

T1 - Improved targeting of human CD4+ T cells by nanobody-modified AAV2 gene therapy vectors

AU - Hamann, Martin V

AU - Beschorner, Niklas

AU - Vu, Xuan-Khang

AU - Hauber, Ilona

AU - Lange, Ulrike C

AU - Traenkle, Bjoern

AU - Kaiser, Philipp D

AU - Foth, Daniel

AU - Schneider, Carola

AU - Büning, Hildegard

AU - Rothbauer, Ulrich

AU - Hauber, Joachim

PY - 2021/12/21

Y1 - 2021/12/21

N2 - Adeno-associated viruses (AAV) are considered non-pathogenic in humans, and thus have been developed into powerful vector platforms for in vivo gene therapy. Although the various AAV serotypes display broad tropism, frequently infecting multiple tissues and cell types, vectors for specific and efficient targeting of human CD4+ T lymphocytes are largely missing. In fact, a substantial translational bottleneck exists in the field of therapeutic gene transfer that would require in vivo delivery into peripheral disease-related lymphocytes for subsequent genome editing. To solve this issue, capsid modification for retargeting AAV tropism, and in turn improving vector potency, is considered a promising strategy. Here, we genetically modified the minor AAV2 capsid proteins, VP1 and VP2, with a set of novel nanobodies with high-affinity for the human CD4 receptor. These novel vector variants demonstrated improved targeting of human CD4+ cells, including primary human peripheral blood mononuclear cells (PBMC) and purified human CD4+ T lymphocytes. Thus, the technical approach presented here provides a promising strategy for developing specific gene therapy vectors, particularly targeting disease-related peripheral blood CD4+ leukocytes.

AB - Adeno-associated viruses (AAV) are considered non-pathogenic in humans, and thus have been developed into powerful vector platforms for in vivo gene therapy. Although the various AAV serotypes display broad tropism, frequently infecting multiple tissues and cell types, vectors for specific and efficient targeting of human CD4+ T lymphocytes are largely missing. In fact, a substantial translational bottleneck exists in the field of therapeutic gene transfer that would require in vivo delivery into peripheral disease-related lymphocytes for subsequent genome editing. To solve this issue, capsid modification for retargeting AAV tropism, and in turn improving vector potency, is considered a promising strategy. Here, we genetically modified the minor AAV2 capsid proteins, VP1 and VP2, with a set of novel nanobodies with high-affinity for the human CD4 receptor. These novel vector variants demonstrated improved targeting of human CD4+ cells, including primary human peripheral blood mononuclear cells (PBMC) and purified human CD4+ T lymphocytes. Thus, the technical approach presented here provides a promising strategy for developing specific gene therapy vectors, particularly targeting disease-related peripheral blood CD4+ leukocytes.

U2 - 10.1371/journal.pone.0261269

DO - 10.1371/journal.pone.0261269

M3 - SCORING: Journal article

C2 - 34928979

VL - 16

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 12

M1 - e0261269

ER -