Etuvetidigene autotemcel

Etuvetidigene autotemcel is an ex vivo genetically modified autologous CD34+ haematopoietic stem and progenitor cell gene therapy. Autologous CD34+ haematopoietic stem and progenitor cells (HSPCs) are enriched from patient mobilised peripheral blood and transduced with a lentiviral vector (LVV), which inserts one or more copies of the human Wiskott-Aldrich Syndrome (WAS) complementary deoxyribonucleic acid (cDNA) into the cell's genome making the genetically modified cells capable of expressing the functional WAS protein. Following administration, the genetically modified cells engraft and repopulate the haematopoietic compartment. These genetically modified cells containing the corrected WAS protein (WASP) differentiate and produce biologically active lymphoid and myeloid progenitors whose progeny express WAS protein.

Etuvetidigene autotemcel is a gene therapy medicinal product consisting of autologous cells that have been genetically modified ex vivo. The nature of etuvetidigene autotemcel is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

Due to the nature of etuvetidigene autotemcel, a standard toxicological assessment was not applicable and conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted.

The pharmacology, toxicology and genotoxicity of etuvetidigene autotemcel were evaluated in vitro and in vivo. Due to the design of the WAS lentiviral vector (LVV) and reliance on co-expression of other interacting proteins, the WAS protein is not overexpressed, even at high vector copy numbers (VCNs). Therefore, no toxicity due protein overexpression has been seen.

Toxicity studies were performed in vivo in two different WAS knock-out mouse models transplanted with Lin- cells transduced with WAS LVV. These studies demonstrated normal engraftment, differentiation and seeding of lymphoid tissues with no adverse clinical signs, mortalities and no pathologic changes related to the integration of WAS LVV. No toxicities or increases in the tumourigenesis occurred in either model.