Studies Illuminate Cause of Fatal Reaction in Gene-Therapy Trial

Targeted delivery of adenoviral vectors by cytotoxic T cells

“…[23][24][25][26][27] Simply increasing the dose of adenovectors administered is not an option because induction of innate inflammatory and immune responses by large quantities of adenoviral proteins may prove lethal. 28,29 One option is to genetically modify the structure of adenoviral vector proteins to remove their native specificities 30,31 and introduce new target cell 15,16,32,33 This approach is of great promise and will likely improve the efficiency and reduce the toxicity of adenoviral vectors. [34][35][36][37][38][39] However, for cancer therapy in particular, retargeting may have a limited ability to allow adenoviral vectors to reach metastatic tumor cell targets that may be present in the multiplicity of different tissues.…”

“…[23][24][25][26][27] Simply increasing the dose of adenovectors administered is not an option because induction of innate inflammatory and immune responses by large quantities of adenoviral proteins may prove lethal. 28,29 One option is to genetically modify the structure of adenoviral vector proteins to remove their native specificities 30,31 and introduce new target cell For personal use only. on April 27, 2019. by guest www.bloodjournal.org From ligands.…”

Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases

“…However, most rAAVs cannot cross the blood–brain barrier (BBB), and different rAAV stereotypes recognize different cell receptors and thus have different tropisms for distinct tissues and cell types ( Agbandje-McKenna and Kleinschmidt, 2011 ; Wang et al, 2019 ), which causes difficulties in delivering rAAVs into the brain by IV administration. Moreover, the required high concentration of virus vectors, rapid immune responses, immunotoxicity, and potential off-targeting to the peripheral tissues may limit the use of IV for rAAV delivery into the brain ( Stephenson, 2001 ; Gessler et al, 2019 ).…”

Gene therapy in nonhuman primate models of human autoimmune disease

“…To understand the cause of this tragic event, rhesus monkeys were treated with high dosages of adenoviral vector, similar to the human trial. 94 From these experiments, evidence emerged that the protein coat of the vector possibly triggered a massive cytokine release by the recipient's immune system.…”