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Report Summary

Assessment of Safety and Tissue Distribution of the Lenti/BAS3-FB Lentiviral Vector in C57BL/6J Mice


Study Summary

Overall Study Design 
The goals of this study are to 1 Assess the safety of LentiBAS3-FB lentivirus vector in C57BL6J mice 
including the potential for insertional mutagenesis Safety will be compared to that observed in animals receiving control 
sham transduced bone marrow cells and animals dosed with cells transduced with a Moloney Murine Leukemia virus 
based y-retroviral vector which served as a positive control 2 Further assess safety by inducing replication stress on the 
transduced bone marrow stem cells by administering a limited dose of bone marrow cells from the primary study animals to 
secondary recipient mice 3 Assess 
the vector genome numbers and integration sites in tissues of primary and secondary recipient mice receiving either 
LentiBAS3-FB or positive control-transduced cells at 4 or 6 months post-dosing 4 Assess leukemogenesis in primary and 
secondary mice receiving either Lenti BAS3-FB or positive control-transduced cells 
Justification 
Integrating gene delivery vectors can lead to stable and inheritable gene modification of hematopoietic stem cells to allow 
for correction of genetic disease A risk of using integrating vectors is the occurrence of insertional mutagenesis in which the 
vector provirus disturbs the genetic function of adjacent chromosomal regions most commonly by trans-activation of 
transcription from nearby cellular genes 
Trans-activation of genes influencing cellular growth survival or differentiation may lead to clonal expansion which can 
further progress to transformation a process called Insertional Oncogenesis IO 
There is no validated toxicology system available to evaluate the risks of IO of specific integrating 
vectors that has been correlated with clinical outcomes IO may be modeled in mouse bone marrow transplants BMT using 
HSC transduced with integrating vectors Vectors with the most potent enhancers cause clonal skewing in which a sub-set 
of the transduced stem cells expand preferentially due to the influence of the integrated vectors on adjacent 
proto-oncogenes Clonal skewing can be detected using high-through-put vector integration site analytical methods In rare 
cases there may be progression 
to leukoproliferation and leukemialymphomas This risk can be estimated 
The goal of this toxicology study was to assess the safety of a new lentiviral vector LentiBAS3-FB by measuring its ability to 
cause clonal skewing and leukemogenesis in a murine BMT model Murine bone marrow lineage-negative cells were 
transduced with the LentiBAS3-FB vector A positive control was used similar to the g-RV that has previously been 
associated with leukoproliferation in human clinical 
trials and animal studies 1 2 Mock-transduced bone marrow was transplanted as a negative control Marrow was 
transplanted into both 1o and 2o recipient mice Clinical and laboratory safety was assessed as well as clonal integration 
site patterns 


 
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