Report Summary

Single Dose Toxicity Study of sc-rAA V2.5IL-1Ra in a Mono-iodoacetate-Induced Experimental Model of Osteoarthritis in Wistar Rats

Study Summary

Overall Study Design The purpose of this study was to determine the target organ toxicity biodistribution and 
efficacy of a single dose of rat and human sc-rAAV25IL-1Ra vector followed by a 12 month observation period 
in a MIA-induced OA model in rats 
One hundred and seventy-three male M and 173 female F Wistar rats were randomized into six dose groups 
40M40F in each of Groups I- IV 8M8F in Group V and 5M5F in Group VI Group I- IV animals received 
vehicle control Group I low Group II 5xl0 
vector genome vgright knee mid Group III 5xl0
knee and high Group IV 5xl0 
vgright knee dose of sc-rAAV25riL-l Ra vector expressing rat IL-l Ra and 
Group V animals received high 5xl0
vgright knee dose ofsc-rAAV25hiL-1Ra vector expressing human IL-
lRa The vector or vehicle was administered via intra-articular injection into the right knee of each rat Groups I- 
V and the left knee received no injection The day an animal received vector or vehicle was designated Study 
Day SD 1 for that animal Dose Groups I-IV rats were further divided into five euthanasia subgroups consisting 
of 8M8F each and were euthanized on SDs 7 26 91 180 and 364 The Group V animals were euthanized on 
SD 26 Group VI rats did not receive vector or vehicle dose and were euthanized on SD 8-9 as an arbitrary 
designation Vector dosing was performed in a fashion to avoid dosing all animals within a vector dose group as a 
block or all animals within a group by the same person 
Three days prior to the vector dosing all animals in dose Groups I - V were administered mono- iodoacetate 
MIA 300u g per knee in their right knees to develop the OA model and saline was administered in their left 
knees To minimize potential dosing variation a single technologist performed all of the MIA dosing and another 
performed all of the saline dosing Group VI rats were not dosed with MIA or saline 
In-life endpoints evaluated included clinical observations body weight and feed consumption Vector 
concentration in blood at 4-5 hrs and 24  1 hrs post vector dose was analyzed for the rats in the SD 180 
euthanasia subgroup Assessment of post-mortem endpoints included hematology serum chemistry gross 
pathology organ weight histopathology vector biodistribution cytokine concentrations in serum IL-l Ra 
concentrations in serum IL-l Ra content in knees neutralizing antibodies NAb to AAV25 vector capsid in 
serum and splenic T cell response to AAV25 capsid protein In-life endpoints and some post-mortem 
evaluations were also made in Group VI rats as naive controls 


After intra-articular MIA dosing the OA model was successfully established in the right knees as evidenced by 
chondrocyte necrosis and subsequent development and progression of OA lesions The MIA-induced knee lesions were 
generally consistent with those previously reported in the literature and also confirmed during the secondary pathology 
review by Dr Christopher Evans 
There were no adverse effects on mortality clinical signs of toxicity feed consumption serum cytokine levels 
hematology serum chemistry or organ weights attributable to vector administration Anatomic and microscopic 
pathology examination also did not identify adverse lesions in the right knees or tissues outside the knee attributable to 
vector administration 
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