The Effect of Bolus Volume and Mechanical Forces on the Biodistribution of ASOs Following Lumbar Intrathecal Administration in Cynomolgus Monkeys (S38.007)

OBJECTIVE: To evaluate the effects of 1) bolus volume and 2) exogenously-applied mechanical forces on exposure of CNS tissue to antisense oligonucleotides (ASOs) along the rostrocaudal neuraxis following lumbar intrathecal (IT) administration in cynomolgus monkeys. BACKGROUND: The IT dosing route offers a solution for bypassing the blood-brain barrier and delivering drugs directly to the CNS. However, use of the lumbar IT dosing route is known to have high inter-patient variability and attempts to use this route to deliver therapeutics to more rostral parts of the neuraxis are challenged by significant caudal-to-rostral drug concentration gradients. DESIGN/METHODS: Animals (n=5 per group, 4 total groups) received a lumbar injection of a pharmacological dose of an ASO targeted to the ubiquitously-expressed long non-coding RNA MALAT1 in either a low (0.8 mL) or high (2.4 mL) volume of injectate and either with or without immediate application of high frequency chest wall oscillation. A microdose of 99mTc-DTPA was spiked into the formulation and the quality of each lumbar injection was monitored by SPECT/CT. Animals were sacrificed 7 days after drug administration and both CNS and peripheral tissues were collected for measurement of tissue ASO concentration and knockdown of MALAT1 RNA message. RESULTS: Early results indicate that the 2.4 mL bolus resulted in greater ASO concentration and RNA knockdown in rostral CNS targets and deep brain structures than the 0.8 mL bolus. The 2.4 mL bolus also lowered local drug exposure in the lumbar spinal cord near the injection site and yielded lower inter-patient variability. CONCLUSIONS: The results from this study will provide strategic guidance for achieving pharmacologically-relevant concentrations of ASOs in specific CNS target tissues in future clinical trials. Disclosure: Dr. Wolf has received personal compensation for activities with Biogen Idec as an employee. Dr. Sullivan has received personal compensation for activities with Invicro as an employee. Dr. Mazur has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Swayze has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Powers has received personal compensation for activities with Isis Pharmaceuticals as an employee. Mr. Hoppin has received personal compensation for activities with inviCRO LLC. Dr. Verma has received personal compensation for activities with Biogen Idec as an employee.