Comparison of MALAT1 antisense oligonucleotide distribution following intracerebroventricular and lumbar intrathecal routes of administration.

Several antisense oligonucleotide (ASO) therapies are currently in clinical trials or approved for treatment of central nervous system (CNS) diseases. Achieving adequate distribution of systemically delivered ASOs in CNS tissues has been hindered by the blood-brain barrier (BBB). To overcome this, delivery of ASOs into cerebrospinal fluid (CSF) via intrathecal-lumbar (IT-L) injection has been utilized in the clinic. However, there is a gradient of distribution resulting in less drug in deep brain regions compared to cortical and spinal cord regions. An alternative direct-to-CSF route of administration, intracerebroventricular (ICV) administration, has been utilized to deliver other therapeutic modalities in the clinic. To our knowledge, a comprehensive comparison study of these two routes of delivery in large animals has not been done for ASOs. Therefore, we conducted a study to compare the ICV and IT-L route of delivery for the MALAT1 ASO in dogs. We delivered the ASO and assessed biodistribution and RNA knockdown (KD) across CNS regions. We found that ICV delivery resulted in substantial bilateral distribution of the ASO and KD. Further, we found that ICV delivery resulted in improved KD in deep brain regions, particularly the caudate, and similar KD in spinal cord regions compared to IT-L delivery.