Systemically administered oligonucleotides do not readily penetrate the blood-brain barrier due to their large size and hydrophilic nature. The intrathecal (IT) route enables the delivery of oligonucleotides to the central nervous system (CNS) by circumventing the blood-brain barrier; however, high concentrations of oligonucleotides in the brain and spinal cord may lead to increased safety concerns. The safety assessment of oligonucleotides via the IT route requires consideration of potential toxicities including hybridization-dependent (on- and off-target effects) and non-hybridization-dependent toxicities. This presentation will provide an overview of relevant guidances, and the type, design, and timing of submission of nonclinical studies intended to support IT administration of oligonucleotide drug products to humans, including treatment of only a small number (usually one or two) of individuals. The presentation will also cover approaches for deriving safety margins to inform human risk assessment. The development of oligonucleotides via direct CNS delivery may raise unique and unknown safety concerns; hence, the safety of oligonucleotide drug products should be carefully evaluated in nonclinical studies.
