Translational Approaches for Brain Delivery of Biologics via Cerebrospinal Fluid

Abstract

Delivery of biologics via cerebrospinal fluid (CSF) has demonstrated potential to access the tissues of the central nervous system (CNS) by circumventing the blood-brain barrier and blood-CSF barrier. Developing an effective CSF drug delivery strategy requires optimization of multiple parameters, including choice of CSF access point, delivery device technology, and delivery kinetics to achieve effective therapeutic concentrations in the target brain region, whereas also considering the biologic modality, mechanism of action, disease indication, and patient population. This review discusses key preclinical and clinical examples of CSF delivery for different biologic modalities (antibodies, nucleic acid-based therapeutics, and gene therapy) to the brain via CSF or CNS access routes (intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, and intranasal), including the use of novel device technologies. This review also discusses quantitative models of CSF flow that provide insight into the effect of fluid dynamics in CSF on drug delivery and CNS distribution. Such models can facilitate delivery device design and pharmacokinetic/pharmacodynamic translation from preclinical species to humans in order to optimize CSF drug delivery to brain regions of interest.

Early distribution of18 F‐labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non‐human primates

“…Subsequently, CSF mixed with interstitial fluid (ISF) is drained through brain capillaries or leaves the brain via the perivenous space and along cranial and spinal nerves. The CSF is eventually transported out of the CNS by lymphatic vessels in the meninges and soft tissue surrounding the skull 29,33,34 . The mechanism underlying AAV vector entry into the brain parenchyma from the CSF is not fully understood, and the effects of CSF flow on the transport of AAV vectors remain to be elucidated.…”

“…In humans, the total volume of CSF is 100-400 ml, and turnover is three to five times per day. 28,29 Each minute, approximately 350 μl of the CSF is produced in the choroidal plexus and distributed into the subarachnoid space through the fourth ventricle.…”

Advancing New Chemical Modalities into Clinical Studies

“…Delivery to the CNS presents a challenge due to the blood–brain barrier. Therapeutic antibodies have very limited brain distribution when administered intravenously, measuring <1% delivered to the brain.…”

Therapeutic Innovations in Neuroscience: What’s New on the Horizon?

“…Efforts to improve drug delivery to the brain have been intensified in recent years also for other increasingly available biologic modalities like antibodies or nucleic acid‐based therapeutics (e.g., antisense oligonucleotides). Sadekar et al 6 . discuss the delivery of biologic modalities to the brain via the cerebrospinal fluid and multiple CNS access routes, e.g., intracerebroventricular, intrathecal‐cisterna magna, intrathecal‐lumbar, intraparenchymal, and intranasal.…”

“…Efforts to improve drug delivery to the brain have been intensified in recent years also for other increasingly available biologic modalities like antibodies or nucleic acid-based therapeutics (e.g., antisense oligonucleotides). Sadekar et al 6 discuss the delivery of biologic modalities to the brain via the cerebrospinal fluid and multiple CNS access routes, e.g., intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, and intranasal. There have already been successful developments of antisense oligonucleotides (ASOs) delivered via the intrathecal route, like nusinersen (Spinraza), an ASO targeting the survival of motor-neuron 2 (SMN2) in SMA patients, whereas others like tominersen (anti-HTT ASO) for Huntington's disease and tofersen (anti-SOD1 ASO) for ALS have failed so far to deliver in the pivotal trials despite promising exploratory results and are still under clinical investigation.…”