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.

Figure 1

CNS delivery access locations require balancing effective delivery with invasiveness of the procedures. CSF access points shown in red (ICV, IT‐CM, and IT‐L); alternative access points to CNS not via CSF shown in grey (IN and IPa). Complexity and risk of administration, as well as achievable drug concentrations in the brain, are lowest for CSF access points that are more distal from the brain (e.g., IT‐L). CSF access points that are in closer proximity to the brain (e.g., IT‐CM) or within the brain (e.g., ICV) can achieve higher drug concentrations in brain, but are more invasive, with increased complexity and higher risks of complications. The IPa delivery can enable high drug exposure in regions of particular interest, but is highly invasive, whereas IN delivery is noninvasive, but so far has fewer applications due to limitations on achievable exposure and compatible drug types. Key examples of biologic modalities via CSF access points are highlighted in figure and further discussed in subsequent section on “Drug delivery considerations for CNS delivery of biologic modalities via CSF.” CNS, central nervous system; CSF, cerebrospinal fluid; ICV, intracerebroventricular; IN, intranasal; IPa, intraparenchymal; IT‐CM, intrathecal‐cisterna magna; IT‐L, intrathecal‐lumbar.