Table 2.
Drug delivery considerations for biologics modalities and explored CSF delivery routes
| Antibody/proteins 1 , 30 | Nucleic acid‐based therapeutics 77 | Gene therapy 78 , 79 , 80 | |
|---|---|---|---|
| Mechanism of action | Neutralization/clearance of pathological extracellular proteins, cytokines, or cell surface receptors | RNA degradation, functional block, and splice modulation | Gene replacement, augmentation, silencing, editing, transgene for immunotherapy |
| Effect site | Brain ISF, cell membrane | Nucleus/cytosol | Nucleus |
| PK driver of effect |
Access to brain ISF Drug concentration in brain ISF Sustained target engagement |
Access to brain ISF Productive cellular uptake Endosomal escape |
Tissue/cell tropism of viral vector Endosomal escape Transgene expression Durable pharmacology |
| CSF delivery route |
Primary: i.v., s.c. Explored: ICV, IT‐L, IN |
IT‐L, IN | i.v., IT‐L; IT‐CM, IPa |
CSF, cerebrospinal fluid; ICV, intracerebroventricular; IN, intranasal; IPa, intraparenchymal; ISF, interstitial fluid; IT‐CM, intrathecal‐cisterna magna; IT‐L, intrathecal‐lumbar; PK, pharmacokinetic.