Skip to main content

Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier Proceedings of a Workshop (2018) / Chapter Skim
Currently Skimming:

3 Modalities and Technologies for Brain Delivery
Pages 13-24

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.


From page 13...
... . • The Trojan horse approach shuttles a therapeutic agent into the brain by fusing the therapeutic molecule to a molecule that en gages a receptor on vascular endothelial cells, thus initiating receptor-mediated transcytosis (Boado, Chakravarthy, Walsh)
Read the entire page →
From page 14...
... There are currently three approved biologics that are delivered into the brain or spinal cord, he said. These are ziconotide, a peptide derived from a cone snail toxin that acts on calcium channels to relieve pain; nusinersen, an antisense oligonucleotide to treat infantile spinal muscular atrophy; and cerliponase alfa, an enzymereplacement therapy for Batten disease, a rare inherited CNS disorder in children.
Read the entire page →
From page 15...
... The Trojan Horse Approach According to Frank Walsh, the characteristics required of the shuttle in the Trojan horse approach include rapid uptake and efficient transfer of the cargo into the brain tissue, potency in therapeutic doses, ability to work with different types of cargo (such as antibodies or enzymes) , safety, and translatability across rodent and human species.
Read the entire page →
From page 16...
... Dogs naturally accumulate amyloid beta in their brains as they age and have measurable levels of CSF Aβ. After treatment with KAL-ABP-BBB, the dogs showed a pharmacokinetic profile, CSF to serum ratio, and decreases in CSF Aβ similar to the rat.
Read the entire page →
From page 17...
... , with an antibody that targets the insulin receptor. The fusion protein has dual targeting effects for entry into the brain via the human insulin receptor and the mannose-6-phosphate receptor, which targets peripheral tissues (Boado et al., 2009, 2013)
Read the entire page →
From page 18...
... enables distribution throughout peripheral tissues (central panel) , and the HIR enables brain penetration (right panel)
Read the entire page →
From page 19...
... . Gradinaru, however, said she wanted to use AAV as a vector to deliver multicolored gene labels to the brain as a way of mapping brain circuits, and she wanted to introduce these viral vectors systemically, which would require traversing the BBB.
Read the entire page →
From page 20...
... FIGURE 3-4 The novel genetically engineered adenoassociated virus, AAVPHP.B, efficiently transduces neurons throughout the adult rodent brain, demonstrating its potential to deliver therapeutic molecules to the brain. For comparison, the left panel shows the low levels of in vivo gene transfer achieved when using the older, common AAV9 gene-vehicle.
Read the entire page →
From page 21...
... Golby described preclinical studies in a rat glioma model that showed that focused ultrasound increased both drug delivery and retention (Park et al., 2017) and improved survival (Aryal et al., 2013)
Read the entire page →
From page 22...
... They have also tried CSF co-infusions of therapeutic molecules with substances such as mannitol that enhance distribution by increasing the access of some therapeutics to the perivascular spaces, leading to deeper brain penetration and more widespread distribution overall within the CNS. Intranasal Delivery Thorne has also explored using intranasal delivery to increase distribution of therapeutic antibodies throughout the CNS.
Read the entire page →
From page 23...
... Because they are created from human endothelial cells, they can provide extra support for moving a preclinical program into human clinical trials, she said. They are characterized by the expression of tight junctions and the function of efflux pumps, and certain receptors (such as the LRP-1 receptor)
Read the entire page →
From page 24...
... This model suggests, for example, that the brain–cerebrospinal fluid barrier may play an important role in transferring antibody molecules into the CSF, and that antibody concentrations vary among different compartments of the CSF circulatory system. Shah suggested that better understanding this process could help drug developers better understand how much drug is actually reaching targets in the brain and predict appropriate dosing.
Read the entire page →

Key Terms

  • therapeutic molecules
  • trojan horse
  • insulin receptor
  • fusion protein
  • endothelial cells

  • horse approach
  • brain tissue
  • deliver therapeutic
  • brain uptake
  • therapeutic molecule

  • clinical trials
  • replacement therapy
  • brain tumors
  • brain penetration
  • delivering therapeutic

  • therapeutic doses
  • therapeutic agent
  • therapeutic genes
  • human insulin
  • drug delivery

  • peripheral tissues
  • throughout peripheral
  • eric schaeffer
  • transduced neurons
  • neurons throughout

  • efficiently transduced
  • preclinical studies
  • enzyme replacement
  • transferrin receptor
  • mouse models


    • This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
    More information on Chapter Skim is available.