Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption

Conor P. Foley, David G. Rubin, Alejandro Santillan, Dolan Sondhi, Jonathan P. Dyke, Y. Pierre Gobin, Ronald Crystal, Douglas J. Ballon

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.

Original languageEnglish
Pages (from-to)71-78
Number of pages8
JournalJournal of Controlled Release
Volume196
DOIs
Publication statusPublished - 28 Dec 2014
Externally publishedYes

Fingerprint

Mannitol
Blood-Brain Barrier
Intra-Arterial Injections
Brain
Therapeutics
Neuronal Ceroid-Lipofuscinoses
Injections
Transgenes
Blood Vessels
Arteries
Magnetic Resonance Imaging
Genes

Keywords

  • Adeno-associated virus
  • Blood brain barrier
  • Intra-arterial
  • MRI
  • Neural drug delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Foley, C. P., Rubin, D. G., Santillan, A., Sondhi, D., Dyke, J. P., Pierre Gobin, Y., ... Ballon, D. J. (2014). Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption. Journal of Controlled Release, 196, 71-78. https://doi.org/10.1016/j.jconrel.2014.09.018

Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption. / Foley, Conor P.; Rubin, David G.; Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Pierre Gobin, Y.; Crystal, Ronald; Ballon, Douglas J.

In: Journal of Controlled Release, Vol. 196, 28.12.2014, p. 71-78.

Research output: Contribution to journalArticle

Foley, Conor P. ; Rubin, David G. ; Santillan, Alejandro ; Sondhi, Dolan ; Dyke, Jonathan P. ; Pierre Gobin, Y. ; Crystal, Ronald ; Ballon, Douglas J. / Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption. In: Journal of Controlled Release. 2014 ; Vol. 196. pp. 71-78.
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