Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system.
OBJECTIVE
Achieving distribution of gene-carrying vectors is a major barrier to the clinical application of gene therapy. Because of the blood-brain barrier, the distribution of genetic vectors to the central nervous system (CNS) is even more challenging than delivery to other tissues. Direct intraparenchymal microinfusion, a minimally invasive technique, uses bulk flow (convection) to distribute suspensions of macromolecules widely through the extracellular space (convection-enhanced delivery [CED]). Although acute injection into solid tissue is often used for delivery of oligonucleotides, viruses, and liposomes, and there is preliminary evidence that certain of these large particles can spread through the interstitial space of the brain by the use of convection, the use of CED for distribution of viruses in the brain has not been systematically examined. That is the goal of this study.


METHODS
Investigators used a rodent model to examine the influence of size, osmolarity of buffering solutions, and surface coating on the volumetric distribution of virus-sized nanoparticles and viruses (adeno-associated viruses and adenoviruses) in the gray matter of the brain. The results demonstrate that channels in the extracellular space of gray matter in the brain are large enough to accommodate virus-sized particles and that the surface characteristics are critical determinants for distribution of viruses in the brain by convection.


CONCLUSIONS
These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS.
Chen
Michael Y
MY
Division of Bioengineering and Physical Science, ORS National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hoffer
Alan
A
Morrison
Paul F
PF
Hamilton
John F
JF
Hughes
Jeffrey
J
Schlageter
Kurt S
KS
Lee
Jeongwu
J
Kelly
Brandon R
BR
Oldfield
Edward H
EH
D000256:Adenoviridae; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000821:virology; D018481:Convection; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000493:pharmacokinetics*; D049329:Nanostructures; D009995:Osmosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship