Convection-enhanced delivery of M13 bacteriophage to the brain

Laboratory investigation

View More View Less
  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke; and
  • 2 Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage.

Methods

Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution.

Results

Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was –2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity.

Conclusions

The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.

Abbreviations used in this paper:AAV = adenoma-associated virus; AD = Alzheimer disease; CED = convection-enhanced delivery; PBS = phosphate-buffered saline; PD = Parkinson disease; Vd = volume of distribution; Vi = volume of infusion.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address correspondence to: Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3D20, Bethesda, Maryland 20892-1414. email: lonserr@ninds.nih.gov.

Please include this information when citing this paper: published online May 18, 2012; DOI: 10.3171/.2012.4.JNS111528.

  • 1

    Alzheimer's and Parkinson's diseases: advances, concepts and new challenges. Proceedings of the 9th International Conference on Alzheimer's and Parkinson's Diseases. Prague, Czech Republic March 11–15, 2009. Neurodegener Dis 7:5215, 2010

    • Search Google Scholar
    • Export Citation
  • 2

    Asthagiri AR, , Walbridge S, , Heiss JD, & Lonser RR: Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer. Laboratory investigation. J Neurosurg 115:467473, 2011

    • Search Google Scholar
    • Export Citation
  • 3

    Bankiewicz KS, , Eberling JL, , Kohutnicka M, , Jagust W, , Pivirotto P, & Bringas J, : Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 164:214, 2000

    • Search Google Scholar
    • Export Citation
  • 4

    Bobo RH, , Laske DW, , Akbasak A, , Morrison PF, , Dedrick RL, & Oldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:20762080, 1994

    • Search Google Scholar
    • Export Citation
  • 5

    Chen MY, , Hoffer A, , Morrison PF, , Hamilton JF, , Hughes J, & Schlageter KS, : Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg 103:311319, 2005

    • Search Google Scholar
    • Export Citation
  • 6

    Croteau D, , Walbridge S, , Morrison PF, , Butman JA, , Vortmeyer AO, & Johnson D, : Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:9097, 2005

    • Search Google Scholar
    • Export Citation
  • 7

    Deinhardt K, & Schiavo G: Endocytosis and retrograde axonal traffic in motor neurons. Biochem Soc Symp 72 139150, 2005

  • 8

    Dimant H, , Sharon N, & Solomon B: Modulation effect of filamentous phage on alpha-synuclein aggregation. Biochem Biophys Res Commun 383:491496, 2009

    • Search Google Scholar
    • Export Citation
  • 9

    Dimant H, & Solomon B: Filamentous phages reduce alphasynuclein oligomerization in the membrane fraction of SHSY5Y cells. Neurodegener Dis 7:203205, 2010

    • Search Google Scholar
    • Export Citation
  • 10

    Fiandaca MS, , Varenika V, , Eberling J, , McKnight T, , Bringas J, & Pivirotto P, : Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 47:Suppl 2 T27T35, 2009

    • Search Google Scholar
    • Export Citation
  • 11

    Frenkel D, & Solomon B: Filamentous phage as vector-mediated antibody delivery to the brain. Proc Natl Acad Sci U S A 99:56755679, 2002

    • Search Google Scholar
    • Export Citation
  • 12

    Hadaczek P, , Kohutnicka M, , Krauze MT, , Bringas J, , Pivirotto P, & Cunningham J, : Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther 17:291302, 2006

    • Search Google Scholar
    • Export Citation
  • 13

    Havas D, , Rauter G, , Prokesch M, , Hutter-Paier B, , Windisch M, & Solomon B: Effects of filamentous phage treatment on brain pathology of alpha-synuclein tg mice. Neurodegenerative Dis 4:Suppl 1 169, 2007. (Abstract)

    • Search Google Scholar
    • Export Citation
  • 14

    Heiss JD, , Walbridge S, , Asthagiri AR, & Lonser RR: Imageguided convection-enhanced delivery of muscimol to the primate brain. Laboratory investigation. J Neurosurg 112:790795, 2010

    • Search Google Scholar
    • Export Citation
  • 15

    Kaspar BK, , Lladó J, , Sherkat N, , Rothstein JD, & Gage FH: Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839842, 2003

    • Search Google Scholar
    • Export Citation
  • 16

    Kells AP, , Hadaczek P, , Yin D, , Bringas J, , Varenika V, & Forsayeth J, : Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc Natl Acad Sci U S A 106:24072411, 2009

    • Search Google Scholar
    • Export Citation
  • 17

    Krauze MT, , Forsayeth J, , Yin D, & Bankiewicz KS: Convection-enhanced delivery of liposomes to primate brain. Methods Enzymol 465:349362, 2009

    • Search Google Scholar
    • Export Citation
  • 18

    Lieberman DM, , Laske DW, , Morrison PF, , Bankiewicz KS, & Oldfield EH: Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:10211029, 1995

    • Search Google Scholar
    • Export Citation
  • 19

    MacKay JA, , Deen DF, & Szoka FC Jr: Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res 1035:139153, 2005

    • Search Google Scholar
    • Export Citation
  • 20

    Matteoli M, , Verderio C, , Rossetto O, , Iezzi N, , Coco S, & Schiavo G, : Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons. Proc Natl Acad Sci U S A 93:1331013315, 1996

    • Search Google Scholar
    • Export Citation
  • 21

    Rasched I, & Oberer E: Ff coliphages: structural and functional relationships. Microbiol Rev 50:401427, 1986

  • 22

    Rosenbluth KH, , Luz M, , Mohr E, , Mittermeyer S, , Bringas J, & Bankiewicz KS: Design of an in-dwelling cannula for convection-enhanced delivery. J Neurosci Methods 196:118123, 2011

    • Search Google Scholar
    • Export Citation
  • 23

    Saito R, , Krauze MT, , Bringas JR, , Noble C, , McKnight TR, & Jackson P, : Gadolinium-loaded liposomes allow for realtime magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol 196:381389, 2005

    • Search Google Scholar
    • Export Citation
  • 24

    Sanchez CE, , Tierney TS, , Gale JT, , Alavian KN, , Sahin A, & Lee JS, : Recombinant adeno-associated virus type 2 pseudotypes: comparing safety, specificity, and transduction efficiency in the primate striatum. Laboratory investigation. J Neurosurg 114:672680, 2011

    • Search Google Scholar
    • Export Citation
  • 25

    Su X, , Kells AP, , Huang EJ, , Lee HS, , Hadaczek P, & Beyer J, : Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther 20:16271640, 2009

    • Search Google Scholar
    • Export Citation
  • 26

    Szerlip NJ, , Walbridge S, , Yang L, , Morrison PF, , Degen JW, & Jarrell ST, : Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg 107:560567, 2007

    • Search Google Scholar
    • Export Citation
  • 27

    Varenika V, , Kells AP, , Valles F, , Hadaczek P, , Forsayeth J, & Bankiewicz KS: Controlled dissemination of AAV vectors in the primate brain. Prog Brain Res 175:163172, 2009

    • Search Google Scholar
    • Export Citation

Metrics