Ron Mandel, Ph.D.
Professor
Department of Neuroscience
McKnight Brain Institute
Powell Gene Therapy Center
Contact
information and Mandel lab page
Research Area:
Application of gene transfer to study
animal models of neurodegenerative disorders including Parkinson's disease,
Huntington's disease, Alzheimer's disease, brain tumors, and ischemia.
Current Research:
We investigate two different
strategies to alleviate behavioral deficits in rat models of Parkinson's
disease (PD). We are pursuing both
direct intrastriatal transmitter replacement (L-dopa delivery) and neurotrophic
support strategies (GDNF delivery) in the unilateral 6-OHDA lesion model of PD
(see Kirik et al., 1998.
Exp.Neurol. 152: 259-277 ) using recombinant adeno-associated viral
vectors (rAAV) see
Björklund et al., Brain Research 2002 . We have started analogous studies in primates
to obtain the data necessary to support a Phase I clinical trial using rAAV in
PD. This field has been greatly engergized by very positive findings reported
from Jeffrey Kordower's laboratory using a recombinant lentivirus to deliver
GDNF to the rhesus monkey striatum (see Kordower et
al. 2000, Science 290:767-773 ). We also have very important studies underway to
develop regulated vectors to express GDNF. Click here for recent press article in Applied Neurology that details recent
developments in GDNF for PD.
Another major interest in the laboratory is using rAAV
vectors to study the etiology of Parkinson's disease (see Kirik et al., 2002 below). This interest was
fueled by the important observation that rAAV vectors have a proclivity to
transduce substantia nigra, thus allowing us to render the nigrostriatal tract
transgenic (see first picture here ). We were originally funded by
the Michael J. Fox Foundation for these studies.
We are currently using rAAV to transfer siRNA to the
striatum of transgenic mice expressing a mutant form of huntingtin to determine
if knocking down gene expression will block Huntington's disease-like pathology
(see Rodriguez-Lebron et
al., 2005 and Harper
et al., 2005). Other projects involving gene transfer in Huntington's
disease models concern the trophic factors brain derived neurotrophic factor
(BDNF) and ciliary neurotrophic factor (CNTF).
We have also begun studying a leukodystrophy called
Canavan's disease which is caused by a mutation in the enzyme aspartoasylase
that converts N-acetylacetic acid to aspartate (see below). This disorder
is characterized by vacuolarization and white matter pathology specifically in
the brain. Depending on the remaining enzyme activity, children die between
2-19 years of age and are severely mentally disabled.
We collaborate with Dr. Terry Flotte on ALS related studies to deliver trophic
factors to the entire spinal cord and with Dr. Sean Sullivan in the College of Pharmacy
For information on
Noel N. Batten, the world’s biggest snake oil salesmen. Click here
Representative Publications:
Click here for review papers
click on the appropriate link to download a
specific reprint in Acrobat Reader pdf format (click here for Acrobat Reader)
Reprints are for personal use only. By downloading a reprint you
automatically agree to obey copyright laws.
Denovan-Wright, E., Attis, M.,
Rodriguez-Lebron, E., and Mandel, R.J.
Sustained striatal CNTF expression negatively affects behavior and gene
expression in normal and R6/1 mice Journal
of Neuroscience Research in press.
Burger,
C., Lopez, M.C., Baker, H.V., Mandel,
R.J., and Muzyczka, N. Genome-wide
analysis of aging and learning-related genes in the hippocampal dentate gyrus. Neurobiology of Learning and Memory in
press.
download
preprint
Gorbatyuk, O., Li, S., Sullivan, L., Chen, W.,
Kondrikova, G., Manfredsson, F.P., Mandel,
R.J., and Muzyczka, N. Phosphorylation at Ser129 of α synuclein promotes neurodegeneration in the rat model
of Parkinson disease. Proceedings of the
National Academy of Sciences in press. download reprint
Denovan-Wright, E.M., Rodriguez-Lebron, E., Lewin,
A.S., and Mandel, R.J. Unexpected In vivo off-targeting effects of
ribozymes and siRNA directed against a specific region of human huntingtin
mRNA. Neurobiology of Disease in
press. download
preprint
Foust, K.D., Poirier, A.,
Foust, K.D., Flotte, T.R., Reier, P.J., and Mandel, R.J. Recombinant adeno-associated virus (rAAV)-mediated
global anterograde delivery of GDNF to the spinal cord: comparison of the rubrospinal
and corticospinal tracts in the rat. Human
Gene Therapy 19 (2008) 71-81. download reprint.
Manfredsson, F.P., Burger, C., Muzyczka, N., Lewin, A.S, and Mandel, R.J. rAAV-mediated nigral human
parkin over-expression partially ameliorates motor deficits in a rat model of
Parkinson’s disease. Experimental
Neurology 207 (2007) 289-301. download reprint
Reimsnider, S.K., Manfredsson, F.P., Muzyczka, N. and Mandel, R.J. Time course of transgene expression after intrastriatal pseudotyped
rAAV2/1, rAAV2/2, rAAV2/5, and rAAV2/8 transduction in the rat. Molecular Therapy epub 6-12-07. download reprint
Eslamboli, A., Romero-Ramos, M., Burger, C., Bjorklund, T.,
Fryer, T., Muzyczka, N., Mandel, R.J.,
Baker, H., Ridley, R.M., Kirik, D. Long-term consequences of human
alpha-synuclein over-expression in the primate ventral midbrain. Brain 130 (2007) 799-815. download reprint
Xiromerisiou, G., Hadjigeorgiou, G.M., Eerola, J, Fernandez,
H.H., Tsimourtou, V. Mandel, R., Hellström,
O., Gwinn-Hardy, K. Okun, M.S. Tiernari, P.J. and Singleton, A.B. BDNF tagging
polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse
ethnic groups. Neuroscience Letters
415 (2007) 459-463. download reprint
Scholz, S.W., Mandel,
R.J., Fernandez, H.H., Foote, K.D., Rodriguez, R.L., Barton, E., Munson,
S., Singleton, A., Okun, M.S. LRRK2
mutations in a clinic-based cohort of Parkinson’s disease; video of a G2019S
mutation carrier. European Journal of
Neurology 13 (2006) 1298-1301. download reprint
Fung HC, Scholz S, Matarin M,
Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR,
Langefeld C, Stiegert ML, Schymick J, Okun MS,
Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E,
De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A
Genome-wide genotyping in Parkinson's disease and neurologically normal
controls: first stage analysis and public release of data. Lancet Neurology, 5 (2006) 911-916. download
reprint.
Scholz, S.W., Xiromerisou, G., Fung, H.C., Eerola, J.,
Hellstrom, O., Papadimitriou, A., Hadjigeorgiou, G.M., Tiernari, P.J.,
Fernandez, H.H., Mandel, R., Okun,
M.S., Gwinn-Hardy, K., and Singleton, A.B.
The human prion gene M129V polymorphism is not associated with
idiopathic Parkinson’s disease in three distinct populations. Neuroscience
Letters 395 (2006) 227-229. download reprint
Burger, C., Lopez, M.C., Feller, J.A., Baker, H.V., Muzyczka,
N. and Mandel, R.J. Changes in
transcription within the CA1 field of the hippocampus are associated with age related
memory impairments. Neurobiology of
Learning and Memory 87 (2007).21-41. download preprint. Supplementary
data link1 Supplementary
data link2
Kearns, S., Scheffler, B., Goetz, K.A., Lin,
D., Roper, S., Mandel, R.J., and Steindler, D.A. A high through-put slice
culture bioassay for modeling and repairing Parkinson’s disease. 157 (2006) 1-9. download
reprint
Rodriguez-Lebron, E., Denovan-Wright, E., Nash, K., Lewin,
A.S., Mandel, R.J. Intrastriatal rAAV-mediated delivery of anti-huntingtin
shRNAs induces partial reversal of disease progression in R6/1 Huntington’s
disease transgenic mice. Molecular Therapy 12 (2005) 618-633. download reprint
Tumer, N., Scarpace, P.J., Dogan, M.D., Broxon,
C.S., Matheny, M., Yurek, D.M, Peden, C.S., Burger, C., Muzyczka, N., and Mandel, R.J. Hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related
obesity. Neurobiology
of Aging 27 (2005)
459-470. download reprint.
Carlsson, T., Winkler, C., Burger,
C., Muzyczka, N., Mandel, R.J., Cenci, M.A., Bjorklund, A, and Kirik, D. Reversal of
dyskinesias in an animal model of Parkinson’s disease by continuous L-DOPA
delivery using recombinant AAV vectors. Brain 128 (2005)
559-569 . download reprint
Eslamboli, A., Georgievska, B., Ridley, R., Baker, H.F., Muzyczka, N., Burger, C., Mandel, R.J., Annett, L. and Kirik, D. Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant AAV vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s Disease. Journal of Neuroscience 25 (2005) 769-777. download reprint
Irani, B., Xiang,Z., Mandel, R.J., and Haskell-Leuvano, C. Voluntary exercise overcomes monogenetic
obesity and reproductive dysfunction of the melanocortin-4 receptor knockout
mouse. Biochemical
and Biophysical Research Communications 326 (2005) 638–644. download reprint
Burger, C.,
Nguyen, F. N., Deng, J. and Mandel, R.J. Systemic mannitol-induced hyperosmolality amplifies rAAV-mediated
striatal transduction to a greater extent than co-infusion. Molecular Therapy 11 (2005) 327-331. download reprint
Rogaeva, E., Johnson, J. Lang, A.E., Gulick, C., Gwinn-Hardy, K., Kawarai, T., Sato, C., Morgan, A., Werner, J., Nussbaum, R., Okun, M.S., McInerney, A., Mandel, R., Groen, J.L., Fernandez, H.H., Postuma, R., Foote, K.D., Salehi-Rad, S., Liang, Y., Reimsnider, S., Tandon, A., Hardy, J., St. George-Hyslop, P., Singleton, A.B. Analysis of the PINK1 gene in large cohort of cases with Parkinson’s disease. Annals of Neurology 61 (2004) 1898-1904. download reprint
