The McBride Laboratory focuses on finding therapies for the neurodegenerative brain disorder, Huntington's disease (HD). HD is a fatal, genetic neurodegenerative disorder caused by a mutation on chromosome 4. The genetic mutation (CAG repeat) in the HTT gene encodes a mutant huntingtin protein (HTT) with an expanded polyglutamine stretch at the N-terminus of the protein. The characteristic hallmarks of HD neuropathology include mutant HTT-containing aggregates and robust cell loss in numerous regions throughout the brain, such as the striatum (comprised of the caudate nucleus and putamen) cortex, thalamus, hypothalamus and the substantia nigra. Clinically, the most obvious symptoms of HD involve involuntary hyperkinetic movements of the arms, legs, and face, known as chorea. Additionally, HD patients suffer from cognitive deficits, particularly those involving working (short-term) memory, and personality changes including emotional disturbances such as depression, anxiety, impulsivity and apathy.
Currently, projects in the McBride Laboratory focus on using a technique known as RNA interference to shut down expression of the disease causing gene:
RNA interference in the HD mouse and non-human primate striatum to improve motor and cognitive symptoms (direct brain injection)
RNA interference in the HD mouse cortex to improve anxiety and depressive symptoms (direct brain injection)
CNS wide delivery of RNA interference in the HD mouse brain (delivery into vasculature or CSF)
Another focus of the McBride Laboratory has been the creation of a non-human primate model of HD, which recapitulates several of the neuropathological changes and behavioral symptoms seen in human HD patients. Currently, the lab is investigating changes in brain connectivity in this new model using diffusion tensor imaging and resting state functional MRI.
The McBride Lab has recently been involved in a large effort at the ONPRC to characterize a new, genetic model of the neurodegenerative disorder, Batten Disease (BD) in the Japanese Macaque Colony. BD affected animals show key genetic, pathological and behavioral manifestations of disease that seen in human children suffering from BD.
The goal with both the HD and BD models will be to use them to better understand disease progression, to develop biomarkers of disease progression and to assess viable therapies that can translate into the clinic to help human patients suffering from these fatal diseases.
Areas of interest
- Developing therapies for neurodegenerative diseases, including Huntington's and Batten diseases
- Creating non-human primate models of neurodegenerative diseases
- Developing and testing novel gene therapy strategies to deliver genes to the brain
- Assessing brain connectivity in neurodegenerative diseases using novel imaging techniques
- Translational therapeutics
- Viral vectors
- B.S., University of Illinois 1998
- Ph.D., Rush University Medical Center 2005
- Post-doctoral fellowship, Gene Therapy, University of Iowa, 2005-2008
- Post-doctoral fellowship, Neuroscience, Oregon National Primate Research Center, 2008-2010
Honors and awards
- 2008 Keynote Address, Huntington’s disease Society of America conference, Chicago, IL
- 2015 OHSU Technology Transfer and Business Development Award: Top Industry Collaboration
- 2016 OHSU Technology Transfer and Business Development Award: Recognized Industry Collaboration for 2016
Memberships and associations
- American Society of Gene and Cell Therapy, member
- Society for Neuroscience, member
- Society for Neuroscience, Oregon Chapter, member
Kordower JH, Emborg ME, Bloch J, Shuang M, Chu Y, Leventhal L, McBride JL, Chen E, Palfi S, Roitberg BZ, Brown D, Holden J, Pyzalski R, Taylor MD, Carvey P, Ling ZD, Trono D, Hantraye P, Deglon N, Aebischer P. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290(27):767-773, 2000.
McBride JL, Ramaswamy S, Bartus R, Gasmi M, Herzog C, Brandon E, Zhou L, Pitzer MR, Barry-Kravis E, Kordower JH. Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease. Proceedings of the National Academy of Sciences 103(24):9345-50, 2006
Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature 5;448 (7149):39-43, 2007
McBride JL, Boudreau R, Harper SQ, Staber PD, Mas Monteys A, Martins I, Burstein H, Peluso RW, Polisky B, Carter B and Davidson BL. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proceedings of the National Academy of Sciences, 105(15) 5868-5873, 2008
Boudreau RL, McBride JL, Martins I, Shen S, Xing Y, Carter BJ and Davidson BL. Non-allele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Molecular Therapy, 17(6):1053-63, 2009
McBride JL, Pitzer, MR, Boudreau RL, Dufour B, Ojeda SR and Davidson BL. Preclinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington's Disease. Molecular Therapy, 19(12): 2152-2162, 2011
Dufour BD, Smith C, Clark R, Walker T and McBride, JL. Intra-jugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington’s Disease mice, Molecular Therapy, 22(4):797-810, 2014
Keiser M, Kordasiewicz H and McBride JL. Gene Silencing Strategies for Dominantly Inherited Neurodegenerative Diseases: lessons from Huntington’s Disease and Spinocerebellar Ataxia. Human Molecular Genetics, 25(r1):53-64, 2016
Dufour BD and McBride JL. Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington’s disease. Experimental Neurology, 283 (Pt A):308-17, 2016
McBride JL, Neuringer M, Ferguson B, Renner L, McGill T, Stoddard J, Peterson S, Zweig R, Kohama S, Tagge I, Su W, Sherman L, Domire J, Ducore R, Colgin L and Lewis A. Discovery of a CLN7 model of Batten Disease in non-human primates, Neurobiology of Disease, 119: 65-78, 2018
- "Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease." Neurobiology of Disease In: , Vol. 121, 01.01.2019, p. 214-229.
- "Discovery of a CLN7 model of Batten disease in non-human primates." Neurobiology of Disease In: , Vol. 119, 01.11.2018, p. 65-78.
- "Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington's disease." Experimental Neurology In: , Vol. 283, 01.09.2016, p. 308-317.
- "Gene suppression strategies for dominantly inherited neurodegenerative diseases : lessons from Huntington's disease and spinocerebellar ataxia." Human Molecular Genetics In: , Vol. 25, No. R1, 15.04.2016, p. R53-R64.
- "Intravascular AAV9 administration for delivering RNA silencing constructs to the CNS and periphery." Methods in Molecular Biology. Vol. 1364 Humana Press Inc., 2016. p. 261-275 (Methods in Molecular Biology; Vol. 1364).
- "Stereotaxic surgical targeting of the nonhuman primate caudate and putamen : Gene therapy for huntington’s disease." Methods in Molecular Biology. Vol. 1382 Humana Press Inc., 2016. p. 409-428 (Methods in Molecular Biology; Vol. 1382).
- "Viral vector mediated expression of mutant huntingtin in the dorsal raphe produces disease-related neuropathology but not depressive-like behaviors in wildtype mice." Brain Research In: , Vol. 1608, 22.05.2015, p. 177-190.
- "Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain." Nucleic Acids Research In: , Vol. 42, No. 21, 01.12.2014, p. 13315-13327.
- "Intrajugular VEIN DELIVERY OF AAV9-RNAi prevents neuropathological changes and weight loss in huntington's disease mice." Molecular Therapy In: , Vol. 22, No. 4, 2014, p. 797-810.
- "Mutant Huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease." Human Molecular Genetics In: , Vol. 21, No. 2, ddr475, 01.2012, p. 406-420.
- "Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease." Molecular Therapy In: , Vol. 19, No. 12, 12.2011, p. 2152-2162.
- "Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease." Neurobiology of Disease In: , Vol. 34, No. 1, 04.2009, p. 40-50.
- "Transduction of nonhuman primate brain with adeno-associated virus serotype 1 : Vector trafficking and immune response." Human Gene Therapy In: , Vol. 20, No. 3, 01.03.2009, p. 225-237.
- "Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice." Molecular Therapy In: , Vol. 17, No. 6, 2009, p. 1053-1063.
- "Restoring acid-sensing ion channel-1a in the amygdala of knock-out mice rescues fear memory but not unconditioned fear responses." Journal of Neuroscience In: , Vol. 28, No. 51, 17.12.2008, p. 13738-13741.
- "Artificial miRNAs mitigate shRNA-mediated toxicity in the brain : Implications for the therapeutic development of RNAi." Proceedings of the National Academy of Sciences of the United States of America In: , Vol. 105, No. 15, 15.04.2008, p. 5868-5873.
- "Transvascular delivery of small interfering RNA to the central nervous system." Nature In: , Vol. 448, No. 7149, 07.07.2007, p. 39-43.
- "Neurturin gene therapy improves motor function and prevents death of striatal neurons in a 3-nitropropionic acid rat model of Huntington's disease." Neurobiology of Disease In: , Vol. 26, No. 2, 05.2007, p. 375-384.
- "Animal models of Huntington's disease." ILAR Journal In: , Vol. 48, No. 4, 2007, p. 356-373.
- "Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease." Proceedings of the National Academy of Sciences of the United States of America In: , Vol. 103, No. 24, 13.06.2006, p. 9345-9350.
- "Human neural stem cell transplants improve motor function in a rat model of Huntington's disease." Journal of Comparative Neurology In: , Vol. 475, No. 2, 19.07.2004, p. 211-219.
- "Structural and functional neuroprotection in a rat model of Huntington's disease by viral gene transfer of GDNF." Experimental Neurology In: , Vol. 181, No. 2, 01.06.2003, p. 213-223.
- "Neuroprotection for Parkinson's disease using viral vector-mediated delivery of GDNF." Progress in Brain Research In: , Vol. 138, 2002, p. 421-432.
- "Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease." Science In: , Vol. 290, No. 5492, 27.10.2000, p. 767-773.