Jodi L. McBride
The McBride laboratory focuses the majority of its efforts in finding therapies for the neurodegenerative brain disorder, Huntington's disease (HD). Currently, 30,000 people in North America have HD and another 150,000 people are at risk of getting the disease. HD is a fatal, dominant, neurodegenerative disorder caused by a mutation is an expanded trinucleotide (CAG) repeat in DNA at the IT15 locus on chromosome 4. The mutation HD gene (HTT), in turn, encodes mutant huntingtin protein (HTT) with an expanded polyglutamine (PolyQ) stretch at the N-terminus of the protein. The characteristic hallmarks of HD neuropathology include mutant HTT-containing aggregates and pronounced 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 pars compacta. Although aggregates and cell loss are observed in multiple brain regions, neuropathology is most pronounced in the GABA-ergic, medium-sized spiny neurons of the caudate nucleus and putamen, as well as in the glutamatergic, pyramidal cells of the overlaying cortex. 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, there is no treatment that has a significant impact on the devastating course of the disease. Unlike other neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis, HD is strictly genetic and identification of the genetic marker provides the unique opportunity to intercede therapeutically prior to the onset of symptoms that result from neuronal degeneration. In this vein, therapies that can halt or suppress expression of the diseased gene will likely have the greatest success. RNA interference (RNAi) had recently emerged as a leading candidate approach to reduce expression of disease genes by degrading the encoding mRNA.
This laboratory is currently investigating RNAi as a potential therapy for HD using a variety of mouse and nonhuman primate models of the disease. We are currently delivering micro RNAs (miRNAs) that target HTT using different serotypes of recombinant adeno-associated viral vectors (rAAVs) as delivery vehicles. We are interested in assessing the success of these approaches following direct brain injection specifically targeting the striatum, as well as following systemic, vascular delivery of rAAVs that can cross the blood-brain-barrier and transduce cells in multiple brain regions.
Specific projects in the laboratory:
1. Assessing the safety and therapeutic efficacy of RNAi in transgenic and knock-in mouse models of HD using a stereotaxic surgical approach (direct brain injections into the striatum).
2. Assessing the safety and therapeutic efficacy of RNAi in transgenic and knock-in mouse models of HD using a systemic surgical approach to target multiple brain affected regions (systemic injections into the jugular vein or carotid artery).
3. Developing a nonhuman primate model of HD via rAAV delivery of mutant HTT to the caudate and putamen, with a specific emphasis on trying to recapitulate both the motor and cognitive aspects of the disease.
4. Assessing the therapeutic efficacy of RNAi in a nonhuman primate model of HD.
Jodi L. McBride is an Assistant Professor in the Division of Neuroscience at the Oregon National Primate Research Center (ONPRC) and has a joint appointment as an Assistant Professor in the Department of Neurology at Oregon Health and Science University (OHSU). She received a B.S. in Integrative and Molecular Physiology in 1998 from the University of Illinois Champaign/Urbana, then went on to receive a Ph.D. in Neuroscience from Rush University in Chicago in 2005. She conducted her post-doctoral research at the University of Iowa from 2005-2008 and ONPRC from 2008-2010, when she became an Assistant Scientist.
McBride JL, Ramaswamy S, Gasmi M, Bartus RT, Herzog CD, Brandon EP, Zhou L, Pitzer MR, Berry-Kravis EM, Kordower JH. (2006) Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease. Proc Natl Acad Sci 103:9345-9450.
Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N. (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448:39-43.
McBride JL, Boudreau RL, Harper SQ, Staber PD, Monteys AM, Martins I, Gilmore BL, Burstein H, Peluso RW, Polisky B, Carter BJ, Davidson BL. (2008) Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci 105:5868-5873.
Boudreau RL, McBride JL, Martins I, Shen S, Xing Y, Carter BJ, Davidson BL. (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther 17:1053-1063.
See a full listing of Dr. McBride's publications