RESEARCH PROGRAM
The Bohn lab is interested in
understanding and applying developmental mechanisms to generate novel
approaches for neurodegenerative diseases. The present focus is on developing
gene and stem cell therapies using rodent models of Parkinson’s disease and
amyotrophic lateral sclerosis (ALS).
Previous studies in the lab on the effects of the neurotrophic factor,
glial cell line-derived (GDNF) in rat models of Parkinson’s disease are now
being translated to clinical trials for patients afflicted with Parkinson’s
disease. Current studies are
focused on neuronal rejuvenating therapies using stem cells derived from bone
marrow, gene silencing of a gene linked to hereditary forms of Parkinson’s
disease and on therapeutic gene targeting of upper motoneurons for ALS.
Mesenchymal stem cell
therapies for Parkinson’s disease.
Parkinson’s disease is a
prevalent movement disorder that debilitates over 1.5M individuals in the US. There is no cure for Parkinson’s and
the effects of drugs that ameliorate clinical symptoms in early stages of the
disease lose effectiveness as the disease progresses. The primary basis of Parkinsonian symptoms is the slow
degeneration of nigrostriatal dopaminergic neurons. In addition to attempts to develop new drugs and surgical
approaches, experimental strategies are focused on either replacing the
dopamine neurons with stem cells or fetal dopamine neurons, or stimulating
rejuvenation of damaged dopamine neurons with gene therapy. While each of these strategies
has merit, to date, none has met with clear success in the clinic. We are working on a paradigm shift in
thinking about how stem cells can be used to rejuvenate, rather than replace, the intrinsic
DA neurons that are lost in
Parkinson’s by harnessing the tropic effects of mesenchymal stem cells
(MSC) derived from bone marrow. These cells are easily procured, they lack the ethical issues
presented by other stem cell sources, and host immune responses leading to
rejection or graft-vs-host disease could be precluded in the clinic through the
use of patient-specific stem cells. In addition, cell approaches for Parkinson’s disease are
usually focused on replacing dopamine neurons, thus presenting an extreme
challenge not only in directing differentiation of the cells to the correct
phenotype, but also of re-establishing the sophisticated circuitry of the
nigrostriatal system. In our
approach, the circuitry is already in place or partially in place, but is
damaged and needs to be rejuvenated.
The grafted cells do not need to be differentiated into dopamine
neurons. MSC secrete an
array of extracellular matrix
molecules and factors with neurotrophic and neuroprotective activities,
suggesting these cells may promote recovery of DA neurons better than delivery
of a single neurotrophic factor, such as GDNF. Studies in
progress in the Bohn laboratory are focused on using neuroprogenitors derived
from genetically modified MSC to reinvigorate damaged nigrostriatal dopamine
neurons and their striatal projections. This approach is in distinct contrast to other stem
cell approaches being developed to replace dead or dying DA neurons and is supported
by key observations from studies in our laboratory.
Small Interference RNA
vectors and cell death genes.
A small percentage of cases of
Parkinson's disease are linked to mutations in the gene alpha-synuclein. In
addition, alpha-synuclein is known to aggregate in cells forming Lewy bodies.
Lewy bodies are characteristic of both Parkinson's disease and other
neurodegenerative diseases called synucleinopathies, such as Dementia with Lewy
Bodies (DLB). Our lab has generated viral vectors that express a small
inhibitory double stranded RNA in cells that completely turns off expression of
human alpha-synuclein. Various designs of silencing vectors have been made in
the context of lentivirus and/or adeno-associated virus (AAV). These are being tested in vivo and in vitro for specificity of gene silencing and degree of neurotoxicity. In vivo studies are in progress in an alpha-synuclein
dependent rat model of Parkinson’s disease to test the hypothesis that
silencing alpha-synuclein gene expression in dopamine neurons will lead to
protection of these neurons and dopaminergic function. In addition, viral vector mediated gene
silencing is being applied to other genes that are up-regulated in endoplasmic
reticulum (ER) stress induced neuronal cell death with the idea of using gene
therapy to interfere directly with cell death pathways.
Gene therapy for ALS.
Previous studies in the Bohn laboratory have shown that delivery of a neurotrophic factor gene to lower motoneurons in the spinal cord protects these neurons from cell death and ameliorates motor deficits in a mouse model of ALS. In studies being carried out in collaboration with hande Ozdinler's laboratory at Northwestern, gene therapy approaches are being developed to target upper motoneurons in mouse cortex. Varoius serotypes of adeno-associated viral vectors (AAV) are being tested for their ability to deliver therapeutic gene products to upper motoneurons following injection into the spinal cord. Studies are based on the capability of AAV to be retrogradely transported by axoms. Identification of a following injection into the spinal cord. Studies are based on the capability of AAB to be retrogradely transported by axons. Identification of a highly tropic AAV serotype for upper motoneurons will lead to functional studies of gene delivery to these neurons in novel mouse models of ALS.
MEMBERSHIPS
Center for Genetic Medicine
Lurie Cancer Center
Interdepartmental graduate program (IGP)
Northwestern University Institute for Neuroscience graduate
program (NUIN)
American Association for the Advancement of Science
New York Academy of Sciences
Society for Neuroscience
International Society for Neurochemistry
American Society for Neural Therapy and Repair
Gene Therapy/Molecular Biology International Society
Society for Neurochemistry
American Society of Gene Therapy
International Society for Stem Cell Research
RESEARCH FUNDING ACKNOWLEDGMENT
National
Institutes of Health, Department of Defense, Medical Research Institute Council, State of Illinois
Excellence in Academic Medicine, Chicago Biomedical Consortium, State
of Illinois Regenerative Medicine Institute, NUCATS, Michael J. Fox
Foundation, Chaddick Foundation, Walden W. and Jean Young Shaw
Foundation, Mrs. Sandra Kamin, Parkinson's Disease Foundation, National Science
Foundation, Muscular Dystrophy Foundation, National Parkinson's Disease
Foundation, United Parkinson's Disease Foundation, American Parkinson's
Disease Foundation, New York State Center for Biotechnology
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