Daniel A. Peterson

The adult brain is vulnerable to a wide variety of injury and disease. Unfortunately, there is very little endogenous repair capacity in the mature CNS and the currently available therapeutic options have had limited utility. My lab focuses on two complimentary and clinically-relevant approaches to repair the injured brain using gene therapy and neural stem cells. The main techniques used in the lab include stereotaxic surgery for experimental lesion and in vivo gene delivery, cell culture, immunocytochemistry, confocal microscopy, quantitative design-based stereology, electron microscopy, ELISA, and RT-PCR analysis. At present, the personnel composition of the lab includes two post-doctoral fellows, three technicians, a graduate student, and an M.D./Ph.D. student.



Stem Cells for Brian Repair Over the last decade, I have been investigating the role of neural stem cells within the adult CNS with regard to their identification, differentiation, and suitability for repopulating damaged regions of the adult CNS. Culture techniques have been developed that permit the in vitro isolation and expansion of neural progenitors from the adult CNS in the presence of growth factors. My collaborators and I have demonstrated that it is possible to genetically modify these neural progenitors in vitro and subsequently graft them back into the adult CNS. When placed in certain regions of the adult CNS, where we postulate that appropriate cues continue to be expressed, these progenitor cells migrate and differentiate into neurons and glia. The proposed instruction of differentiation by target tissue argues for the possibility of identifying appropriate factors in these tissues. Once identified, such factors may enable the survival, differentiation, and integration of adult progenitors either through expressing these factors in grafted progenitors or using gene therapy approaches to deliver the factors to recruit endogenous progenitors. To advance our understanding of the factors regulating neurogenesis, we are also focusing on the aging brain. Apart from traumatic brain injury, most patients requiring therapeutic brain repair as a result of stroke or neurodegenerative disease are beyond middle age. Most research has been carried out using young animals and it is unclear if the aging brain retains the same capacity to support neurogenesis and differentiation as seen in the young brain. Through discovering differences between young and aging brains, it may be possible to both stop or reverse age-related decline and to treat the aging brain to provide a more receptive environment for transplanted neural stem cells.



Therapeutic Gene Delivery for Batten’s Disease Batten’s disease or Neuronal Ceroid Lipofuscinosis (NCL) is a collection of rare lysosomal storage diseases that result in progressive degeneration of cells in the retina and brain, leading to death within the first decade of life. There is no effective therapeutic intervention available to the children suffering from this tragic disease. Genotyping studies have established that mutations in the CLN2 gene and the associated absence or deficiency in tripeptidyl peptidase (TPP-I) the CLN2 gene product, are responsible for NCL. Treatment of this disease will require the delivery and sustained expression of TPP-I to a large volume of the patient’s brain. It is estimated that expression of TPP-I at five percent of the normal level may be adequate to arrest neurodegeneration. Gene therapy using viral vectors as delivery vehicles for the CLN2 gene may be suitable for accomplishing this goal. This project represents a collaboration between my laboratory and Drs. Ron Crystal and Dolan Sondhi at Cornell University School of Medicine’s Institute of Genetic Medicine, Dr. John Sladek at the University of Colorado Health Sciences Center, and Dr. Eugene Redmond of Yale University. The scientists at Cornell provide the viral vectors and perform the intracranial injections of rodents, my laboratory performs the analysis of gene expression in the rodent brain, and Drs. Sladek and Redmond have initiated gene delivery to the primate brain. The in vivo portion of this work, performed in my lab, consists of determining the optimal in vivo gene delivery parameters to achieve widespread infection and expression of both reporter and therapeutic transgenes and determining the anatomical distribution of both transgene expression and secreted gene product. These data, combined with the primate studies, will provide the necessary background for the ultimate transfer of this approach to the clinic.







Ray, J., Peterson, D.A., Schinstine, M., and Gage, F.H. (1993) Proliferation, differentiation and long-term culture of primary hippocampal neurons. Proc. Natl. Acad. Sci., USA 90:3602-3606.



Peterson, D.A., Lucidi-Phillipi, C.A., Eagle, K.L., and Gage, F.H. (1994) Perforant path damage results in progressive neuronal death and somal atrophy in layer II of entorhinal cortex and functional impairment with increasing post-damage age. Journal of Neuroscience 14:6872-6885.



Gage, F. H., Coates, P.W., Palmer, T.D., Kuhn, H.G., Fisher, L.J., Suhonen, J.O., Peterson, D.A., Suhr, S.T., and Ray, J. (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci., USA 92:11879-11883.



Peterson, D.A., Lucidi-Phillipi, C.A., Murphy, D., and Gage, F.H. (1996) FGF-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death. Journal of Neuroscience 16(3):886-898.



Suhonen, J.O., Peterson, D.A., Ray, J. and Gage, F.H. (1996) Differentiation of adult-derived hippocampal progenitor cells into olfactory bulb neurons. Nature 383:624-627.



Peterson, D.A., Leppert, J.T., Lee, K-F., and Gage, F.H. (1997) Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75. Science 277(5327):837-838.



Kafri, T., Blömer, U., Peterson, D.A., Gage, F.H., and Verma, I. (1997) Sustained expression of genes delivered directly in liver and muscle by lentiviral vectors. Nature Genetics 17:314-317.



Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A-M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998) Neurogenesis in the adult human hippocampus. Nature Medicine 4(11):1313-1317.



Gage, F.H., Kempermann, G., Palmer, T.D., Peterson, D.A. and Ray, J. (1998) Multipotent Progenitor Cells in the Adult Dentate Gyrus. Journal of Neurobiology 36:249-266.



Peterson, D.A., Dickinson-Anson, H.A., Leppert, J.T., Lee, K-F., and Gage, F.H. (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. Journal of Comparative Neurology 404(1):1-20.



Peterson, D.A. and Gage, F.H. (1999) Trophic factors in experimental models of adult central nervous system injury. in Neurodegeneration and Age-Related Changes in Structure and Function of Cerebral Cortex, Jones E.G., Peters, A. and Morrison, J.H. (Eds.) Cerebral Cortex vol. 14, Plenum Publishing Corp., New York pp. 129-173.



Peterson, D.A. and Gage F.H. (1999) Trophic factor therapy for neuronal death. in Alzheimer Disease, Second Edition, Terry, R.D., Katzman, R., Bick, K.L. and Sisodia, S.S. (Eds.) Lippincott-Raven Publisher, Philadelphia pp. 373-388.



Peterson, D.A., Ray, J. and Gage, F.H. (1999) Future prospects of gene therapy for treating CNS diseases. in Innovative Animal Models of CNS Diseases: From Molecule to Therapy, Emrich, D.F., Dean, R.L., and Sanberg, P.R. (Eds.) Humana Press, New Jersey, pp. 483-506.



Peterson, D.A. (1999) Quantitative histology using confocal microscopy: Implementation of unbiased stereology procedures. Methods: A Companion to Methods in Enzymology 18:493-507.



Kaspar, B., Schaeffer, D.S., Erickson, D.A., Hinh, L., Gage, F.H., and Peterson, D.A. (2002) Targeted retrograde gene delivery for neuronal protection. Molecular Therapy 5:50-56.



Chao, S.Z., Ariano, M.A., Peterson, D.A., and Wolf, M.E. (2002) D1 dopamine receptor stimulation increases GluR1surface expression in nucleus accumbens neurons. Journal of Neurochemistry 83:1-9.



Lazarov, O., Peterson, D.A., and Sisodia, S.S. (2002) Evidence that synaptically released Ab accumulates as extracellular deposits in the hippocampus of transgenic mice. Journal of Neuroscience (in press)



Peterson, D.A. (2002) Stem Cells in Brain Plasticity and Repair. Current Opinion in Pharmacology 2:34-42.



Ray, J. and Peterson, D.A. (2002) Adult Hippocampal Neural Stem Cells. in Zigova, T., Snyder E.Y, and Sanberg, P.R. (eds.) Neural Stem Cells for CNS Repair, Humana Press. (in press)



Peterson, D.A. (2002) The use of fluorescent probes in cell counting procedures. In Quantitative Methods in Neuroscience, Jansen, A.M., Evans, S., and Møller A. (Eds.) Oxford University Press (in press)



Gnatenco, C. and Peterson D.A. (2002) Neurogenesis following brain injury: Managing a renewable resource for repair? Journal of Clinical Investigation (in press).
 


 http://www.finchcms.edu/cms/neuro/facultypages/Peterson/petersonpublications.htm