Curt Freed, MD

Professional Titles

• Division Head

Research Interests

Research in my laboratory has focused on improving treatments for Parkinson's disease. In 1988, we performed the first transplant of dopamine-producing brain cells into an American patient with Parkinson's. We have done more brain cell transplants than any other group. While the transplanted cells can replace the need to take drugs like L-DOPA, they do not stop the relentless progression of the underlying disease. In 2006, we began the search for a drug to stop Parkinson’s and have found phenylbutyrate. In animal testing, phenylbutyrate can prevent Parkinson’s from advancing. We are now testing phenylbutyrate in patients and should know in the next few years if it is able to stop the progression of Parkinson's disease in people.

Publications

• Zhou, W. and Freed, C.R. DJ-1 upregulates glutathione synthesis during oxidative stress and inhibits A53T ?-synuclein toxicity. J. Biol. Chem. 280 (2005) 43150-43158.
• Alvarez E, Zhou W, Witta SE, Freed CR. Characterization of the Bex gene family in humans, mice, and rats. Gene. 2005: 357: 18-28.
• Schilling B, Bharath M M S, Row RH, Murray J, Cusack MP, Capaldi RA, Freed CR, Prasad KN, Andersen JK, Gibson BW.Rapid purification and mass spectrometric characterization of mitochondrial NADH dehydrogenase (Complex I) from rodent brain and a dopaminergic neuronal cell line. Mol Cell Proteomics. 2005: 84-96.
• Simpson SA, Manchak MD, Hager EJ, Krummenacher C, Whitbeck JC, Levin MJ, Freed CR, Wilcox CL, Cohen GH, Eisenberg RJ, Pizer LI. Nectin-1/HveC Mediates herpes simplex virus type 1 entry into primary human sensory neurons and fibroblasts. J Neurovirol. 2005: 208-18.
• C.R. Freed and W. Zhou: DJ-1 protects dopamine neurons by selective activation of either glutathione or heat shock protein. 13th Annual Meeting, American Society for Neural Therapy and Repair, Clearwater, FL, May 11-14, 2006.
• Freed, Curt R., Breeze, Robert E., Zawada, Michael, Zhou, Wenbo, Leehey, Maureen, DeMasters, Bette K., Greene, Paul, Fahn, Stanley, Eidelberg, David: Human embryonic dopamine neurons survive transplantation in Parkinson patients and improve motor function for at least 10 years with no immunosuppression. 4th Annual International Society for Stem Cell Research Meeting, Toronto Canada, June 29-July 1, 2006.
• C. R. Freed, et al, In utero stem cell transplantation for Down syndrome. The Anna and John J. Sie Foundation Symposium, Aurora, CO, January 13, 2006.
• C.R. Freed, M. Zawada, S. Jones, K. Ellison, B.K. DeMasters, M. Leehey, P.E. Greene, S. Fahn, D. Eidelberg, R.E. Breeze. Human embryonic dopamine neurons transplanted into Parkinson patients survive and improve motor function for at least 10 years without immunosuppression. 35th Annual Society for Neuroscience Meeting. Washington, DC November 12-16, 2005
• Reich, Stephen, Verhagen Metman, Leo, Karp, Barbara, Bara-Jimenez, William, Greene, Paul, Eidelberg, David, Fahn, Stanley, Breeze, Robert E., Freed, Curt R. Persistent Dyskinesias Following Fetal Dopamine Neuron Implantation for Parkinson's Disease: A Case Report with 9-Year Follow-Up
• 130. Zhou, W. and Freed, C.R. DJ-1 upregulates glutathione synthesis during oxidative stress and inhibits A53T ?-synuclein toxicity. J. Biol. Chem. 280 (2005) 43150-43158.
• 131. Bjugstad KB, Crnic LS, Goodman SI, Freed CR.. Infant mice with glutaric acidaemia type I have increased vulnerability to 3-nitropropionic acid toxicity. J Inherit Metab Dis. 2006 Oct;29(5):612-9.
• 132. Chiba, S, Lee, Y-M, Zhou, W., Freed, CR, Behavioral improvement after transplantation of dopamine neurons derived from human embryonic stem cells treated with noggin. Submitted, Cell Stem Cells, 2007.
• 133. Zhou, W., Freed, CR, Mice with green fluorescent protein knocked into the dopamine transporter show gene expression only in authentic dopamine neurons. Submitted, Stem Cells, 2007.
• Zhou W, Milder JB, Freed CR. Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human {alpha}-Synuclein: A progressive neurodegenerative model of diffuse Lewy body disease. J Biol Chem. 2008 Apr 11;283(15):9863-70. Epub 2008 Jan 30
• Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK, Leurgans S; Parkinson Study Group. Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008 Jan 28; [Epub ahead of print]
• S. KEARNS, Y. LEE, W. ZHOU, V. GUY, C. FREED; Transfection of lmx1a into mouse embryonic stem cells, Div. Clin. Pharmacol., Univ. Colorado, Denver, CO, Society for Neuroscience, 778.27/D27, San Diego, 2007.
• V. GUY, S. M. JONES, S. KEARNS, C. FREED, Survival and migration of C17.2 neural stem cells in a lesioned mouse model, Div. Clin. Pharmacol, Univ. Colorado Hlth. Sci. Ctr., Denver, CO, Society for Neuroscience, 778.28/D28, San Diego, 2007.
• Y. LEE1, S. CHIBA2, Z. WENBO1, C. R. FREED, Purified pitx3-positive dopamine neurons derived from mouse embryonic stem cells survive cell sorting and improve motor behavior after transplantation into a rat model of Parkinson’s disease, Sch. Med., Univ. Colorado Hlth. Sci. Ctr., Denver, CO; Sch. Med., St. Marianna Univ., Kawasaki, Japan, Society for Neuroscience, (345.10/C16), 2007.
• S. CHIBA1,2, Y. LEE2, W. ZHOU2, C. R. FREED2, Purification of DA neurons from human embryonic stem cells by distinctive colony morphology in culture on PA6 cells, 1Regenerative Med., St. Marianna Univ. Sch. Med., Kawasaki, Japan; 2Clin. Pharmacol., Univ. of Colorado Hlth. Sci. Ctr., Denver, CO, Society for Neuroscience, 803.7/T18, San Diego, 2007.
• C. R. FREED, W. ZHOU, The neuroprotective gene DJ-1 is upregulated by the histone deacetylase inhibitors sodium butyrate and phenylbutyrate which may prevent the progression of Parkinson's disease, Dept. Med., Univ. Colorado Hlth. Sci. Ctr., Denver, CO, Society for Neuroscience 797.6/O10, 2007.
• W. ZHOU, V. C. GUY, C. R. FREED, Generation of GFP/RFP knock-in embryonic stem cells in dopamine neuron specific gene loci - applications for dopamine neuron purification and gene profiling, Dept Med., Univ. Colorado Hlth. Sci. Ctr., Denver, CO, Society For Neuroscience, 803.12/T23, 2007.
• Zhou, W. and Freed, C.R., Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells, submitted, Nature 2009.
• Zhou W, Guy V.C., and Freed C. R. Generation of Dopamine Transporter/GFP knock-in embryonic stem cells and transgenic mouse -- applications for dopamine neuron purification and gene profiling, Stem Cells, in press, 2009.
• Chiba S, Lee YM, Zhou W, Freed C.R. Noggin enhances dopamine neuron production from human embryonic stem cells and improves behavioral outcome after transplantation into Parkinsonian rats. Stem Cells. 2008; 26: 2810-20.
• Zhou W, Milder J, and Freed C. R. Transgenic mice expressing tyrosine-to-cysteine mutant human a-synuclein develop progressive neurodegeneration with motor and cognitive deficits. J. Biol. Chem. 2008: 283:9863-70.
• Goetz CG, Wuu J, McDermott M, Adler CH, Fahn S, Freed C.R., Hauser RA, Lieberman A, Olanow CW, Shoulson I, Shults CW, Siderowf AD, Tandon PK, Parkinson Study Group, Leurgans S. Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. Movement Disorders, 2008; 23: 690-9
• Greene PE, Fahn S, Kao R, Tsai WY, Winfield H, Dillon S, Winfield L, Eidelberg D, Breeze RE, Freed C.R.. Persistent Dyskinesias as a complication of fetal tissue transplantation for the treatment of Parkinson Disease. Movement Disorders, submitted, 2009.
• Freed CR, Zawada WM, Leehey M, Zhou W, Breeze RE. Transplantation. Handb Clin Neurol. 2007; 84: 279-90.
• Zhou, W. and Freed, C.R., Adenoviral vectors can deliver genes to reprogram human skin fibroblasts to induced pluripotent stem cells. Society for Neuroscience Annual Meeting, Washington DC, November 2008.
• Freed, C.R., Bercury, K., Migdall-Wilson, j., and Zhou, W., Phenylbutyrate Can Prevent Accumulation of Mutant ?-Synuclein and Improve Brain Function in a Transgenic Mouse Model of Parkinson’s Disease. Society for Neuroscience Annual Meeting, Washington DC, November 2008.
• Lee,Y-M, Zhou, W., and Freed, C.R., Purification of dopaminergic neurons derived from mouse embryonic stem cells using magnetic beads., Society for Neuroscience Annual Meeting, Washington, DC, November 2008.
• Zhou W and Freed C. R. Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells, 2009; 27: 2667-74.
• Zhou W, Guy V.C., Lee Y-M, and Freed C. R. Generation of Dopamine Transporter/GFP knock-in embryonic stem cells and transgenic mouse -- applications for dopamine neuron purification and gene profiling, Stem Cells. 2009; 27: 2952-61.
• Ma Y, Tang C, Chaly T, Greene P, Breeze R, Fahn S, Freed CR, Dhawan V, Eidelberg D. Dopamine cell implantation in Parkinson's disease: long-term clinical and (18)F-FDOPA PET outcomes. J. Nucl. Med. 2010; 51: 7-15.
• Phenylbutyrate increases plasma and brain DJ-1 as it prevents behavioral deterioration in a transgenic mouse model of Parkinson’s disease. Curt R. Freed*, Wenbo Zhou, Jessica Cummiskey, and Robert C. Murphy, Annual Meeting of Society for Neuroscience, October 2009, Chicago, IL
• Generation of human induced pluripotent stem cells by adenoviral vector without viral gene integration. Wenbo Zhou* and Curt R. Freed, Annual Meeting, Society for Neuroscience, Chicago, IL, October 2009.
• Curt R. Freed, Stem cell therapy: The future for restoring lost neurological function?, 27th Princeton Conference on Cerebrovascular Disease, Boston, MA, April 2010.
• HUNTINGTON DISEASE NEURONS DERIVED IN VITRO FROM HUMAN PATIENT FIBROBLASTS USING ADENOVIRAL VECTORS, Freed, Curt R., Luong, Nancy, Zhou, Wenbo, International Society for Stem Cell Research, annual meeting, San Francisco, June 2010.
• Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells without Viral Integration. Wenbo Zhou and Curt R. Freed, International Society for Stem Cell Research annual meeting, Barcelona, Spain, July 2009.
• Zhou, W., Bercury, K., Cummiskey, J., Luong, N., Lebin, J., and Freed, CR, Phenylbutyrate Upregulates DJ-1 and Protects Neurons in Cell Culture and in Animal Models of Parkinson’s Disease, J. Biol Chem., 2011 Mar 3. [Epub ahead of print].
• Richardson RM, Freed CR, Shimamoto SA, Starr PA. Pallidal neuronal discharge in Parkinson's disease following intraputamenal fetal mesencephalic allograft. J Neurol Neurosurg Psychiatry. 2011; 82(3): 266-71; 2010 Aug 27 epub ahead of print.
• Ma Y, Tang C, Chaly T, Greene P, Breeze R, Fahn S, Freed CR, Dhawan V, Eidelberg D. Dopamine cell implantation in Parkinson's disease: long-term clinical and (18)F-FDOPA PET outcomes. J. Nucl. Med. 2010; 51: 7-15.
• Greene PE, Fahn S, Eidelberg D, Breeze RE, Freed C.R.. Persistent dyskinesias as a complication of fetal tissue transplantation for the treatment of Parkinson Disease. Movement Disorders, in press, 2011
• Lee Y-M, Zhou, W., and Freed C. R. Gene microarray comparison of dopamine neurons generated from Pitx3-GFP mouse embryonic stem cells and from mesencephalon of knock-in mice. Submitted, 2011.
• C. R. Freed, W. Zhou, J. Cummiskey, R. C. Murphy, M. Leehey, Phenylbutyrate to prevent progression of Parkinson's disease, Abstract 51.29,: Society for Neuroscience, San Diego, CA, November 2010.
• C. R. Freed, Stem Cell Transplantation for Parkinson’s Disease, Eighth Seoul Symposium on Stem Cell Research, August, 2010.
• Wenbo Zhou* and Curt R. Freed, Generation of induced pluripotent stem cells from Parkinson and Huntington disease patients, Society for Neuroscience, San Diego, CA, November 2010.
• Zhou, W., Bercury, K., Cummiskey, J., Luong, N., Lebin, J., and Freed, CR, Phenylbutyrate Upregulates DJ-1 and Protects Neurons in Cell Culture and in Animal Models of Parkinson’s Disease, J. Biol Chem., 2011; 286 (17): 14941-51.
• Freed CR, Zhou W, Breeze RE. Dopamine cell transplantation for Parkinson's disease: the importance of controlled clinical trials. Neurotherapeutics. 2011 Oct;8(4):549-61.
• Greene PE, Fahn S, Eidelberg D, Breeze RE, Freed C.R.. Persistent dyskinesias as a complication of fetal tissue transplantation for the treatment of Parkinson Disease. Movement Disorders, in press, 2012.
• Lee Y-M, Zhou, W., and Freed C. R. Gene microarray comparison of dopamine neurons generated from Pitx3-GFP mouse embryonic stem cells and from mesencephalon of knock-in mice. Submitted, 2012.
• W. Zhou, C. R. Freed. Neurons differentiated from Parkinson's and Huntington's iPS cells are more sensitive to oxidative stress. 883.01/X12, Society for Neuroscience, 2011.
• J. Cummiskey, W. Zhou, C. R. Freed. Exercise-induced modification of DJ-1 gene expression in mice. 555.01/D72, Society for Neuroscience, 2011.
• Y.-M. Lee, W. Zhou, C. R. Freed. Dopamine neurons produced from mouse embryonic stem cells are genetically identical to ventral mesencephalic dopamine neurons in normal midbrain. 227.11/A20, Society for Neuroscience, 2011.
• H. Wang, M. D. Taussig, L. A. Beck, G. Astarita, D. Piomelli, I. J. Goldberg, W. Zhou, C. R. Freed, R. H. Eckel. Altered brain lipid metabolism and n-3 fatty acid deficiency lead to cognitive impairments in neuron-specific lipoprotein lipase knockout mice. 538.03/146A, Society for Neuroscience, 2011.
• Freed, CR, Lee, Y-M, Zhou, W. Dopamine neurons produced from embryonic stem cells are identical to A9-midbrain dopamine neurons. Keystone Symposium on Mechanisms of Whole Organ Regeneration, April 2012.
• Lee, K.S., Zhou, W, Scott-McKean, J.J., Cai, G., Krah, D.L., Costa, A.C., Freed, C.R. and Levin, M.J. Human sensory neurons derived from induced pluripotent stem cells support varicella-zoster virus infection. PLoS One (2012) 7(12):e53010.
• Greene PE, Fahn S, Eidelberg D, Breeze RE, Freed C.R.. Persistent dyskinesias as a complication of fetal tissue transplantation for the treatment of Parkinson Disease. Movement Disorders, in press, 2013.
• Lee Y-M, Zhou, W., and Freed C. R. Gene microarray comparison of dopamine neurons generated from Pitx3-GFP mouse embryonic stem cells and from mesencephalon of knock-in mice. Submitted, 2013.
• Zhou, W., Cummiskey, J., and Freed, C.R. Running wheel exercise reduces a-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson disease., submitted 2013.
• Neurons differentiated from Parkinson and Huntington iPS cells are more sensitive to oxidative stress. Wenbo Zhou and Curt R. Freed. RMRNG Annual Meeting, 2012
• J.Cummiskey, C. R. Freed and W. Zhou. Exercise-induced modification of DJ-1 gene expression in mice. RMRNG Annual Meeting, 2012.
• Lee, Y-M, W. Zhou and C. R. Freed. Dopamine neurons produced from embryonic stem cells are identical to A9 midbrain dopamine neurons. RMRNG Annual Meeting, 2012.
• C. R. Freed, W. Zhou, Y.-M. Lee, M. Leehey, R. E. Breeze. Transplantation of human embryonic dopamine neurons into Parkinson patients predicts outcome of stem-cell derived neurons. 314.13, Society for Neuroscience, 2012.
• T. Yu, M. D. Taussig, G. Astarita, D. Piomelli, W. Zhou, C. R. Freed, R. H. Eckel, H. Wang. Lipoprotein lipase is involved in providing the brain with n-3 and n-6 polyunsaturated fatty acids to prevent learning and memory decline and excessive anxiety. 814.19/FFF59, Society for Neuroscience, 2012.
• W. Zhou, J.Cummiskey and C. R. Freed. Running wheel exercise reduces a-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson disease. Neuroscience Program retreat, 2012.
• Yun D, Famili A, Lee YM, Jenkins PM, Freed CR, Park D. Biomimetic poly(serinol hexamethylene urea) for promotion of neurite outgrowth and guidance. J Biomater Sci Polym Ed. 2014;25(4):354-69. Epub 2013 Nov 27
• Greene PE, Fahn S, Eidelberg D, Breeze RE, Freed C.R. Persistent dyskinesias after fetal dopamine cell transplantation mimic the preoperative effects of levodopa. Movement Disorders, in press, 2014.
• Zhou, W, Cummiskey, J., Freed, CR, Running wheel exercise reduces a-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease, Submitted J. Neuroscience, 2014.
• C.R. Freed1*, R.E. Breeze2, M. Zawada1, S. Jones1, S. Fahn,3; D. Eidelberg4; and W. Zhou,1 Human embryonic dopamine neurons transplanted into putamen of Parkinson patients survive for at least 22 years without immunosuppression, Society for Neuroscience Annual Meeting, San Diego, November 2013.
• Wenbo Zhou1,2, Jessica Cummiskey1,3 and Curt R. Freed1. Exercise on running wheels reduces a-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease. Society for Neuroscience Annual Meeting, San Diego, November 2013.
• J. Cummiskey1*, W. Zhou1, J. Benson1, B. Fitzwalter1, M. A. Leehey3 T. A. McKinsey2, R. C. Murphy2, C. R. Freed1, Phenylbutyrate stops the progression of Parkinson’s disease by increasing expression of the DJ-1 gene, thereby enhancing clearance of misfolded proteins from dopamine neurons. Society for Neuroscience Annual Meeting, San Diego, November 2013.
• Yun D, Famili A, Lee YM, Jenkins PM, Freed CR, Park D. Biomimetic poly(serinol hexamethylene urea) for promotion of neurite outgrowth and guidance. J Biomater Sci Polym Ed. 2014;25(4):354-69. PubMed PMID: 24279744
• Xiong R, Zhou W, Siegel D, Kitson RR, Freed CR, Moody CJ, Ross D. A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and Autophagy and Alleviates Mutant A53T a-Synuclein Toxicity. Mol Pharmacol. 2015 Dec;88(6):1045-54. PubMed PMID: 26405178
• Jenkins PM, Laughter MR, Lee DJ, Lee YM, Freed CR, Park D. A nerve guidance conduit with topographical and biochemical cues: potential application using human neural stem cells. Nanoscale Res Lett. 2015 Dec;10(1):972. PubMed PMID: 26071111
• Yun D, Lee YM, Laughter MR, Freed CR, Park D. Substantial Differentiation of Human Neural Stem Cells Into Motor Neurons on a Biomimetic Polyurea. Macromol Biosci. 2015 Sep;15(9):1206-11. PubMed PMID: 26033933
• Gao L, Zhou W, Symmes B, Freed CR. Re-Cloning the N27 Dopamine Cell Line to Improve a Cell Culture Model of Parkinson's Disease. PLoS One. 2016 Aug 11;11(8):e0160847. PubMed PMID: 27512998
• Bahmed K, Messier EM, Zhou W, Tuder RM, Freed CR, Chu HW, Kelsen SG, Bowler RP, Mason RJ, Kosmider B. DJ-1 Modulates Nuclear Erythroid 2-Related Factor-2-Mediated Protection in Human Primary Alveolar Type II Cells in Smokers. Am J Respir Cell Mol Biol. 2016 Sep;55(3):439-49. PubMed PMID: 27093578
• Greene PE, Fahn S, Eidelberg D, Breeze RE, Freed C.R. Persistent dyskinesias after fetal dopamine cell transplantation mimic the preoperative effects of levodopa. Movement Disorders, in press, 2017.
• Lee Y-M, Zhou, W., and Freed C. R. Gene microarray comparison of dopamine neurons generated from Pitx3-GFP mouse embryonic stem cells and from mesencephalon of knock-in mice. In preparation, 2017.
• Cummiskey, J., Zhou, W., Mathews, E., Benson, J., Freed, C.R., Gene regulation screen reveals neuroprotective mechanisms activated by phenylbutyrate to prevent the progression of Parkinson’s disease, In preparation 2017.
• Bahmed K, Messier EM, Zhou W, Tuder RM, Freed CR, Chu HW, Kelsen SG, Bowler RP, Mason RJ, Kosmider B. DJ-1 Modulates Nuclear Erythroid 2-Related Factor-2-Mediated Protection in Human Primary Alveolar Type II Cells in Smokers. Am J Respir Cell Mol Biol. 2016 Sep;55(3):439-49. PubMed PMID: 27093578
• C. R. FREED, S. M. GARCIA, G. LEHMICKE, M. A. LEEHEY, W. ZHOU, Div. of Clinical Pharmacology., Dept. of Neurology, Univ. Colorado School Med., Aurora, CO. "Phenylbutyrate may stop progression of idiopathic Parkinson's disease." Society for Neuroscience Annual Meeting, San Diego, November 2018.
• Zhou W, Barkow JC, Freed CR. Running wheel exercise reduces a-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease. PLoS One. 2017;12(12):e0190160. PubMed PMID: 29272304
• Zhou, W. Breeze, R.E., Symmes, B.A., Gao, L., Fahn, S., Eidelberg, D., Freed, C.R. Transplanted fetal dopamine neurons for treating Parkinson disease: A clinical study of 61 cases and histological analysis of 15 postmortem brains. Submitted 2018.

Practice Locations

Hospital Affiliation

• University of Colorado Hospital

Specialty Information

Specialties

• Clinical Pharmacology