Double Blind Trial of the Safety and Efficacy of GM-CSF Leukine in the Treatment of Alzheiemer's Disease

Huntington Potter, Ph.D.

University of Colorado

Department of Neurology
Funded in September, 2012: $150000 for 3 years


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Investigators will undertake the second phase of their clinical study to determine in a small number of people with Alzheimer’s disease whether the drug Leukine shows promise in improving patients’ cognitive abilities and arrests brain atrophy.
About 40 percent of people over the age of 85 have Alzheimer’s disease (AD). No current therapies can arrest or reverse its course, and the few approved AD therapies only minimally slow cognitive decline.  Investigators are exploring the drug Leukine as a potential AD treatment. Leukine currently is approved by the Food and Drug Administration for treating leukemia. The Foundation’s Directors in April 2011 approved support for a clinical study of Leukine, based on observations in several animal and human studies.
Among these observations: 1) Animal model studies conducted by the investigators showed that Leukine reduced the abnormal build-up of brain amyloid that is a hallmark of AD; 2) Analysis of data from a prior controlled trial of Leukine in patients with leukemia found that the drug not only enhanced development of immune system “macrophages,” which clear away debris, but also resulted in significantly better cognitive functioning in the Leukine-treated patients at both six months and a year following treatment; and 3) Patients with autoimmune rheumatoid arthritis do
not tend to develop AD, possibly due to a factor in the patients—called “Granulocyte-Macrophage- CSF (GMCSF)”--that stimulates production of immune macrophages. GMCSF is the active ingredient in Leukine. The common thread, therefore, is that Leukine might stimulate production of macrophages that help to clear way amyloid and prevent it from accumulating in the brain.
The investigators hypothesize that patients treated with Leukine will show better cognitive functioning, reduced amyloid build-up, and less brain tissue loss compared to patients receiving placebo. They have successfully completed the first phase of the double-blind study (in which neither the clinicians nor the patient know what substance the patient is receiving). In this phase, which was conducted at the University of South Florida, investigators enrolled 11 AD patients who were randomly assigned to receive either Leukine, at half of the standard dose, or a placebo. All participants completed the three-week treatment course with no adverse effects. Investigators now will initiate the second Phase of the study in a total of 40 AD patients. This phase will be conducted at the University of Colorado, where the principal investigator recently moved to assume the role of director of the Alzheimer’s disease program. The 40 patients will be randomly assigned (20
patients in each group) to receive Leukine —at the standard full dose—or placebo. Investigators will assess tolerability of the full dose of Leukine treatment. Additionally, they will determine whether the Leukine-treated patients, compared to those receiving placebo, show: 1) better functioning on cognitive tests; 2) less atrophy in the brain’s medial temporal area as determined by brain imaging; 3) reduced levels of AD biomarkers in the blood; and 4) improvement in activities of daily living.
Benefits and Challenges: Leukine is not a new drug; it already has met FDA requirements for demonstrating relative safety and efficacy in treating leukemia patients. Results from the first phase of the study indicate that Leukine, at half the standard dose, is tolerable and safe in AD patients. Now they will confirm that this is also the case for patients receiving full-dose Leukine. Additionally, investigators will have to determine whether a three-week course of Leukine treatment is sufficient to show any effect on the brain and on cognition. If not, this will establish the need for undertaking a longer, and possibly larger, study in AD patients prior to initiating a large-scale
clinical trial.

Significance: If promising results are obtained, the research would lead to a larger-scale study of a potentially promising drug treatment for this devastating degenerative disorder.


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Huntington Potter, Ph.D.


eRA COMMONS USER NAME (credential, e.g., agency login)
EDUCATION/TRAINING  (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)
(if applicable) MM/YY FIELD OF STUDY
Harvard College AB 1972 Physics & Chemistry
Harvard University MA 1975 Biochem & Mol Biology
Harvard University PhD PhD 1979 Biochem & Mol Biology
A. Personal Statement
I have planned the experiments and overseen the post-doctoral fellows, graduate students, and technicians who carried out the preliminary experiments that form the preclinical foundation of this application. I also conceived of, initiated and together with Dr. Jim, assessed the analysis of data form the Moffitt Cancer Society bone marrow transplant patients receiving GCSF and GM-CSF. I will oversee the project, analyze the data in a blinded manner with the chief co-investigator, Dr. Raj, write and/or mentor the writing of the papers and progress reports, and decide on new experimental directions as new data warrant. For the last five years I have served as Director of the Florida Alzheimer’s Disease Research Center, and have published expertise in all of the technical aspects of the project except that requiring direct patient contact, which I am theoretically familiar.
B. Positions and Honors
1998-present Professor and Eric Pfeiffer Chair for Research on Alzheimer’s Disease,
 2005-2010    Director, NIA/NIH designated Florida Alzheimer’s Disease Research Center
1996              American Society for Cell Biology/Glenn Foundation Award for “outstanding research in aging”
2000              Kaul Foundation “Award for Excellence and a gift of $100,000 for outstanding achievements in the field of neurobiology and gerontology.”
2005              Tampa Bay Business Journal – Health Care Heroes Award – Care Innovation & Research
2005              Nominated for the Kyoto Prize for Advanced Technology for the development of the electroporation technique for transfer of DNA into cells; renominated 2009
2005-present Member, Florida Governors’s Alzheimer’s Disease Advisory Council
2007              Work on electroporation featured in Dr. Oliver Smithies Nobel Lecture as essential for the
                      development of knockout mice for which the 2007 Nobel Prize or Medicine or Physiology was
2009              President of the Faculty of the USF College of Medicine
2010 President, Faculty Senate USF Tampa

C. Selected Peer-reviewed Publications

1) Potter H. Review and hypothesis: Alzheimer's disease and Down syndrome - chromosome 21 nondisjunction may underlie both disorders. Am. J. Hum. Genet. 1991;48:1192-1200.
2) Li J, Xu M, Zhou H, Ma J and Potter H. Alzheimer presenilins in the nuclear membrane, interphase
kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 1997; 90:917-927.
3) Boeras, D.I., Granic, A., Crespo, N.C., Rojiani, A.M. and Potter, H. (2008; epub Dec 13, 2006) Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging 29:3119-28
4) Arendash GW, Jensen MT, Salem N Jr, Hussein N, Cracchiolo J, Dickson A, Leighty R, Potter H.A
(2007) A diet high in omega-3 fatty acids does not improve or protect cognitive performance in
Alzheimer's transgenic mice.Neuroscience. Oct 26;149(2):286-302. Epub 2007 Aug 14.
5) Cracchiolo JR, Mori T, Nazian SJ, Tan J, Potter H, Arendash GW.(2007) Enhanced cognitive
activity--over and above social or physical activity--is required to protect Alzheimer's mice against
cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity. Neurobiol
Learn Mem. 88:277-94. Epub 2007 Aug 21.
6) Cao, C., Lin, X., Wahi, M.M., Jackson, E.A., Potter, H. (2008) Successful adjuvant-free vaccination
of BALB/c mice with mutated amyloid beta peptides. BMC Neurosci. 9:25
7) Duara, R., Loewenstein, D.A., Potter, E.,Appel, J., Greig, M.T., Urs, R., Shen, Q., Raj, A., Small, B.,
Barker, B., Schofield, E., Wu, Y., Potter, H. (2008) Medial temporal lobe atrophy on MRI scans and
the diagnosis of Alzheimer's disease. Neurology 9:1986-92.
8) Arendash, G.W., Mori, T., Cao, C., Mamcarz, M., Runfeldt, M., Dickson, A., Rezai-Zadeh, K., Tan, J., Citron, B.A., Lin, X., Echeverria, and Potter, H. (2009) Caffeine Reverses Cognitive Impairment and Decreases Brain Aβ Levels in Aged Alzheimer’s Mice. J. Alz. Dis. 17: 661-680
9) Granic, A., Padmanabhan, J., Norden, M., Potter, H. (2009) Chromosome mis-segregation, trisomy 21 induced by mutant Alzheimer APP, A peptides, or tau KO genotype. Mol. Biol. Cell Dec 23,2009 Epub
10) Schinka JA, Raj A, Loewenstein DA, Small BJ, Duara R, Potter H. (2009) Cross-Validation of the Florida Cognitive Activities Scale (FCAS) in an Alzheimer's Disease Research Center Sample. J Geriatr Psychiatry Neurol. 2010 Mar;23(1):9-14. Epub 2009 Aug 24.
11) Appel, J., Potter, E., Bhatia, N., Shen, Q., Zhaao, W., Greig, M.T., Taj, A., Barker, W.W., Potter, H., Schofield, E., Wu, Y., Lowenstein, D.A., Duara, R. (2009) Association of white matter hyperintensities on brain MRI to neurodegenerative and vascular risk factors. Am. J. Neuroradiology. 30: 1870-1876.
12) Abisambra, J.F., Fiorelli, T., Padmanabhana, J., Neame, P., Wefes, I., Potter, H. (2009) LDLR expression
and localization are altered in and in vivo and in vitro models of Alzheimer’s disease. PLoSONE January 1, 2010 Vol 5:e8556
13) Duara, R., Loewenstein, D.A., Greig, M.T., Acevedo, A., Potter, E., Appel, J., Raj, A., Schinka, J., Schofield, E., Barker, W., Wu, Y., Potter, H. (2010). Reliability and Validity of an Algorithm for the Diagnosis of Normal Cognition, MCI and Dementia: Implications for Multi-Center Research Studies. Am. J. Geriatric Psychiatry 18:363-370.
14) Duara R, Loewenstein DA, Greig-Custo MT, Raj A, Barker W, Potter E, Schofield E, Small B, Schinka J, Wu Y, Potter H. (2010) Diagnosis and staging of mild cognitive impairment, using a modification of the clinical dementia rating scale: the mCDR. Int J Geriatr Psychiatry. 2010 Mar;25(3):282-9.
15) Boyd, T., Bennett, S.P., Mori, T., Governatori, N., Runfeldt, M., Norden, M., Padmanabhan, J., Neame, P., Wefes, I., Sanchez-Ramos, J., Arendash, G.W., Potter, H. (2010) GM-CSF up-regulated in Reumatoid Arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alz Dis 21:508-512 [Epub Jun 16 ahead of print]
D. Research Support
Ongoing Research Support

NIH: Director of the Florida ADRC supplemental grant from the NIA (AG025711)
(No Overlap; ends 2011)

Completed Research Support

NIH: Florida ADRC (AG025711) 5/1/2005—3/31/2010
No overlap