Determining whether Leukine may have therapeutic effects in Alzheimer’s disease

Huntington Potter, Ph.D

University of South Florida College of Medicine

Funded in April, 2011: $300000 for 3 years


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Determining whether Leukine may have therapeutic effects in Alzheimer’s disease

Investigators will undertake an initial study of the Food and Drug Administration (FDA)-approved drug Leukine in a small number of patients with Alzheimer’s disease, to obtain preliminary evidence of whether the drug shows positive effects on patients’ cognitive abilities and helps to arrest brain atrophy.

Alzheimer’s disease affects between one-third and one-half of all adults over the age of 85, and the few approved drugs for treating cognitive decline in patients produce only minimal effects. No therapies have been shown to prevent the disease or reverse its course of cognitive decline. Investigators at the University of South Florida, however, have developed preliminary data suggesting that the recombinant drug Leukine, approved by the FDA and used for two decades in treating patients with leukemia, might help to reverse the abnormal build-up of brain amyloid in Alzheimer’s disease patients, and correspondingly might improve patients’ cognitive functioning.

Leukine stimulates immune system macrophages, which ingest and dispose of harmful microorganisms and waste products. Based on evidence that patients with the autoimmune disease rheumatoid arthritis do not tend to develop Alzheimer’s disease, the investigators first determined that a factor in these patients called “Granulocyte-Macrophage-CSF (GMCSF)” that stimulates production of immune system macrophages might help to protect them from developing Alzheimer’s. That possibility is consistent with recent research suggesting that patients with Alzheimer’s disease may have reduced capacity to clear away amyloid from the brain. GMCSF is the active ingredient in Leukine.  

In prior studies, these researchers gave Leukine to the animal model of Alzheimer’s disease and found that it reduced brain amyloid levels and completely reversed the animals’ cognitive impairment. Then they found promising evidence of Leukine’s effect on cognition in humans by reviewing data from a prior study of cancer patients. Study patients who had received Leukine to enhance bone marrow production of macrophages and other immune cells, following hematopoietic stem cell transplantation had significantly better total neurocognitive performance at six months and one year compared to patients who did not receive Leukine.

Based on the promising animal model studies and on the retrospective study of Leukine’s effects in leukemia patients, the researchers now plan to investigate Leukine’s effects in patients with Alzheimer’s disease in a clinical study that has been approved by the University of South Florida’s Institutional Review Board (IRB). They will study 40 patients with mild-to-moderate Alzheimer’s disease, in which 20 patients will receive Leukine and 20 will receive a placebo. They hypothesize that patients treated with Leukine will show better cognitive functioning and less brain tissue loss than patients receiving placebo. 

Patients in both groups will receive baseline MRI imaging to assess amyloid build-up, and neurocognitive performance. Then, the 20 patients that will receive Leukine will be divided into three groups (two groups of five patients each and one group of ten patients) as will the 20 patients that will receive placebo, so that each group (Leukine and placebo) can be tested serially to determine the best dose of Leukine. The first group of five patients on Leukine will receive a three-week course of treatment at a dose that is 50 percent lower than that given to leukemia patients to assess tolerability and brain and cognitive effects, compared to first group of five patients receiving placebo.  If tolerability is not a problem, the second group of Leukine patients will receive the full dose of Leukine over the three-week treatment period and be compared to the second group of placebo patients.

Based on the results using the two different dosages, researchers will determine the best dose to be given to the final group of ten patients receiving Leukine; these patients similarly will be compared to the ten patients receiving placebo.  They will determine whether Leukine patients, in comparison to placebo patients, show better cognitive functioning, less atrophy in the brain’s medial temporal area, improvements in activities of daily living, and reduced levels of Alzheimer’s disease biomarkers in the blood.

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.  One challenge now is to determine that Leukine is tolerable and safe in Alzheimer’s disease patients. The study has been carefully designed to assess this by starting with a low dose and assessing effects before increasing the dose to full strength.   A second challenge is to see whether the three-week course of treatment is sufficient to show any effect on brain amyloid and cognition. If not, additional, longer, studies may be needed.

Significance: This first study in Alzheimer’s disease patients, if successful, would lead to larger-scale studies that could demonstrate that Leukine effectively treats 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)



Harvard College



Physics & Chemistry

Harvard University



Biochem & Mol Biology

Harvard University PhD



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


  • 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.
  • 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.

  • 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
  • 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.

  • 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.

  • 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

  • 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.

  • 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
  • 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
  • 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.
  • 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.
  • 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 

  • 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.
  • 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.
  • 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




Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES.



Ashok Raj M.D.


Scientific Researcher, USF Health Byrd Alzheimer’s Institute.

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)



Madras Medical College, Chennai, India

M.B., B.S.


Doctor of Medicine

University of South Florida , Tampa, Fl

Residency in Psychiatry

Diplomate ABPN

Added Qualification






General Psychiatry

General Psychiatry

Geriatric Psychiatry

Geriatric Psychiatry






A. Personal Statement

Alzheimer’s dementia is a growing problem in the USA and in the world.  It is a condition for which despite great effort there is a remarkable lack of effective treatments.  I have spent the majority of my working years in clinical research.  The last few years have been almost exclusively devoted to Alzheimer’s research.  Having been the PI in more than 25 drug treatment trials for AD, phase 2 to 4, with durations of 6 months to 2 years, I am well informed in the design and conduct of trials for AD.  This particular project is exciting and challenging for me as it involves taking a compound that has been tested in mouse models in our own labs and testing it in human volunteers. This is the bench to bedside dream of any scientist.  I have been a long time collaborator with Dr. Potter in the Florida ADRC and direct its clinical core.  My team and I are well qualified to complete this project ethically and successfully.

B. Positions and Honors


Positions and Employment

1992-2005 Director, Division of Geriatric Psychiatry, USF College of Medicine, Tampa, FL.

1994-2005 Director, Geriatric Psychiatry Training Program, USF College of Medicine, Tampa, FL.

1998-2005 Professor of Psychiatry, USF College of Medicine, Tampa, FL.

2003-2005 Principal Investigator, USF Memory Disorders Clinic, Tampa, FL.

2005-2008 Research Physician, Byrd Alzheimer’s Center & Research Institute, Tampa, FL.

2008-         Scientific Researcher, USF Health Byrd Alzheimer’s Institute, Tampa, FL.

2008-         Professor of Neurology, USF College of Medicine, Tampa, FL.


1979 - Hibbs-Bourkard Award, Department of Psychiatry.


1984- Outstanding Service Award, Department of Psychiatry

1997, 98, 2001, 02, 05:  Included in The Best Doctors in America:  Southeast Region.


C. Selected Peer-reviewed Publications (Selected from __ peer-reviewed publications) 


Most relevant to the current application

1.    Duara R., et al:  Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer’s disease.  Neurology 2008; 71:1986-92

2.    Schinka JA., et al:  Defining mild cognitive impairment:  Impact of varying decision criteria on neuropsychological diagnostic frequencies and correlates.  Am J of Geriatric Psychiatry 684-691, 18:8, August 2010.

3.    Malek-Ahmadi M, Raj A, Small BJ:  Semantic clustering as a neuropsychological predictor for Amnestic-MCI.  Aging, Neuropsychology and Cognition (accepted).

4.    Shen Q., et al: Volumetric and visual rating of MRI scans in the diagnosis of amnestic MCI and Alzheimer’s disease.  Alzheimer’s &  Dementia / NIH public Access

5.    Loewenstein DA. et al:  Severity of medial temporal atrophy and amnestic MCI:  Selecting type and number of memory tests.  American Journal of Geriatric Psychiatry (accepted).

6.    Duara R et al:  Diagnosis and staging of Mild Cognitive Impairment using a modification of the Clinical Dementia Rating Scale:  the mCDR.  Int J  Geriatric Psychiatry  (in press)



D. Research Support


Ongoing Research Support

1.  Co-investigator / PI Huntington Potter PhD - Florida ADRC, Tampa Clinical Core. Supported by the NIH.

2.  Élan Pharmaceuticals:  Principal Investigator, Protocol ELN115727-301,302 & 351.  Phases 3, multicenter, double blind, placebo controlled, parallel group, efficacy and safety trial of Bapineuzumab in patients with mild to moderate Alzheimer’s disease.

3.  Wyeth Research:  Principal Investigator, Protocol 3133K1-3000, 3001, 3003.  A phase 3 multicenter, randomized, double blind, placebo controlled, parallel group, efficacy and safety trial of Bapineuzumab in subjects with mild to moderate Alzheimer’s disease.

4.  Toyoma Chemical Co:  Principal Investigator Protocol AA4437420.  A phase 2a multicenter, double blind, placebo controlled study to investigate the efficacy and safety of T-817MA in patients with mild to moderate Alzheimer’s disease.

5.  Eli Lilly:  Principal Investigator Protocol H6L-MC-LFAN (b).  Effect of gamma-secretase inhibition on the progression of Alzheimer’s disease:  LY450139 versus placebo.

6.  Eli Lilly:  Principal Investigator Protocol H8A-MC-LZAN (a).  Effect of passive immunization on the progression of Alzheimer’s Disease:  Solanezumab versus placebo.

7.  Bayer Health Care:  Principal Investigator, Protocol 14595.  An open label, non randomized study, to evaluate the efficacy and safety of BAY 94-9172 PET imaging for detection/exclusion of cerebral beta amyloid when compared to postmortem histopathology.

8.  Co-investigator – Efficacy and safety of Filgastrim as a procognitive agent for Alzheimer’s disease.  Supported by Alzheimer’s Disease Drug Discovery Foundation.