To Evaluate the Efficacy and Safety/Tolerability Profiles of G-CSF in Subjects With Mild to Moderate Alzheimer's Disease

Summary

With the enrichment of living environment and the progress of medicine, the scale of aging population has increased in many countries of the world. Alzheimer's disease (AD), the leading cause of dementia, counts for approximately 60% to 70% in dementia in aged population. AD is a well-known neurodegenerative disease and characterized by the formation of neurofibrillary tangles and deposition of amyloid in the brain. It also affects more than 12 million patients worldwide and puts a tremendous burden on family caregivers and causes high nursing home costs for society. So far, the mechanisms of AD have not been elucidated and currently no curable treatment exists. Thus, clinical trials concerning the treatment of AD are in urgent expectation. Granulocyte-colony stimulating factor (G-CSF) is a growth factor that presents in human body in small quantity and is known to promote the blood cell proliferation and differentiation. Previous studies showed injection of G-CSF could help release hematopoietic stem cell (HSCs) from bone marrow to the peripheral blood, and then migrate to repair damaged areas, e.g. heart tissue and ischemia brain tissue. We have found that G-CSF triggering release of stem cells from bone marrow shows the potential as an effective reagent for treatment of AD by using two AD mouse models. The one was generated by injecting the brains of normal mice with amyloid and another was by using a strain of transgenic mice which naturally exhibit Alzheimer's disease-like neuronal apoptosis and memory loss. Subcutaneous administration of G-CSF into mice significantly rescued their cognitive/memory functions. G-CSF has already been widely used in clinical practice, for example, neutropenia caused by chemotherapy in cancer and bone marrow transplantation. The new finding shows G-CSF can release HSCs from bone marrow and these cells not only can pass through the blood-brain barrier but can selectively migrate to the region of damaged brain to improve neurological recovery. Thus, we conduct this clinical trial to investigate the potential effect of G-CSF for the cognitive function of AD patients. If successful, G-CSF could open up a new window for AD treatment which is less invasive and more effective than the current therapies.

Timeline

Start

2009-03

Primary completion

2014-07

Completion

2014-08

Publications

• Background Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016 Apr;12(4):459-509. doi: 10.1016/j.jalz.2016.03.001.
• Background Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer's disease. Lancet. 2016 Jul 30;388(10043):505-17. doi: 10.1016/S0140-6736(15)01124-1. Epub 2016 Feb 24.
• Background Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer's disease. Brain. 2015 Oct;138(Pt 10):2814-33. doi: 10.1093/brain/awv236. Epub 2015 Aug 17.
• Background Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844-6. doi: 10.1038/353844a0.
• Background Tigue CC, McKoy JM, Evens AM, Trifilio SM, Tallman MS, Bennett CL. Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. Bone Marrow Transplant. 2007 Aug;40(3):185-92. doi: 10.1038/sj.bmt.1705722. Epub 2007 Jun 11.
• Background Yanqing Z, Yu-Min L, Jian Q, Bao-Guo X, Chuan-Zhen L. Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. Brain Res. 2006 Jul 7;1098(1):161-9. doi: 10.1016/j.brainres.2006.02.140. Epub 2006 Jul 11.
• Background Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schabitz WR. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005 Aug;115(8):2083-98. doi: 10.1172/JCI23559. Epub 2005 Jul 7.
• Background Tsai KJ, Tsai YC, Shen CK. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med. 2007 Jun 11;204(6):1273-80. doi: 10.1084/jem.20062481. Epub 2007 May 21.
• Background Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience. 2009 Sep 29;163(1):55-72. doi: 10.1016/j.neuroscience.2009.05.071. Epub 2009 Jun 14.

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