Despite considerable effort over several decades on the part of academic investigators and the pharmaceutical industry, an effective, disease-modifying therapy for Alzheimer's disease (AD) remains elusive. The prevailing hypothesis for the pathogenesis of this disease involves a cascade of events beginning with the formation and deposition of aggregates of the amyloid-beta (A?) protein. Many therapeutic development efforts aimed at removing toxic species of A? or preventing their build up, either through the administration of monoclonal antibodies against one or more forms of A? or antagonists of enzymes involved in its formation have, to date, not met expectations. At present it is unclear if the unimpressive results to date are related to target biology, the specific properties of the test drug used or limitations of trial design and/or patient selection. Nevertheless, epidemiologic and genetic data continue to point strongly to A? being a valid target in AD, especially if targeted early in the course of the disease. Moreover, several lines of evidence suggest that A? deposits represent a potential target for the innate immune system including intracerebral microglia and bone-marrow-derived mononucleocytes. Therefore a valid, alternative approach to AD therapy is to stimulate the innate immune system to remove deposits of A? before there is significant and possibly irreversible neuronal damage and resultant cognitive deficits. With this in mind, we propose to test in a randomized, double-blinded, placebocontrolled, proof-of-concept clinical trial whether an already-approved, immune stimulator, recombinant human, granulocyte-macrophage colony stimulating factor (rhu GM-CSF), specifically sargramostim (Leukine) at its currently approved dose, meets the criteria for more comprehensive clinical testing to reposition this drug as an AD therapeutic. The primary objective of this proposal is to evaluate the effect of direct immune system stimulation with sargramostim on existing beta-amyloid plaque load using quantitative positron emission tomography (PET) in patients with mild cognitive impairment (MCI) due to AD (pre-clinical AD). A secondary objective is to assess the effect of treatment on different cognitive tests that may be used during future clinical development. To summarize, this approach is compelling for the following reasons: (1) microglia/monocyte biology suggests the potential for amyloid-clearing effects, (2) microglial/macrophage activity can be stimulated by GM-CSF, (3) sargramostim's macrophage activity translate into clinical benefits in several settings, (4) serum GM-CSF is not already elevated in patients with Alzheimer's disease, thus exogenous GM-CSF may cause systemic immunostimulation, (5) peripheral administration of sargramostim should allow for therapeutic activity in the CNS, (6) murine GM-CSF (mGM-CSF) reverses both amyloidosis and cognitive impairment in AD mice, (7) the safety profile of sargramostim allows for its long-term use in non-immunocompromised patients and (8) it may enable other therapeutic opportunities for this and other immunostimulatory-based therapeutics. Thus, given that Leukine is an already approved drug with a known dose and safety profile, this effort, if successful, could lead to, in the relatively ear term, at least a partial solution to Alzheimer's disease epidemic that is currently upon us.
This proposal is a request for partial support for a small clinical trial to test whether an existing, approved drug, sargramostim (rhu, GM-CSF, Leukine), at its currently-approved dose, meets the criteria reposition this compound as a therapeutic candidate for AD and to conduct more comprehensive clinical testing aimed at approval. If successful, then this clinical trial will lead to additional clinical testing to determine whether sargramostim (Leukine) can be repositioned to prevent the onset or worsening of Alzheimer's disease which given that sargramostim is already approved and thus has a known dose and safety profile, could lead to at least a partial, solution to the growing Alzheimer's disease epidemic more rapidly than other, earlier-stage approaches.