Funded Programs Clinical

Pilot trial of Metformin in the prevention of Alzheimer's disease Investigator(s): Jose Luchsinger, MD MPH Institution(s): Columbia University, New York, NY

Summary:
Diabetes and "hyperinsulinemia" (high insulin levels) have surfaced as important risk factors for Alzheimer's disease (AD). There are ongoing clinical trials of anti-diabetic agents (e.g. rosiglitazone) in the prevention and treatment of AD based on the hypothesis that reduction of insulin levels will decrease AD progression. However, recent reports of safety concerns with rosiglitazone widely covered by the scientific and lay press have put the use of this medication in the prevention and treatment of AD into question. Dr. Luchsinger proposes to continue a phase II pilot clinical trial of metformin, a safe and effective medication in the prevention and treatment of diabetes and the reduction of insulin levels, in the prevention of cognitive decline among persons with amnestic mild cognitive impairment (AMCI), a transitional stage between normal cognition and AD. Luchsinger will complete recruitment of 40 subjects with grant 270901 from ISOA. With the additional funding raised through the "fund-a-scientist" program, he will continue to follow-up these 40 subjects and will recruit 10 new participants.

Efficacy and Safety of Filgastrim (Neupogen®) as a Pro-cognitive Agent for Alzheimer's Disease Investigator(s): Juan Sanches-Ramos, MD, PhD Institution(s): University of South Florida

Summary:
The use of blood stem cell-mobilizing agents for treatment of neurologic diseases is being applied to patients with Alzheimer's disease (AD). Administration of filgastrim to mouse models of AD resulted in a dramatic improvement in cogntive function and a marked decrease in amyloid plaque deposition. Filgastrim is already clinically approved for other indications (to increase blood stem cell production in leukemia) and in normal donors of blood stem cells. This clinical study will be the first to determine whether filgastrim administration will be effective and safe as a pro-cognitive and disease-modifying agent in patients with AD.

A Pilot Clinical Trial of NAP (AL-108) for Corticobasal Degeneration and Frontotemporal Lobar Degeneration with Predicted Corticobasal Degeneration Pathology Investigator(s): Adam Boxer, MD, PhD Institution(s): University of California, San Francisco

Summary:
There are currently no effective treatments for CBD. CBD is usually thought of as a movement disorder, however, often during life the most prominent symptoms are language impairments or dementia due to a syndrome called frontotemporal lobar degeneration (FTLD). CBD is thought to be caused by accumulation of toxic forms a protein called tau in the brain. The goal of this study is to test a new drug called NAP (AL-108) in patients with CBD. NAP blocks formation of toxic forms of tau protein in brain cells and is able to improve disease in animal models of tau-related brain disease. NAP has recently been tested in humans for treatment of a precursor to Alzheimer's disease called mild cognitive impairment (MCI). This study showed that NAP is safe, has few significant side effects and can improve a number of cognitive deficits. Because the biochemical mechanism of NAP is thought to be even more specific for CBD than for MCI, we hypothesize that NAP may be an effective treatment for CBD. This study will investigate the effects of 6 months of NAP treatment in humans with CBD and forms of FTLD with a high likelihood of underlying CBD pathology. The size of the study (28 subjects due to funding limitations), diminishes the likelihood that the findings will be definitively positive, unless NAP has a large effect on those who receive treatment. Nonetheless, this study will provide access to a promising new treatment for patients with few other options, and will probe potential sensitive biomarkers that might demonstrate treatment effects. Therefore, it will provide invaluable data on how to best design a subsequent clinical trial that would be large enough to determine whether NAP is an effective treatment for CBD and related forms of FTLD.

Validation and Optimization of an Immunoprecipitation Assay for Amyloid Beta from Human Cerebrospinal Fluid Using Novel Antibodies Investigator(s): Tim West, Ph.D. Institution(s): C2N Diagnostics

Summary:
There is currently no validated biomarker for AD, making early detection and diagnosis, monitoring of disease progression, and the objective biological assessment of potential therapeutics in clinical trials difficult. C2N Diagnostics is a start-up company that is commercializing new technology developed at the Washington University, St. Louis, MO. This "break-through" technology provides a new method for the detection of ß-amyloid as it is synthesized and cleared in the brain. The test requires the administration of a radio-labelled amount of beta-amyloid to humans, followed by a spinal tap to obtain spinal fluid and determine how much beta-amyloid has been produced during a given period of time. It is considered that in Alzheimer's disease, more beta-amyloid is being produced, while with novel anti-amyloid drugs, one could measure and demonstrate the reduction in beta-amyloid. Thus, the test could be useful for early diagnosis and in monitoring effectiveness of new drugs in development for AD. The availability and further development of this test has very important implications for research and clinical care of patients with AD.

Development of a Sustained Release Oral Formulation of sGC 1061, A New Therapeutic Agent for the Treatment of Alzheimer's Disease Related Cognitive Deficiency Investigator(s): Doug Cowart, Ph.D. Institution(s): sGC Pharma

Summary:
sGC Pharma is a virtual start-up company developing pro-cognitive agents for Alzheimer's disease (AD). These agents are based on the delivery of nitric oxide, a known neurotransmitter in the brain. The initial formulation of the compound, called GT-1061 improved cognitive function in animal models and in preliminary human clinical trials. These studies were partially funded by ISOA to investigator Greg Thatcher. However, GT-1061 subsequently caused hypotension (low blood pressure) in humans and therefore human trials were not continued. GT-1061 was then reformulated as a slow release tablet, termed sGC-1061. This slow release formulation may retain the cognitive benefits of the drug without the hypotensive side effects. The aim of this grant proposal is to enter into larger scale synthesis of sGC-1061 in anticipation of phase II human clinical trials.