Funded Programs Clinical

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.

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.

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

Summary:
Diabetes and high insulin levels have surfaced as important risk factors for Alzheimer\'s disease. There are ongoing clinical trials of the insulin reducing agent 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 have put the use of this medication into question. The investigators propose to conduct a pilot clinical trial of a different insulin reducing agent, metformin, which is also an effective medication in the prevention and treatment of diabetes and has a better safety profile than rosiglitazone. The PI hypothesizes that reducing insulin levels in persons with amnestic mild cognitive impairment will aid in the prevention of further cognitive decline.

Low Dose Bryostatin Activation of Protein Kinase C as a Novel Therapeutic for Early Alzheimer\'s Disease Dementia Investigator(s): Daniel Alkon, MD Institution(s): Blanchette Rockefeller Neurosciences Institute

Summary:
Many new drug programs for Alzheimer’s disease attempt to prevent the generation of β-amyloid. Investigators at BRNI have shown that protein kinase C (PKC) activation may be beneficial both in enhancing normal memory formation and in ameliorating neurodegeneration in AD. Aβ is formed from its precursor APP by enzymes beta-secretase and gamma-secretase. However, normal cleavage of APP alpha-secretase yields the non-amyloidogenic P3 fragment, rather than Aβ. Cleavage by alpha-secretase is under the control of protein kinase C (PKC). Thus, one effect of PKC activation, in principle, is to shift APP cleavage toward the non-amyloidogenic pathway. Additionally, investigators at BRNI have shown that PKC activation is crucial to numerous types of associative learning in species from mollusks to mammals. PKC also inhibits glycogen synthase 3 kinase, which contributes to tau hyperphosphorylation, another pathological marker of AD. Thus, in principle, PKC activation could be beneficial in at least 3 approaches to memory enhancement and neuroprotection. Attempts to use PKC activators therapeutically have been marred by the discovery that most are tumorigenic (eg, phorbol esters). Recently, however, a macrocyclic lactone termed Bryostatin was discovered to be a potent PKC activator that completely lacked tumorgenicity. In fact, its anti-neoplastic properties have been tested in oncology clinical trials, albeit with limited success. The goal of the current proposal is 1) to test a very low dose range of Bryostatin in human Phase 1 clinical trials to confirm its lack of toxicity; and 2) to evaluate the acute, low-dose regimen in a proof of principle test of efficacy for enhancing recent memory in early AD.

Intranasal Insulin Administration and Memory in AD Investigator(s): Suzanne Craft, PhD Institution(s): University of Washington, Seattle, WA

Summary:
Converging evidence from many laboratories suggests that impaired insulin metabolism may contribute to cognitive decline and development of Alzheimer’s disease; treating insulin abnormalities may, in part, remedy AD-related memory loss. Insulin and insulin receptors are selectively expressed in brain regions (ie, hippocampus) supporting memory. Insulin regulates glucose metabolism and cerebral glucose metabolism is reduced in AD. Furthermore, recent studies suggest that insulin may influence AD by modulation the accumulation of beta-amyloid. Dr. Craft and colleagues have been among the first to show that giving intravenous (IV) insulin can facilitate memory in AD subjects. However, for a number of reasons, IV administrations of insulin make it an unlikely long-term therapeutic strategy. Alternatively, intranasal administration of insulin has been found to facilitate memory and learning in animal models. Thus, intranasal insulin administration makes it possible to test the hypothesis that insulin, acting in the brain, can facilitate memory in human AD subjects. In this program, Dr. Craft and colleagues will conduct a pilot clinical study to test the hypothesis that intranasal administration of insulin will facilitate memory for new information for patients with AD and normal, healthy, older adults.