The Alzheimer’s Drug Discovery Foundation (ADDF) awarded three new grants in July and August. The largest award continues the ADDF’s support of a clinical trial of a synthetic vitamin that treats one of the underlying causes of Alzheimer’s. Two other grants support novel drugs in preclinical stages that target inflammation.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF was at the forefront in our support of drugs targeting neuroinflammation. We continue to invest in the most innovative ideas to treat it, because neuroinflammation is so damaging to the brain. And we are proud to continue our investment in the clinical trial of benfotiamine. Repurposed drugs such as this are exciting because they could be prescribed to patients quickly if they prove effective.”
Gary Gibson, PhD, Winifred Masterson Burk Medical Research Institute
Benfotiamine in Alzheimer's Disease: A Pilot Study
As we age, our neurons become less efficient at using energy, which can lead to neuronal damage and death. This energy failure, known as reduced glucose metabolism, is common in people with Alzheimer’s disease. Vitamin B1 (thiamine) deficiency contributes to reduced glucose metabolism and causes severe memory deficits, and previous studies have shown that vitamin B1 supplementation can reverse these effects. Studies in humans have suggested that administration of B vitamins including B1 can also slow the rate of brain atrophy. This award supports an ongoing clinical trial to see if increasing vitamin B1 using a potent derivative formulation of thiamine (i.e., benfotiamine) will be beneficial in patients with Alzheimer’s disease. Dr. Gibson will assess whether benfotiamine improves memory and other clinical outcomes and improves glucose metabolism.
Elizabeth Bradshaw, PhD, Brigham and Women's Hospital
Identification of Small Molecules that Modulate Microglia/Macrophage Uptake in Primary Human Cells
Though previous studies have shown that the immune system influences the risk of Alzheimer’s disease, it is unclear whether Alzheimer’s therapies should boost the immune system to clear damaged proteins and dying neurons or suppress it to reduce inflammation. Dr. Bradshaw proposes to increase the ability of microglia, immune cells in the brain, to clear protein aggregates and dead cells in a way that limits the damaging inflammatory response. With this funding, she and her team will identify small molecules that increase the ability of microglia to clear damaged neurons and proteins. And then they will evaluate these small molecules for their potential to reduce inflammation, with the goal of identifying the best candidates to develop into potential drugs.
Sung Ok Yoon, PhD, Ohio State University
Discovery and Preclinical Development of Isoform Selective JNK Inhibitors for Alzheimer's Disease
Cellular stressors, including inflammation and metabolic dysfunction, can activate a family of enzymes called JNK kinases. A specific JNK protein, JNK3, is increased in the brains of Alzheimer’s patients and has been shown to cause elevated levels of toxic Alzheimer’s-related proteins. Recently, preclinical studies have suggested that inhibiting JNK3 protects neurons from damage and improves cognition. This award, which is a continuation of the ADDF’s support, will allow Dr. Yoon to further develop a novel class of molecules that inhibit JNK3 activity. In this preclinical phase, her team is focused on developing JNK3 inhibitors that reach the brain when taken orally. Positive results would establish JNK3 inhibitors as a potential new therapeutic avenue for treating Alzheimer’s disease.