The Alzheimer’s Drug Discovery Foundation (ADDF) announces four new grants, including support for an innovative clinical trial, two novel drug programs, and a biomarker for CTE.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF began supporting the allopregnanolone program in 2005, and we are pleased that such a promising drug has now made it to phase 2 human clinical trials. Allopregnanolone has enormous potential to help Alzheimer’s patients and we look forward to the results of this important project.”
Roberta Diaz Brinton, PhD, University of Arizona Health Sciences
Manufacturing of Allopregnanolone
In Alzheimer’s disease, patients lose a significant number of neurons in specific regions of the brain. Scientists assume that regenerating those lost neurons through a process called neurogenesis might restore cognitive function. But previous attempts to spur neurogenesis using stem cells failed. With more than a decade of ADDF funding, Dr. Brinton discovered that the neurosteroid allopregnanolone stimulates the proliferation of stem cells. In preclinical testing, she demonstrated that it did promote neurogenesis, restore cognitive function, and reduce Alzheimer’s pathology in the brain. And a recent phase 1b/2a human clinical trial produced positive findings. Dr. Brinton now plans a larger phase 2 clinical trial. This funding supports the manufacture of allopregnanolone for that trial.
Travis Dunckley, PhD, Arizona State University
Testing of Selective DYRK1A Inhibitors as a Novel Treatment for Alzheimer’s
The accumulation of tau protein into tangles is a hallmark of Alzheimer’s disease. These toxic tangles form when tau is abnormally phosphorylated (or tagged) by enzymes known as kinases. Dr. Dunckley and his colleagues have developed two novel compounds to inhibit DYRK1A, a kinase that phosphorylates tau, as well as other Alzheimer’s-related amyloid proteins. Preliminary data from Dr. Dunckley’s lab indicates that DYRK1A inhibitors safely reduce phosphorylated tau levels in the brain. With this funding, the team will conduct preclinical tests to assess if DYRK1A inhibitors can delay cognitive decline and the onset of Alzheimer’s disease. If successful, the proposed studies will provide critical data to advance one of these drug candidates toward human clinical trials.
William Ray, PhD, The Neurodegeneration Consortium, MD Anderson
Therapeutic Potential of Dual Leucine Zipper Kinase Inhibitors in Alzheimer’s Disease
When the nervous system sustains an injury, our body eliminates the damaged neurons. Scientists recently discovered that a protein called dual leucine zipper kinase (DLK) regulates this process. Dr. Ray hypothesized that DLK might be abnormally activated in Alzheimer’s disease. He found in several preclinical tests that DLK congregates at sites of neuronal damage early in the disease process and activates genes that trigger neuronal death. DLK inhibitors are a promising approach to treating Alzheimer’s because DLK is only found in neurons and only appears to be active when injury occurs, so inhibiting it won’t affect healthy cells. Dr. Ray and colleagues have already synthesized inhibitors that potently block DLK without disturbing other related genes. In this project, they will optimize their DLK inhibitors to develop a clinical candidate and evaluate its ability to modify disease progression.
Sam Gandy, MD, PhD, Icahn School of Medicine at Mount Sinai
Imaging [18F] AV-1451 and [18F] AV-45 in Acute and Chronic Traumatic Brain Injury
Traumatic brain injury (TBI) is a risk factor for chronic traumatic encephalopathy (CTE) and dementia. But our understanding of the long-term effects of TBI is incomplete. Repeated concussions have been associated with an elevated incidence of Alzheimer’s along with a younger age of onset. And brain autopsies of athletes with confirmed CTE have demonstrated tau-containing neurofibrillary tangles and neuropil threads, which are also found in Alzheimer’s patients. But there remains no way to conclusively detect tau and diagnose CTE in living patients. To address this, Dr. Gandy and his team are using PET imaging to investigate amyloid and tau accumulation in subjects with a history of concussions. The investigators are reviewing PET scans along with MRI and neurocognitive data in a cohort of 25 subjects with a history of TBIs and a cohort of 25 subjects with mild cognitive impairment. With this funding, they will add 16 more patients to strengthen their analyses. Their hope is to contribute to the development of biomarkers to diagnose Alzheimer’s and CTE after TBI.