New Investments Fund Research Ranging from Novel Treatments for Postoperative Cognitive Dysfunction to Frontotemporal Degeneration

The Alzheimer's Drug Discovery Foundation (ADDF) announces seven new investments, including four clinical trials, two novel drug programs, and a prevention program which reflects the comprehensive nature of its strategy to prevent and treat Alzheimer's disease and related dementias.

Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: "these investments will help us accelerate the development of therapies through our four core areas: clinical trials, drug discovery, biomarkers, and prevention." Dr. Fillit notes that the new investments cover diverse forms of dementia ranging from a novel treatment for postoperative cognitive dysfunction and delirium, and therapies for frontotemporal degeneration that target both epigenetics and neuroinflammation. Another investment will be used to build and test web-based online education programs on Alzheimer’s prevention for both consumers and healthcare professionals.

TREATMENTS

CLINICAL

Miles Berger, MD, PhD, Duke University Medical Center
APOE Mimetic Drug CN-105 to Reduce Postoperative Delirium and Cognitive Dysfunction after Non-Cardiac Surgery
$1,631,197
Postoperative cognitive dysfunction (POCD) and delirium occur in up to 40% of Americans over age 65 who undergo anesthesia and non-cardiac surgery each year. This is associated with decreased quality of life, increased mortality, and a possible increased dementia risk. These conditions may be caused by brain inflammation and exacerbated by pre-existing Alzheimer's disease. With prior ADDF funding, the investigators developed CN-105, a peptide that mimics the naturally occurring protein, APOE. CN-105 blocks brain damage from Alzheimer's disease and inflammation in preclinical tests. A phase 1 clinical trial showed the drug is safe in humans. With this round of ADDF funding, Dr. Berger will conduct a Phase 2 clinical trial to test whether CN-105 reduces POCD and delirium rates in older orthopedic surgery patients. The trial will also assess if CN-105 can reverse brain inflammation associated with POCD and delirium.

Janice Kranz, PhD, Eikonizo Therapeutics, Inc.
De-Risking an HDAC6 Inhibitor for Neurodegenerative Tauopathies
$841,062
Tauopathies, which include Alzheimer's disease and frontotemporal degeneration, are a class of neurodegenerative diseases caused by the abnormal accumulation of tau protein in the brain. HDAC6, an enzyme that is elevated in the brains of Alzheimer's patients, may play a central role in modifying several proteins involved in neurodegenerative diseases, including tau. Eikonizo Therapeutics is developing a novel HDAC6 inhibitor that was previously shown to prevent tau accumulation in preclinical studies. The current ADDF funding will evaluate the highly selective HDAC6 inhibitor in humans. The team has successfully added a radiolabel to their drug that will allow them to visualize it in the brain through PET imaging. This pivotal study will establish HDAC6 as a therapeutic target in humans and de-risk the clinical development of their drug.

Zachary Miller, MD, UCSF Memory and Aging Center
Therapeutic Regulation of Neuroinflammation in FTD Disorders
$1,563,457
Neuroinflammation, or inflammation in the brain, is one of the hallmarks of neurodegenerative disorders, including Alzheimer disease, Parkinson disease, ALS, and frontotemporal dementia (FTD). Reducing neuroinflammation may beneficially impact this entire class of disorders. NP001 is an investigative proprietary form of sodium chlorite made by Neuraltus Pharmaceuticals. Preclinical data suggests that NP001 can reduce neuroinflammation. Dr. Miller will test multiple doses of NP001 in patients with FTD to determine the safety, optimal dose, and to assess biomarkers of inflammation. This pilot study may reveal the potential of immune modulators as therapeutics for FTD and open a new treatment paradigm for this neurodegenerative disorder. This project is funded through the Treat FTD Fund in partnership with the Association for Frontotemporal Degeneration.

Bruno Vellas, MD, Gerontopole, CHU Toulouse
Prevention of Cognitive Decline in Older Adults with Low DHA/EPA Index in Red Blood Cells
$300,000
Decades of research have suggested that omega-3 fatty acids, like DHA and EPA, may prevent cognitive decline. Levels of DHA, one of the brain's essential building blocks, are lower in brain regions associated with Alzheimer's disease. Large clinical trials have highlighted the role of omega-3 in preventing cognitive decline, particularly in patients with low levels of omega-3 in the blood. However, these trials ultimately yielded mixed results. ADDF is providing funding for a pivotal Phase 3 trial, where Dr. Vellas and his team will evaluate whether omega-3 fatty acid supplementation can prevent cognitive decline in older adults with low omega-3 blood levels. Omega-3 treatment may provide a cost-effective therapy that is well-tolerated and without any severe known side effects. If successful, simple blood tests could be used to guide the use of omega-3 fatty acids to prevent cognitive decline in high risk individuals.

DRUG DISCOVERY

Thomas Kukar, PhD, Emory University
Rescue of Lysosomal Dysfunction, Neuroinflammation, and Neurodegeneration by GRN-2 in a model of Frontotemporal Dementia
$150,000
Mutations in the progranulin gene are one of the most common causes of frontotemporal degeneration (FTD), a rare type of dementia that is fatal and currently untreatable. These mutations lead to increased inflammation in the brain and can result in cell death. Dr. Kukar is developing a strategy to replace the faulty protein in patients with progranulin gene mutations. Multiple labs have shown that progranulin is needed for normal lysosome function. Lysosomes contain enzymes that digest cellular materials. Without working lysosomes, proteins abnormally accumulate into toxic aggregates. Dr. Kukar found that delivering a small piece of progranulin, called GRN-2, can restore normal lysosome function in cells with progranulin mutations. This project will provide critical proof-of-concept preclinical data to develop this novel strategy as a potential treatment for FTD caused by progranulin mutations. This project is co-funded through the ADDF's Drug Discovery partnership with the Association for Frontotemporal Degeneration.

Dianne Perez, PhD, Cleveland Clinic Foundation
Optimization of Novel Positive Allosteric Modulators of the Alpha1A-Adrenergic Receptor to Treat Alzheimer's Disease
$381,340
Dr. Perez was selected as the 2017 ADDF-Harrington Scholar. This partnership program with the Harrington Discovery Institute provides ADDF funding and industry-experienced know-how to help translate academic drug discovery projects to the clinic and towards a commercial path to new drug approval. Dr. Perez is developing a novel drug to improve memory function in Alzheimer’s patients by targeting a specific receptor, called alpha-1a adrenergic receptor, in the brain's memory center. One of the biggest hurdles in developing drugs targeting adrenergic receptors has been their reported side effects on blood pressure. However, Dr. Perez has designed a drug that can improve memory while circumventing the blood pressure issues. In this project, she will work closely with Harrington advisors to demonstrate that her drug is more potent than similar drugs that were discontinued due to blood pressure liabilities. Confirming that it can improve memory and reduce pathology in preclinical models without elevating blood pressure will be a key differentiator and will provide evidence to move forward into clinical trials.

PREVENTION

Richard Isaacson, MD, Weill Cornell Medical College
Evaluating the Effectiveness of CognitiveVitality.org on Learning about Brain Health: A Randomized, Crossover Study in the Lay Public and Healthcare Professionals
$100,000
Online education on Alzheimer's prevention has the potential to reach a large audience. Four years ago, Dr. Isaacson developed the AlzU.org platform, a free online educational platform that offers up-to-date and comprehensive evidence-based educational content on Alzheimer's prevention. AlzU.org has had over 625,000 unique visitors from over 40 countries. Notably, people who participated in the AlzU online lessons had significantly greater knowledge about Alzheimer’s prevention, and were more willing to participate in Alzheimer's prevention clinical trials and make lifestyle changes to reduce Alzheimer's risk. In the proposed study, Dr. Isaacson will collaborate with ADDF's CognitiveVitality.org program to build and test web-based brain health lessons in two randomized controlled trials—one for the lay public and another for healthcare professionals. With these web-based brain health lessons, consumers and healthcare providers are likely to gain greater knowledge of brain health supplements and drugs, which should lead to healthier and safer choices and fewer unnecessary or dangerous complications.