Experimental Therapeutics & Approaches in Alzheimer’s Disease & Related Dementias

GTCbio | August 3rd, 2017

Alzheimer’s disease (AD), is a chronic neurodegenerative disease that usually starts slowly and worsens over time and although often appearing in people over 65 years of age, it is not just a disease of old age. It is estimated that approximately 200,000 Americans under the age of 65 have “early-onset” AD. It is believed that between 60-80% of dementia is due to AD . Data suggest that worldwide, the total number of affected individuals is approaching 100 million. In 1999, it was first reported that injecting transgenic “Alzheimer” mice with beta-amyloid (Aβ) prevented the animals from developing plaques and other AD-like brain changes. While the pathogenesis of human AD is widely believed to be driven by the production and deposition of Aβ, there is at best, a poor correlation between the amount of Aβ plaque formation and clinical dementia. Substantial evidence now suggests that the solubility of Aβ and the quantity of Aβ in different pools may be more indicative of severity of the disease progression. Currently, anticholinesterases and N-methyl-D-aspartate receptor antagonists are the mainstays of AD treatment, while new agents including molecules targeting tau protein-like modulators of tau-kinases or phosphatases, kinase inhibitors, and tau-aggregation inhibitors may hold promise. According to recent data, combination therapy, stem cell therapy, study of neuroinflammation and chaperones (still in preclinical trials) may offer an effective new approach to treating AD. Preliminary phase 2 study findings indicate efficacy of Bryostatin-1, a protein kinase C epsilon activator, for moderate-to-severe Alzheimer’s disease. The examination of peripheral cells from AD patients shows mitochondrial dysfunction, which suggests that tracking these mitochondrial defects in peripheral cells could be a potential mechanism of early diagnosis of AD.

The neurovascular unit which controls cerebral blood flow dynamics, blood-brain barrier integrity, peripheral immune cell infiltration into the CNS and drug transport plays a key role in neurodegenerative disease processes and presents unique potential for novel therapeutics. Similarly, neurovascular dysfunction can directly contribute to key aspects of neuroinflammation, neuronal injury and impaired brain energetics. Further, ongoing research has shown that overactivity in the hippocampus contributes to cognitive impairment and drives later neurodegeneration. This overactivity is characteristic of mild cognitive impairment, the symptomatic pre-dementia stage before AD fully develops. Therefore, researchers have developed a novel GABAA discovery program targeting hippocampal overactivity.

Maintenance of cellular homeostasis is regulated by molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as “clients,” have major roles in the pathogenesis of numerous neurological disorders, including the tau tangles in Alzheimer’s disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. In addition, novel human-based in vitro models of the vasculature are being developed to study the role of high-density lipoproteins in cerebrovascular function in the context of AD.

Namzaric, Aricept, Razadyne, Exelon, Memantine, Donepezil, Galantamine, And Rivastigmine are some of the approved drugs for treatment of AD. However, there are still 105 agents in the AD treatment development pipeline, of which 25 agents are in 29 trials in phase I, 52 agents are in 68 trials in phase II, and 28 agents are in 42 trials in phase III.

Some of the above mentioned programs will be discussed at GTCbio’s CNS diseases summit to be held on September 11-12, 2017 in Boston, MA. The following speakers will discuss about “Experimental Therapeutics & Approaches in Alzheimer’s Disease & Related Dementias”.

Alzheimer’s Therapeutics Speakers

•   Gabriela Chiosis, Professor, MSKCC

Dr. Gabriela Chiosis received her graduate training at Columbia University in New York and joined Memorial Sloan Kettering Cancer Center in 1998, first as a fellow and, since 2005, as faculty. Research in the Chiosis lab is aimed at developing pharmacologic tools that selectively target the pathogenic role of molecular chaperones; understanding how molecular chaperones effect their specialized roles in pathogenic cells; and creating a map of disease-specific molecular alterations, using selective chaperone modulators. She will talk about “Chaperome Alterations in AD as a Target of Intervention”.

•   Robert Bell, Senior Principal Scientist, Neurovascular Biology Lab Head, Pfizer

Dr. Bell is the Lab Head of Neurovascular and BBB Biology within Integrative and Circuit Neuroscience in the Neuroscience Research Unit at Pfizer. He pursued education at St. Bonaventure University and Oxford University. Robert has authored over 25 scientific papers and was previously an associate editor for the Journal of Alzheimer’s Disease. Robert’s lab is working to identify and validate novel vascular-based targets for CNS disease and to enhance delivery of medicine across the blood-brain barrier. He will talk about “Targeting the Neurovascular Unit in Neurodegeneration”.

•   Cheryl Wellington, Clinical Professor, Djavad Mowafaghian Centre for Brain Health, University of British Columbia

Dr. Wellington obtained her PhD at the University of British Columbia and performed postdoctoral fellowships at Harvard Medical School, the University of Calgary, and the University of British Columbia. Dr. Wellington’s research program encompasses the genetic and environmental risk factors that affect dementia, including apolipoprotein E metabolism, history of traumatic brain injury (TBI), and cerebrovascular dysfunction. She will talk about “Clearance of Beta-Amyloid Is Facilitated By Apolipoprotein E and Circulating High-Density Lipoproteins in Bioengineered Human Vessels”.

•   Sharon Rosenzweig-Lipson, Vice President of R&D, Agenebio

Dr. Rosenzweig-Lipson received her BA in Biological Basis of Behavior from the University of Pennsylvania and her PhD in Behavioral Neuroscience from Harvard University. She is President of IVS Pharma Consulting. She offers AgeneBio expertise in screening strategies, in vivo models, translation and early clinical development strategy. She has over 20 years experience developing compounds for psychiatric and neurologic indications in the pharmaceutical industry. She will talk about “Attenuating Hippocampal Overactivity as a Therapeutic Strategy for Mild Cognitive Impairment Due to Alzheimer’s Disease”.

We invite you to join us at the 11th Annual CNS Diseases Summit, to be held on September 11-12, 2017 in Boston, MA.