Alzheimer's disease is the most common form of dementia, affecting more than 6 million Americans age 65 and older. However, early onset Alzheimer’s can begin even as soon as a person’s 30s. Among all people who develop Alzheimer's disease, approximately 30 percent have the APOe4 allele, a genetic variant that may increase the risk for early onset Alzheimer’s.
Pharmaceutical research out of Auburn University could lead to new treatment options for these at-risk individuals. Dr. Raj Amin, associate professor in the Department of Drug Discovery and Development at the Auburn University Harrison College of Pharmacy, has received a $1.18 million grant from the National Institutes of Health (NIH) to develop a compound to help fight Alzheimer’s. This grant comes to Amin’s laboratory through the NIH Blueprint Neurotherapeutics Network, which aids the development of new drugs for nervous system disorders.
The NIH funding is focused on a set of compounds that target individuals who express the APOe4 allele. The compound AU403IS, which Amin’s lab discovered through in silico modeling, may activate the nuclear receptor liver-X receptor beta, or LXR beta, which may help regulate APOe4 in the brain. The hope is that this compound could be developed into a therapeutic to help prevent the harmful effects or progression of Alzheimer’s disease.
“This class of compounds actually changes the cholesterol pattern in the brain,” Amin said. “This will turn on certain genes or certain proteins and helps clear away many of the bad effects [of Alzheimer’s].” Such effects include amyloid beta plaques, damaged or dead neuronal material and some neurofibrillary tangles, which accumulates inside or surrounds the neurons, leading to neuronal degeneration.
To apply for the NIH grant, Amin’s team had to write up a proposal for submission to a review panel. The program officer discussed the project and offered feedback to the lab. “The IGNITE program is for advancing compounds with high promise,” Amin said. “It goes through a very rigorous review panel…you have people who are from pharma, basic science and clinicians.” According to some of the reviewers, the compound “could transform the way we look at the LXR class of drugs.”
From Compound to Therapeutic
The three-year NIH grant will allow the researchers to develop a formulation for the current compound. This formulation can then be applied to a variety of animal models to better understand which population may benefit the most. This will also help the lab determine which stage of Alzheimer's disease the eventual drug is best suited for and how long it should be used.
When the compound is developed further, the lab can partner with a pharmaceutical company to help conduct additional studies for toxicity, absorption, distribution, metabolism and excretion (ADME) analysis. Next would be applying to the FDA for the Pre-Investigational New Drug Application (Pre-IND) Consultation Program, an early step in bringing a drug to market, before launching human studies. This lengthy process could take many more years to complete. “The compound is always a step,” Amin said. “It helps us understand how we could develop a better therapeutic.”
Auburn’s Department of Drug Discovery and Development functions much like a biotech firm, with three branches that serve different purposes. Medicinal chemists help design and synthesize the compounds; pharmacology scientists then test these compounds in animals and cell cultures. Those in the third group, pharmaceutics, study the effects of the compound, its bioavailability and other factors that help determine whether a compound is feasible as a pharmaceutical.
This type of work allows pharmacy schools to develop intellectual property from drug discovery, which they can license to pharmaceutical companies. Most of all, it provides valuable experience for faculty and students. “The development of an intellectual property at the university basis is really to help educate and advance our field of pharmacy,” Amin said. “Programs like this help advance the knowledge depth for students as well as for faculty.”