One of a group of RFU researchers working to understand neurodegenerative disease, Grace "Beth" Stutzmann, PhD, founded the biotech startup NeuroLucent, based on her study of target compounds that show promise in impeding the progression of Alzheimer's disease.

A drug created by an interdisciplinary team of RFU researchers could be the first medication to effectively treat the most devastating symptoms of Alzheimer's disease (AD), which robs memory and cognitive function and affects more than five million people in the United States. Worldwide, a staggering 46.8 million people were living with dementia in 2015.

"We've found a way to restore synaptic structure and function and prevent much of the Alzheimer's-related pathology," said Grace "Beth" Stutzmann, PhD, associate professor of neuroscience, who has formed NeuroLucent, a small biotech startup company that will help move her new therapeutics into the pharmaceutical pipeline.

Faster translation of basic science research into therapeutics is key to RFU's mission to improve the health of the population, said Ronald Kaplan, PhD, RFU executive vice president for research.

"The work of Dr. Stutzmann is a perfect example," he said. "She's starting from the molecular level and identifying inhibitors of a calcium channel that is dysregulated in AD, then developing high-affinity compounds to restore regulation."

The university is facilitating the startup efforts of several faculty members through the Office of Technology Transfer and a compliance structure that emphasizes cutting-edge, best-practice policies. It has engaged SmartHealth Activator, a North Chicago, IL-based healthcare accelerator, which is working with NeuroLucent to identify investors and work through the business side of drug development.

NeuroLucent and its foundational drugs spring from Dr. Stutzmann's many years of research into AD. A progressive brain disorder, AD is often associated with the presence in the brain of abnormal clumps — amyloid plaques — and tangled bundles of fibers — tau tangles. These abnormalities disrupt neuronal function and cause healthy neurons to die. The damage is permanent.

No cure for Alzheimer's exists and current treatments only temporarily improve symptoms. Some of the recently tested drugs targeting aggregated proteins were effective at clearing plaques and tau tangles in brains of AD patients in clinical trials, but had no positive effect on memory or cognitive function and sometimes made them worse.

Dr. Stutzmann, who has been studying AD for 15 years, noted that she and her team are taking their research in a new direction.

"The AD field desperately needs new conceptual approaches to develop effective therapeutics, particularly ones that focus on upstream pathogenic mechanisms," she said. "The underlying challenge is identifying those early mechanisms. We feel we've tapped into that unmet need. Time, more experiments and, hopefully, clinical trials will ultimately tell."

Dr. Stutzmann's approach addresses the early changes that take place in the brain that lead to disease rather than the late stage development of plaques and tangles.

Very early in the disease's progression, before diagnosis is possible, she detected the release of two to 10 times more calcium within neurons in mice and humans than in those without the disease.

Calcium is fundamental to the neurochemical processes that drive and store memories, and Dr. Stutzmann's research shows how aberrant calcium signaling ultimately leads to the loss of synapses and impairment in the cellular mechanisms that drive learning and memory.

"By maintaining normal calcium signaling in early stages, you can protect the synapses that form and store memory," Dr. Stutzmann said. "This approach also serves to reduce amyloid and tau pathology, as these are aggravated by increased calcium levels as well."

Dr. Stutzmann's research in mouse models of AD shows that excess calcium is released through a particular type of calcium channel, called the ryanodine receptor.

"We've spent many years trying to identify and understand the consequences of this aberrant calcium release," she said. "Now that we feel confident we've worked that out, we've changed our focus to the development of therapeutic strategies around this calcium channel."

Dr. Stutzmann and her colleagues validated the ryanodine receptor as a target for AD therapeutics using an existing compound that inhibits this receptor, although this compound is intended for muscle disorders and not ideal for brain targets. Earlier work demonstrated that this calcium channel was also vital for neuronal functioning.

"We decided to test this drug in our AD mouse models and found that stabilizing this calcium channel not only prevents the excess calcium release in neurons, but also prevents a broader range of pathogenic effects, including the typical features of AD," Dr. Stutzmann said. "It reduces the amyloid plaques. It reduces the tau pathology. It restores synaptic structure and function. It protects organelles. We were truly amazed at the breadth of the therapeutic actions."

Dr. Stutzmann, who said her drugs would be best used for patients exhibiting early symptoms of AD, hopes to soon begin testing them in human neurons. This is a critical step, she said, as many test drugs have performed well in mouse models, only to fail miserably in human clinical trials. Because her drugs are entirely different and are screened specifically for preserving synaptic function, she believes they offer new hope.

Success in making the drug available to Alzheimer's patients, in bringing bench to bedside using novel approaches, in stopping the damage and suffering caused by AD, keeps the basic research scientist and her team motivated.

"I've been so focused on identifying disease mechanisms that drive neurological disorders at the basic science level," Dr. Stutzmann said. "Actually testing a drug in humans has always been a remote concept. The fact this possibility is looming closer and closer is a fulfillment beyond my expectations."