Protecting the Brain Against Alzheimer’s: Study to Advance Novel Gene Therapy

By Jillian Rose Lim

From Batten disease to inherited blindness, gene therapies are revolutionizing the way scientists think about treating conditions once considered written into a person’s DNA. Fueled by the creation of effective viral vectors, the tools that deliver corrective or protective genes to cells, researchers are driving discoveries for the treatment of rare diseases such as hemophilia B. Now, at Children’s Hospital of Philadelphia, our scientists are harnessing the same viral vector methods to advance their work on a novel gene therapy for the most common cause of dementia in older adults: Alzheimer’s disease (AD). 

Years in the making, the approach builds on breakthroughs first achieved working with mouse models of AD in 2013. With a recent grant from the National Institute of Neurological Disorders and Stroke, Beverly Davidson, PhD, Chief Scientific Strategy Officer and Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP, will lead a series of studies in order to bring the work closer to approval for clinical trials in humans. 

What excites me the most is finally moving from data in animal models to treating patients,” said Dr. Davidson, also a professor of genetics at the Perelman School of Medicine in the University of Pennsylvania. “It’s a dream come true for a researcher when what you’ve been working on for many years will actually impact people."

Genetics, lifestyle, environmental factors, and other variables can influence a person’s susceptibility to AD. Although the genetics of the disease are complex, scientists know that one of the strongest modifiers for age of onset and progression is a gene called APOE (apolipoprotein E), sometimes known as the “forgetting gene.” Strong data shows that the version of APOE a person inherits can influence their risk for developing AD, as well as when and how quickly the condition progresses. The three major types of the APOE gene, called alleles, are APOE2, APOE3, and APOE4.

APOE2, for example, appears to have a protective effect; if a person inherits APOE2 and develops AD, the disease comes later and progresses slower. But if one inherits APOE4, the reverse is true; the disease onset is earlier and its progression quicker.

In collaboration with researchers at Massachusetts General Hospital in 2013, Dr. Davidson showed that introducing the APOE2 protein in mice with increased amyloid beta (A-beta) brain plaques — a characteristic found in the brains of Alzheimer’s patients — reduced A-beta deposition, retention, and neurotoxicity. In other words, flooding the brain with more of the protective version of APOE appeared to improve disease readouts in the animal models. The findings, published in Science Translational Medicine, led the researchers to wonder whether something similar could be achieved in humans who inherited a bad APOE gene variant.

“We know that just having one allele of APOE2 in your brain is enough to improve the outcome,” Dr. Davidson said. “A way to think about this is putting the APOE2 gene back (via viral vectors) in a group of cells that allows the APOE2 protein to move into the cerebrospinal fluid, or the fluid that bathes the brain. By doing that, the whole brain receives access to this new protein that should be protective.”

The researchers already know what happens when mouse models receive a transfer of APOE2, but what’s required to move ahead into clinical trials is identifying the right dose for humans. By the end of this grant, Dr. Davidson anticipates the team will be able to go to the U.S. Food and Drug Administration with a package of data that will allow them to apply for a Phase 1 clinical trial in human patients with AD to identify optimal dosing and safety.

The approach used by the team to provide this therapy is arm-in-arm with those that they are using to continue developing gene therapies for childhood onset neurodegenerative diseases, and their research findings may open the door for new approaches to other hard-to-treat conditions.

“We envision this as a platform approach for many other neurological disorders that involve the inheritance of either one or two bad alleles,” Dr. Davidson said.