UAB scientists explore gene therapy for frontotemporal dementia

Gene therapy has shown promise for treating a neurodegenerative disease known as frontotemporal dementia and a related condition called neuronal ceroid lipofuscinosis, according to new findings presented in the Journal of Neuroscience by researchers from the University of Alabama at Birmingham.

Frontotemporal dementia, or FTD, is a devastating disease in which patients have rapid and dramatic changes in behavior, personality and social skills. The age of onset for FTD is relatively young, usually striking patients in their mid- to late 50s. FTD is often caused when an individual has only one copy of the GRN gene, which encodes for a protein called progranulin. Progranulin production is cut in half in individuals with only one copy of GRN.

A mutation resulting in the loss of both copies of the GRN gene leads to an almost complete absence of progranulin, causing a condition called neuronal ceroid lipofuscinosis, which often strikes adults in their 20s. NCL causes blindness and seizures, and can lead to premature death.

A research team led by Erik Roberson, M.D., Ph.D., associate professor in the Department of Neurology and director of the Alzheimer's Disease Center, examined the effects of boosting progranulin by adding the GRN gene to brain cells via an adeno-associated virus to mouse models of FTD and NCL.

"Our goal was to see if adding the missing protein progranulin through gene therapy would reverse the effects even after symptoms had begun," said Roberson, the Patsy W. and Charles A. Collat Professor of Neuroscience. "The adeno-associated virus is a commonly used gene therapy vector, as it does not cause human disease and has a low immune response."

Progranulin is involved in a part of the cell called the lysosome. Lysosomes are the body's garbage collectors, removing waste material that accumulates in the cells. In the absence of progranulin, cells build up granules of fat called lipofuscin that are often associated with aging or the 'wear and tear' on a cell. The accumulation of lipofuscin in a cell is a marker of poor lysosomal function.

"Our study showed that the return of progranulin to the cells meant that lipofuscin levels decreased and overall lysosomal function improved," said Andrew Arrant, Ph.D., a scientist in the Department of Neurology and first author of the paper. "In other words, progranulin helped lysosomes take out the trash."

Increased progranulin levels were detected most robustly at brain areas near the injection site; but the team also found that progranulin levels also showed some increase in areas farther from the site, indicating that the AAV vector migrated within the brain to some extent.

"This is a potentially exciting development in the field of neurodegeneration," Arrant said. "We are able to show that boosting progranulin helped reduce lipofuscin levels and markers of neuroinflammation. Importantly, gene therapy allows the cells to make their own progranulin, rather than just supplementing the protein from the outside. This could allow the cells to continue producing progranulin after a single treatment, potentially providing a long-term benefit."

Arrant and Roberson say the findings should boost interest in exploration of gene therapy as a viable form of treatment for these diseases.

"In other diseases involving dementia, such as Alzheimer's disease, there is considerable disagreement among scientists regarding the most appropriate therapeutic pathways to explore," Roberson said. "With many targets, we aren't even sure if our goal should be to increase or decrease them. But in this type of FTD, there is consensus - verified by this study -; that adding progranulin would be a beneficial therapy for both FTD and NCL."

Roberson and Arrant say many questions are still to be answered before this type of gene therapy could progress to clinical trials in humans, but that these findings are promising and worthy of additional research.​