Mice Study May Have Profound Impact on Gene Therapy to Treat Alzheimer’s

Researchers have successfully used a viral transport mechanism to deliver a gene to the brain of mice that prevented the development of Alzheimer’s disease (AD). The results could have a profound impact on the future of gene therapy in treating Alzheimer’s.

These were the findings from a study conducted by researchers at London’s Imperial College through a collaborative funding project between Alzheimer’s Research UK and the European Research Council.

The study, “PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model,” was published in the latest edition of the Proceedings of the National Academy of Sciences of the United States of America, PNAS.

The aim of the study was to generate a lentiviral vector expressing the gene human PGC-1α, and target it to be delivered in specific areas of the brain in mice models of AD (animals that have been experimentally modified to be susceptible to the disease) and then evaluate the effect of the delivered therapeutic gene.

The researchers used the lentiviral vectors, which are experimentally modified retroviruses (i.e., HIV) that can infect both dividing and nondividing cells, because they have been shown to successfully treat, in the lab, a range of conditions including arthritis and cancer. The study’s authors also previously have used a lentivirus vector in clinical trials to deliver genes into the brains of Parkinson’s disease patients.

The human PGC-1α gene was tested as a potential therapeutic gene target because it codes the protein PGC-1–alpha, which has been found to play a major role in the regulation of cellular energy metabolism. It also has been implicated in other disorders, such as obesity, diabetes and cardiomyopathy when the quantities of the protein are below normal ranges.

The mice used in the study were treated experimentally during the early stages of their AD before the development of amyloid plaques. The gene therapy was injected into two areas of their brains most susceptible to the increased amyloid development and the protein-clumping associated with AD: the hippocampus and the cortex.

After injection the mice were given behavioral tasks, such as being able to distinguish between new and familiar objects within their cages,  to achieve at one and four months, then the tissue was harvested to analyze the amount of plaque.

After analysis the findings showed that:

• At four months the brain tissue of the mice who received the gene therapy had fewer amyloid plaques observed than those animals that did not receive the therapy
• Throughout the experimental timeline the treated mice performed as well on tasks as mice that did not receive the treatment
• There were no losses of brain cells in the hippocampus observed in mice treated with the gene therapy

An interesting finding researchers had not expected was a reduction in the brain’s glial cells, which are implicated in AD due to the inflammatory response that damages neighboring neurons in the brain.

In an Imperial College press release about the significance of the study findings, senior author,  Magdalena Sastre, PhD, and senior lecturer and faculty in the Department of Medicine, said “Although these findings are very early they suggest this gene therapy may have potential therapeutic use for patients. There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain. However, this proof of concept study shows this approach warrants further investigation,” she said.

Sastre’s colleague at Alzheimer’s Research UK, David Reynolds, PhD and chief scientific officer, agreed. “There are currently no treatments able to halt the progression of damage in Alzheimer’s, so studies like this are important for highlighting new and innovative approaches to take us toward that goal.”

“This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease,” Reynolds added. “The findings support PGC-1-alpha as a potential target for the development of new medicines, which is a promising step … ”