Image 1 shows brain cells from a mouse cortex that didn't receive the gene therapy. The amyloid plaques are shown in green and the glial cells, which surround the plaques, are shown in red (microglia) and magenta (astrocytes). Image 2 shows a mouse cortex that received the gene therapy and so had fewer amyloid plaques. [Imperial College London]
Image 1 shows brain cells from a mouse cortex that didn’t receive the gene therapy. The amyloid plaques are shown in green and the glial cells, which surround the plaques, are shown in red (microglia) and magenta (astrocytes). Image 2 shows a mouse cortex that received the gene therapy and so had fewer amyloid plaques. [Imperial College London]

Researchers at the Imperial College London have just released data from animal studies in which they were able to prevent the development of Alzheimer’s disease (AD) by using a virus to deliver a specific gene into the brain. The results from this study could open avenues toward potential new treatments for the disease.

“Although these findings are very early, they suggest this gene therapy may have potential therapeutic use for patients,” explained senior study investigator Magdalena Sastre, Ph.D., senior lecturer in the department of medicine at the Imperial College London. “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.”

The Imperial College researchers used a modified lentivirus to deliver the peroxisome proliferator-activated receptor-γ (PPARγ)-coactivator-1α (PGC-1α) gene to brain cells, which previous studies suggested may prevent the formation of amyloid-beta peptide (Aβ)—at least for cells grown in vitro. Aβ peptide is the main component of amyloid plaques, the sticky clumps of protein found in the brains of people with AD. These plaques are thought to trigger the death of brain cells.

“Scientists harness the way lentivirus infects cells to produce a modified version of the virus, that delivers genes into specific cells,” remarked co-study author Nicholas Mazarakis, Ph.D., chair of molecular biomedicine and head of gene therapy at Imperial College London. “It is being used in experiments to treat a range of conditions from arthritis to cancer. We have previously successfully used the lentivirus vector in clinical trials to deliver genes into the brains of Parkinson's disease patients.”

The findings from this study were published recently in PNAS in an article entitled “PPARγ-Coactivator-1α Gene Transfer Reduces Neuronal Loss and Amyloid-β Generation by Reducing β-Secretase in an Alzheimer’s Disease Model.”

Worldwide, 47.5 million people are affected by dementia—of which AD constitutes the most common form. Symptoms include memory loss, confusion, and change in mood or personality. Currently, there is no cure, although some existing drugs can help treat the symptoms of the disease.

In the new study, the investigators injected the virus containing the PGC-1α gene into two areas of the brains of mice susceptible to AD. The areas targeted were the hippocampus and the cortex, as these are the first regions to develop amyloid plaques in AD.

Damage to the hippocampus affects short-term memory and leads to a person forgetting recent events, such as a conversation or what they ate for breakfast. The hippocampus is also responsible for orientation, and damage results in a person becoming lost on familiar journeys, such as driving home from the shops. The cortex, meanwhile, is responsible for long-term memory, reasoning, thinking, and mood. Damage can trigger symptoms such as depression and agitation.

The mice in this study were treated at the early stages of AD when they still had not developed amyloid plaques. After 4 months, the team found that mice who received the gene had very few amyloid plaques, compared with the untreated mice, who had multiple plaques in their brain. Moreover, the treated mice performed as well in memory tasks as healthy mice. The tasks included challenges such as replacing a familiar object in the mouse's cage with a new one. If the mice had a healthy memory, they would explore the new object for longer.

The investigators also discovered that there was no loss of brain cells in the hippocampus of the mice who received the gene therapy. In addition to this, the treated mice had a reduction in the number of glial cells, which in AD can release toxic inflammatory substances that cause further cell damage.

The researchers are optimistic about their findings but urge caution in over interpretation of the results. “We are still years from using this in the clinic,” Dr. Sastre noted. “However, in a disease that urgently needs new options for patients, this work provides hope for future therapies.”

“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,” added David Reynolds, Ph.D., chief scientific officer at Alzheimer's Research UK, who was not connected with the current study. “This research sets a foundation for exploring gene therapy as a treatment strategy for AD, but further studies are needed to establish whether gene therapy would be safe, effective, and practical to use in people with the disease. The findings support PGC-1α as a potential target for the development of new medicines, which is a promising step on the road toward developing treatments for this devastating condition.”








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