New gene therapy 'may target' Alzheimer's

Monday March 21 2011

“Scientists have successfully switched off a gene thought to cause Alzheimer’s by using a new way to deliver drugs directly to the brain,” reported the Daily Mirror . The newspaper said that researchers have used “tiny particles called exosomes, which are released by cells, to administer drugs into the brains of mice”.
The laboratory study behind these headlines was carried out in mice. The findings are significant, demonstrating that exosomes could be used to carry gene therapy to particular genes in the brain. One of these genes is BACE1, which produces a protein associated with Alzheimer’s disease.

The study paves the way for future research, and the finding will be of great interest to the scientific community. Exosomes appear to be able to deliver specific ‘cargoes’ to brain cells so the technology has a number of potential applications. However, this is early research and the technology has not been tested in human cells. There is also a range of technical and ethical issues associated with gene therapy in humans.

Where did the story come from?

This study was carried out by researchers from the University of Oxford. The work was funded by Muscular Dystrophy Ireland and the Muscular Dystrophy Campaign. The paper was published in the peer-reviewed medical journal Nature Biotechnology .

The newspapers have covered the study well. However, some headlines and images may give the false impression that it was in humans or that it will change the way that Alzheimer’s disease is currently treated. This is not the case. This is early research and it has yet to be established how the findings can be applied to treating Alzheimer’s in humans.

What kind of research was this?

A lot of medical research is targeted at finding new ways to deliver drugs into cells. In this laboratory study, scientists explored whether they could use a naturally occurring process in the body which moves material into and out of cells.

This process involves exosomes, small vesicles (bubbles) that are produced inside cells and then released, transporting proteins and nuclear material such as RNA to other cells or to the cell exterior. The researchers wanted to see whether they could use exosomes to transport specific genetic material across the blood-brain barrier in mice. The blood-brain barrier is a vital defence mechanism that stops contaminants in the blood stream infecting the brain, but it also makes it difficult to deliver drugs to the brain. If exosomes could be used in this way, the researchers thought the same mechanisms could be used to target genes in specific sites of the brain.

What did the research involve?

Using immature cells from the bone marrow in mice, researchers produced some exosomes that would not trigger an immune response. They then fused a molecule to some of the proteins in the exosome membrane. The molecules fused to the exosomes had specific binding capability, meaning they would only be able to attach to certain cells in the body. In this case, the researchers added a particular molecule that binds to cells in the central nervous system and another that is specific for muscle cells. The researchers’ theory was that this binding capability could enable the exosomes to be used as vehicles to transport cargoes, such as drugs, to these particular cells. To test whether they could deliver substances to target the different tissues, they loaded the exosomes with genetic material called short interfering RNA or (si)RNA, which can interfere with or stop the expression of a particular target gene.

The researchers then tested whether the loaded exosomes could deliver their cargoes to muscle and brain cells from mice grown in the laboratory. They then tested whether they could use the exosomes to deliver the genetic material to a specific gene that is linked with Alzheimer’s disease. These cell cultures were also tested to determine whether the modified exosomes caused an immune response.

It was important to determine whether these processes could work in live animals. To establish this, the researchers modified some exosomes with the appropriate receptor molecules and siRNA that would attach to a specific gene, GAPDH, which is active in all cells in the body. The modified exosomes were injected into live mice in a glucose solution. Further experiments then tested whether the exosomes had found their specific targets and whether the siRNA they were carrying had affected the way that GAPDH is expressed.

The researchers also used this technique to target the BACE1 gene in living organisms. This gene makes a protein that has been linked to Alzheimer’s disease. Inhibiting the way this gene works is a potential therapeutic approach to the disease.

What were the basic results?

The modified exosomes were able to deliver (si)RNA into mouse muscle and brain cells as effectively as other methods. The study demonstrated that the exosomes could bind to the brain cells and deliver siRNAs that are specific to a particular gene known to be faulty in people with Alzheimer’s disease. The cell culture showed that there appeared to be no immune response to these modified cells.

In live animals, the brain-specific exosomes significantly reduced the expression of the GAPDH in particular brain regions. Exosomes that targeted the BACE1 gene in the brain were also effective, and mice injected with them showed reduced levels of the BACE1 protein that has been linked to Alzheimer’s disease. There was no apparent immune response to these exosomes in the mice.

How did the researchers interpret the results?

The researchers say that finding ways to deliver gene therapies directly into the brain is a challenge. Targeted exosomes to which genetic cargoes can be loaded are potentially a valuable way of administering gene therapy in a way that evades the body’s immune responses. They say their study demonstrates the therapeutic potential of this approach for a gene that has been linked with Alzheimer’s disease.


This is a well-conducted laboratory study which found that exosomes carrying genetic material that can switch off the expression of particular genes can be directed to specific cells in the muscles and brains of mice.

This is a significant finding that has many potential applications. However, it is important to interpret the finding in context. The technology has not been tested in human cells and certainly not in humans with Alzheimer’s disease. There are also several technical and ethical issues associated with gene therapy in humans.

Regarding its potential for treating Alzheimer’s disease, there are several genes associated with the condition, and it is unclear how switching off the activity of one of them will benefit the course of the disease. In fact, the mice in this study did not have an Alzheimer’s-like disease and were actually healthy. Again, much more research will be needed.

The important finding from the study is that exosomes were able to delivery potential therapy to the gene in question.

Analysis by Bazian
Edited by NHS Choices