Forced Entry: The Clever Sneaks of Gene Therapy

Sneaking genes into cells without causing damage or harm requires cleverness and skill. The first story details work by Ames (Iowa) Laboratory researchers, who have developed a very clever porous silica nanosphere that can be taken up by a cell, and deliver its payload of genes or other molecules on command.

Currently, scientists have difficulty introducing chemicals or genes into cells without either damaging the cell or causing a chain-reaction of events that can’t be tracked.

“With current gene therapy, it’s possible to switch genes on and off, but you don’t really know if you are affecting other parts and processes of the cell as well,” Lin said. “You may be able to get a plant cell to produce a certain desired product, but the yield may drop significantly.”

By using externally controlled nanospheres, Lin explains that it may be possible to sequentially release genes, chemical markers and other materials within cells in order to track what happens and what specific changes take place. This phase of Lin’s research ties into a larger plant metabolomics project at Ames Laboratory.

Read the entire fascinating report here. This report fascinated me due to the exquisite level of control it promises, at the cellular level. This approach will bear watching.

The second report on gene smuggling comes from this Eurekalert newsrelease on research from the University of North Carolina, Chapel Hill, and the University of Pittsburgh. In this case, the reserchers are using a customized vector called adeno-associated virus (AAV) to introduce the dystrophin gene into muscles of boys suffering from Duschenne Muscular Dystrophy (DMD).

The trial was launched March 28, at Columbus Children's Hospital in Ohio, an affiliate of Ohio State University's School of Medicine. In the trial, six boys with DMD will receive replacement genes for an essential muscle protein.

Each of the boys will receive replacement genes via injection into a bicep of one arm and a placebo in the other arm. Neither the investigators nor the participants will know which muscle got the genes. After several weeks, an analysis of the injected muscle tissue's microscopic appearance, as well as extensive testing of the health and strength of the trial participants, will reveal whether gene therapy for DMD is likely to be safe and whether it's likely to result in persistent production of the essential protein in muscle cells.

Muscular dystrophies are genetic disorders characterized by progressive muscle wasting and weakness that begin with microscopic changes in the muscle. As muscles degenerate over time, the person's muscle strength declines.

Duchenne muscular dystrophy is a genetic disease that begins in early childhood, causes progressive loss of muscle strength and bulk, and usually leads to death in the 20s from respiratory or cardiac muscle failure. DMD occurs when a gene on the X chromosome fails to make the essential muscle protein dystrophin. One of nine types of muscular dystrophy, DMD primarily affects boys.

Currently, the best medical therapy can only slow the progressive muscle weakness of DMD.

The gene for dystrophin is one of the largest genes in the human body, and miniaturizing it, while retaining the crucial elements of its set of DNA instructions, has been among the greatest challenges to the gene therapy field.

The new Biostrophin therapy uses a novel combination of advanced technologies, including a miniaturized replacement dystrophin gene and nano delivery technology called biological nanoparticles. Developed from a virus known as adeno-associated virus (AAV), the nanoparticles are engineered specifically to target and carry the "minidystrophin" gene to muscle cells.

Read more at the source. This approach uses a virus-derived vector particle that should be safer than the virus itself as a vector. Expect to see more of this type of custom vectors, derived from a number of different viruses.

The final report on forced entry of therapeutic genes comes from this eurekalert newsrelease detailing research on Alzheimer's Disease from UT Southwestern Medical Center. The "vector" in this case was gold nano-particles.

By pressure-injecting the gene responsible for producing the specific protein – called amyloid-beta 42 – the researchers caused the mice to make antibodies and greatly reduce the protein's build-up in the brain. Accumulation of amyloid-beta 42 in humans is a hallmark of Alzheimer's disease.

"The whole point of the study is to determine whether the antibody is therapeutically effective as a means to inhibit the formation of amyloid-beta storage in the brain, and it is," said Dr. Roger Rosenberg, the study's senior author and director of the Alzheimer's Disease Center at UT Southwestern.

The gene injection avoids a serious side-effect that caused the cancellation of a previous multi-center human trial with amyloid-beta 42, researchers said. UT Southwestern did not participate in that trial. In that earlier study, people received injections of the protein itself and some developed dangerous brain inflammation.

The new study is available online and appears in an upcoming issue of the Journal of the Neurological Sciences.

Here is the full report. This report interested me due to the fact that it was the gene for the errant protein, rather than the protein itself, that elicited the antibodies against the protein. In this case, the gene was not injected into the cells, but rather elicited an immune response from the extracellular space--the gene was utilised as a vaccine.

There you have it. Three different methods of introducing genes and therapeutic molecules. The clever cat burglars and drug smugglers of molecular and cell biology. We can only urge them on.