February 24, 2003
Ultrasound Microbubble Gene Therapy

The use of ultrasound microbubble gene therapy to successfully deliver genes into muscles in mice raises hopes of use of this technique to treat muscular dystrophy.

Scientists at the Hammersmith Hospitals NHS Trust, Imperial College London and the Medical Research Council have pioneered a new way of delivering gene therapy, using an innovative combination of ultrasound and microbubbles. Research published today (20th February 2003) in Gene Therapy1 shows how this new delivery technique not only improves the efficiency of modifying genes, but may offer safety advantages over other methods.

Gene therapy has the potential to treat or cure many diseases where there is an underlying genetic cause, but its progress has been severely hampered by concerns over the way in which genes are delivered. There are a number of safety and other issues surrounding the use of viruses and existing non-viral techniques have proved to be less effective.

Dr Martin Blomley (Senior Lecturer in Radiology) and Dr Qi-Long Lu (Senior Research Scientist), together with Dr Haidong Liang (Research Associate) and Professor Terry Partridge at the Hammersmith Hospitals NHS Trust, Imperial College London, and the Medical Research Council Clinical Sciences Centre, have been developing this new gene delivery technique. They have been studying skeletal muscle in mice, which gives insight into how we might use gene therapy to treat muscular dystrophy in children.

Microbubbles are already in use around the world to improve patient ultrasound scans in the heart, liver and many other areas and are known to be both safe and effective. They are tiny gas bubbles measuring about 3 microns, and are usually injected intravenously to boost ultrasound signals. There is evidence that when ultrasound is applied to microbubbles the microbubbles are disrupted (or "pop") and this can cause small perforations in the target cells, which allows the DNA to enter. This could allow for a "point and shoot" approach, as ultrasound can be pointed at a particular target area.

The Hammersmith Hospital, together with Imperial College, is a leading international centre for the use of the use of microbubbles in imaging and is also at the forefront of research into gene therapy.

The researchers mixed a commercial microbubble, already used by doctors for scanning patients, with DNA that coded for a "reporter gene" and injected it into the skeletal muscle of mice of different ages. The trial showed that the microbubbles and ultrasound helped in delivering DNA, and the efficiency of gene therapy was improved by about ten times. They also observed that even when the microbubbles were used without ultrasound, an improvement in efficiency could be seen, especially in younger mice. In younger mice, no additional improvement in efficiency was conferred by using ultrasound. In addition, in experiments where microbubbles were used, the amount of inflammation and damage associated with the injection was reduced.

Overall results from the trial, which was supported by the Medical Research Council, showed:

  • Microbubble ultrasound improved the delivery of DNA to the muscle
  • The microbubbles have some effect intrinsically and may reduce local inflammation

As non-viral methods are not usually very efficient, viruses have been used in many gene therapy applications. Although efficient at actually delivering genes into target cells, there are problems associated with their use including infection of non-target tissues and dangerous immune responses.

Dr Martin Blomley, Consultant Radiologist at the Hammersmith Hospitals NHS Trust and Senior Lecturer in the Imaging Sciences Department of Imperial College London, commented:

"What we’ve found here seems a promising lead into a new, safe and effective way of delivering genes into target cells – in this case muscle tissue. The combination of microbubbles and ultrasound may offer a targeted approach to gene therapy. In addition, the microbubbles alone have some effect, and we are exploring why this is in further work.

Gene therapy holds great promise in future for curing and ultimately preventing serious diseases but is still in its infancy as a clinical tool. This promising study suggests that there may be a less invasive and more efficient, safe and accurate technique for targeting tissue, than those currently in use.

Now we’ve found a good delivery system, we need to build on the research to improve the technique and assess the possible impact it could have on diseases such as muscular dystrophy."

This technique is much more effective.

The technique proved to be 10 times more effective than more conventional methods.

While some of the news reports on this story are phrased in a way that suggests this is a brand new breakthru cardiovascular ultrasound microbubble gene therapy was reported in 2000.

Progress in cardiovascular gene therapy has been hampered by concerns over the safety and practicality of viral vectors and the inefficiency of current nonviral transfection techniques. We have previously reported that ultrasound exposure (USE) enhances transgene expression in vascular cells by up to 10-fold after naked DNA transfection, and enhances lipofection by up to three-fold. We report here that performing USE in the presence of microbubble echocontrast agents enhances acoustic cavitation and is associated with approximately 300-fold increments in transgene expression after naked DNA transfections.

The latest report used muscle as a target and so it is valuable for its demonstration of the potential value of the technique for muscle targets. One downside of this approach is that it is likely to deliver genes into other tissue that is near the muscles. For instance, blood vessel cells would likely receive some of the genes. Delivery of a muscle gene into blood vessels or nerves or other tissue could cause problems if that gene started being expressed in one of those cell types. Therefore its not clear that this technique will turn out to be work well in practice. Whether it does turn out to be useful might depend on the gene being delivered and the type of tissue it is being delivered to. In some cases the gene's regulatory region may prevent it from being activated in tissue that is not the desired target tissue type.

The exact mechanism of action of microbubble gene therapy is not understood.

A new trend in bubble medicine is to use the same kind of microbubbles for therapy, in which the bubbles can act as vectors for directed drug delivery and gene transfection into living cells. The permeability of cell walls for large molecules (both drugs and genes) is dramatically increased in the presence of ultrasound and microbubbles.15 The nature of the mechanism behind this phenomenon is not yet understood. Jet formation, induced by collapsing bubbles, is one of the candidates for enhancing cell-wall permeation: Electron micrographs of insonated leukemia cells show conspicuous holes in their walls.16 Jet cavitation damage and cell-wall permeation could thus be two manifestations of the same process. However, other high-energy processes besides jets are associated with the bubble collapse and could be important: Shear and pressure forces, sound waves, and shock waves also provide significant mechanical interactions between bubble and cell.

Share |      Randall Parker, 2003 February 24 01:49 PM  Biotech Therapies

Dr. Aftab Ahmed Shaikh said at June 5, 2004 4:16 AM:

It is encouraging to read this article, showing ray of hope to millions of the patients and to the families of the patients suffering in muscular dystrphoies.
My youngest son is suffering in Duchenne's MD. I have been looking and searhing for any promising treatment ,gene therapy seems be the ultimate remedy. I hope and wish that soon these efforts of scientists will be fruitful and lives of millions will be saved. ?Just curious to know how long woould it take when it may be tried on human. I recently read that first human Gene therapy trial is in the way at Imperial Hospital-London under the supervision of Prof. Francesco, pleae update me, if possible.

My all best wishes and prayers with you all for your success.

Dr. Aftab Ahmed Shaikh
Consultant Nuclear Physician
Nuclear Medicne Department
King Fahad Hospital, Madina Munnawwarah,
Kingdom of Saudi Arabia.

courtney wirkus said at February 2, 2005 12:15 PM:

Hey I think the gene therapy aspect is very interesting but is there any more information about what kind of ultrasound is being used. I am an ultrasound student and I was wondering if this related to diagnostic ultrasound at all. Like what kind of transducers are being used etc.

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