June 03, 2004
Naked DNA Gene Therapy Technique Advance

Reports of advances in gene therapy research have not been coming anywhere near as fast as reports about stem cell research advances. However, some University of Wisconsin researchers have achieved exciting successes in delivering genes into laboratory animals.

One group, consisting of researchers from the Medical School, the Waisman Center and Mirus Bio Corporation, now reports a critical advance relating to one of the most fundamental and challenging problems of gene therapy: how to safely and effectively get therapeutic DNA inside cells.

The scientists have discovered a remarkably simple solution. They used a system that is virtually the same as administering an IV (intravenous injection) to inject genes and proteins into the limb veins of laboratory animals of varying sizes. The genetic material easily found its way to muscle cells, where it functioned as it should for an extended period of time.

“I think this is going to change everything relating to gene therapy for muscle problems and other disorders,” says Jon Wolff, a gene therapy expert who is a Medical School pediatrics and medical genetics professor based at the Waisman Center. “Our non-viral, vein method is a clinically viable procedure that lets us safely, effectively and repeatedly deliver DNA to muscle cells. We hope that the next step will be a clinical trial in humans."

Wolff conducted the research with colleagues at Mirus, a biotechnology company he created to investigate the gene delivery problem. He will be describing the work on June 3 at the annual meeting of the American Society of Gene Therapy in Minneapolis, and a report will appear in a coming issue of Molecular Therapy. The research has exciting near-term implications for muscle and blood vessel disorders in particular.

Love that bit about "near-term implications". This technique could be used to treat Duchenne’s muscular dystrophy and a number of other diseases.

Duchenne’s muscular dystrophy, for example, is a genetic disease characterized by a lack of muscle-maintaining protein called dystrophin. Inserting genes that produce dystrophin into muscle cells could override the defect, scientists theorize, ensuring that the muscles with the normal gene would not succumb to wasting. Similarly, the vein technique can be useful in treating peripheral arterial occlusive disease, often a complication of diabetes. The disorder results in damaged arteries and, frequently, the subsequent amputation of toes.

What’s more, Wolff says, with refinements the technique has the potential to be used for liver diseases such as hepatitis, cirrhosis and PKU (phenylketonuria).

In the experiments, the scientists did not use viruses to carry genes inside cells, a path many other groups have taken. Instead, they used “naked” DNA, an approach Wolff has pioneered. Naked DNA poses fewer immune issues because, unlike viruses, it does not contain a protein coat (hence the term “naked”), which means it cannot move freely from cell to cell and integrate into the chromosome. As a result, naked DNA does not cause antibody responses or genetic reactions that can render the procedure harmful.

Researchers rapidly injected “reporter genes” into a vein in laboratory animals. Under a microscope, these genes brightly indicate gene expression. A tourniquet high on the leg helped keep the injected solution from leaving the limb.

“Delivering genes through the vascular system lets us take advantage of the access blood vessels have — through the capillaries that sprout from them — to tissue cells,” Wolff says, adding that muscle tissue is rich with capillaries. Rapid injection forced the solution out of the veins into capillaries and then muscle tissue.

The injections yielded substantial, stable levels of gene activity throughout the leg muscles in healthy animals, with minimal side effects. “We detected gene expression in all leg muscle groups, and the DNA stayed in muscle cells indefinitely,” notes Wolff.

In addition, the scientists were able to perform multiple injections without damaging the veins. “The ability to do repeated injections has important implications for muscle diseases since to cure them, a high percentage of therapeutic cells must be introduced,” he says.

The researchers also found that they could use the technique to successfully administer therapeutically important genes and proteins. When they injected dystrophin into mice that lacked it, the protein remained in muscle cells for at least six months. Similar lasting power occurred with the injection of erythropoietin, which stimulates red blood cell production.

Furthermore, in an ancillary study, the researchers learned that the technique could be used effectively to introduce molecules that inhibit — rather than promote — gene expression, a powerful new procedure called RNA interference.

Given a way to reliably and safely deliver genes there are literally thousands of different diseases that potentially could be treated with gene therapy. The lack of good mechanisms for delivery of genes has been the major factor holding back the development of gene therapies. Whether this mechanism will turn out to be safe remains to be seen. For a gene therapy technique to work one has to have ways to avoid causing gene expression in the wrong kinds of cells other than the desired target type. One also has to avoid overexpression in the desired target cell type and achieve fairly even distribution to all cells of the target type. Plus, there is also a very real worry about risk of damage to genomes that could cause cancer. Whether this latest therapy technique will get tripped up by one or more of these problems remains to be seen.

Share |      Randall Parker, 2004 June 03 12:38 PM  Biotech Advance Rates


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