Gene Therapy Applications Of RNA Interference

Article ID: 520905

Released: 2-Jun-2006 8:00 AM EDT

Source Newsroom: American Society of Gene & Cell Therapy (ASGCT)

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Newswise — A study demonstrating one of the first therapeutic applications to exploit microRNA, for the treatment of diseases such as hemophilia will be presented on Saturday, June 3 at the 9th Annual Meeting of the American Society of Gene Therapy (ASGT) in Baltimore.

Gene therapy has been successful for certain immunodeficiencies, but for the treatment of diseases where the patients have a functioning immune system, such as hemophilia, it has been more difficult. The immune system has often prohibited the gene from working because it sees it as an invader and fights it off.

A team of scientists led by Luigi Naldini, MD, PhD, and Brian D. Brown, PhD, at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in Milan have developed a way to prevent the immune system from disturbing the efforts of gene therapists.

To accomplish this, they utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Over the past 5 years, research has revealed that microRNAs have a role in almost every cellular process, including those involved in the development of cancer.

MicroRNAs downregulate the expression of specific genes in cells where the gene is not needed, and thereby have an important influence over the identity of a cell.

The HSR-TIGET group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and spectacularly, the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used.

"The discovery of microRNAs has changed our understanding of biology," Dr. Brown noted. "Almost every week a new study comes our implicating them in some cellular process or pathology. Now we can take advantage of this information for creating therapies."

Dr. Naldini's group is now beginning to exploit microRNAs further for developing gene therapies to treat diseases, including hemophilia, and even cancer.

RNAi has enormous therapeutic potential for HBV in miceA study investigating the effects of long-term high-level expression of short hairpin RNAs (shRNAs) in the livers of adult mice to target hepatitis B virus (HBV), and other numerous genes, was presented today at the 9th Annual Meeting of the American Society of Gene Therapy (ASGT) in Baltimore.

Dirk Grimm, PhD, and Mark A. Kay, MD, PhD, from Stanford University Medical School and colleagues developed a genetically optimized shRNA delivery vehicle based on a non-disease causing monkey virus (Adeno-associated virus type 8) to efficiently induce RNAi in the livers of the mice.

When infused, the vehicle infected the entire liver and resulted in high-level shRNA expression in each liver cell.

The team discovered a limit of shRNA molecules which is tolerated by individual cells, and that exceeding this limit often results in toxicity and cell death. Cell death frequently occurred in 50% of all shRNAs, severe enough to cause massive liver injury and death of the animal. In many other cases, the mice fully recovered, but completely lost the RNAi effect.

This research strongly implies that for future clinical RNAi use in humans, control over intra-cellular shRNAs expression levels will be mandatory to bypass the inherent risks of this promising new technology. Persistent and efficient silencing of HBV in transgenic mice, achieved by Kay's team using one of their shRNAs at a low dose, demonstrates that RNAi has, in fact, an enormous therapeutic potential.

siRNAs may be useful for reducing RSV infectionA study reporting that small inferring RNAs (siRNAs) may be useful for inhibiting Respiratory Syncytial Virus (RSV) infection of respiratory tissue by targeting the destruction of viral messenger RNAs (mRNAs) will be presented on Saturday, June 3 at the 9th Annual Meeting of the American Society of Gene Therapy (ASGT) in Baltimore.

Respiratory Syncytial Virus is a leading cause of infant hospitalizations worldwide. Currently there is no vaccine for RSV and treatment of acute infections is limited to supportive measures. Recent reports also state that RSV is an important disease in elderly and immunocompromised populations.

Anthony J. Fischer, BS, from the University of Iowa and colleagues evaluated siRNA-based approaches to slow down viral replication in vitro and in vivo.

The group evaluated a series of siRNAs to target a strain of RSV. They observed a dose-dependant reduction in viral gene expression following the administration of siRNAs into a cell culture.

This shows that siRNAs may be useful for reducing RSV infection of respiratory tissue by destroying viral mRNAs.

Study shows useful method in treating neurodegenerative diseasesA study demonstrating a method of protein delivery to the brain may prove useful in treating many neurodegenerative diseases, including Alzheimer's, Parkinson's or Huntington's diseases, was presented today at the 9th Annual Meeting of the American Society of Gene Therapy (ASGT) in Baltimore.

Treatment of many neuronal degenerative diseases is not possible due to the blood-brain barrier that prevents passage of most proteins and molecules in the blood from reaching the highly fragile and protected environment of the neurons of the brain.

Proteins that are required by the brain have specific receptors on the blood-brain barrier that allow their transport to the neurons from the blood.

Brian J. Spencer, PhD, and Inder M. Verma, PhD, at The Salk Institute for Biological Studies in California hypothesized that by piggy backing on these receptors, they could deliver a therapeutic protein to the brain to treat a neuronal degenerative disorder.

The system was tested in a mouse model of Sly disease, a lysosomal storage disease that leads to progressive neuronal degeneration and eventually an early death.

Researchers found significant quantities of the fusion protein in the brains of these mice. Improvements in coordination and balance as well as learning and memory in these mice were also observed.

This study suggests that this fusion protein was able to prevent the death of neurons in the mice affected with Sly disease, and that this may be a useful method of protein delivery in the brain for other neurodegenerative diseases.

The American Society of Gene Therapy is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of gene and related cell and nucleic acid therapies and the promotion of professional and public education in the field. For more information, visit


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