ASGT Press Release 

Gene therapy applications of RNA interference,
presented at the ASGT 9th Annual Meeting

Researchers exploit microRNAs to treat hemophilia

BALTIMORE -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 mice

A 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 9 th 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 infection

A 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.

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 www.asgt.org.

# # #