NASTECH'S IN VIVO RNAI-BASED TREATMENT SHOWS PROMISE,
per Marketwatch headline.
The press release:
Nastech Presents Promising In Vivo Research Findings with RNAi-Based Therapeutics for Rheumatoid Arthritis
Tuesday April 5, 10:30 am ET
- Data Presented in Late-Breaking Session at ASBMB Meeting
BOTHELL, Wash., April 5 /PRNewswire-FirstCall/ -- Nastech Pharmaceutical Company Inc. (Nasdaq: NSTK - News) today announced the presentation of data demonstrating the successful preclinical, in vivo use of an RNA interference (RNAi)-based therapeutic drug directed against the expression of human tumor necrosis factor alpha (H-TNF-alpha), a protein that is over-expressed in rheumatoid arthritis and plays an important role in disease pathology. The research involved screening 56 candidate small interfering RNA (siRNA) sequences in human cells that secrete H-TNF-alpha and identifying potent siRNAs that, when formulated with Nastech's proprietary delivery excipients, can reduce TNF-alpha production by up to 85 percent with IC50 values of less than 10 pM. The results were highlighted in a late-breaking poster presentation at the 2005 American Society for Biochemistry and Molecular Biology Annual Meeting in San Diego, California.
"We are pleased to present this first-ever data on our RNAi research program. The successful in vivo use of a proprietary peptide-based delivery system to suppress arthritis in mice demonstrates our progress in addressing the delivery barriers that have made it prohibitive to apply RNAi as a therapeutic product," said Steven C. Quay, M.D., Ph.D., Chairman, President and CEO of Nastech. "We believe this research marks the first demonstration of successful systemic delivery in a clinically relevant setting of an RNAi- based therapeutic in rheumatoid arthritis, and we anticipate that this approach may provide improved therapeutic potential compared to existing therapies. Some people have compared the potential of RNAi-based therapeutics to the two foundational technologies of biotechnology, gene cloning and monoclonal antibodies, and I am pleased that Nastech can take a leadership role in this important new technology."
The most potent of the 56 siRNA sequences was combined with Nastech's proprietary delivery peptides to form the therapeutic drug. The peptide-siRNA formulations efficiently knock down TNF-alpha mRNA and protein levels in activated human monocytes in vitro. One candidate siRNA/delivery peptide formulation was evaluated in two transgenic mouse models of rheumatoid arthritis (RA) constitutively expressing human TNF-alpha. Animals treated twice weekly beginning at age 6 weeks with either 2 mg/kg siRNA by IV injection or infliximab showed RA score stabilization (paw and joint inflammation) beginning at age 7 weeks, compared to controls that persisted through week 10. At age 9 weeks, siRNA-treated animals showed comparable reductions in RA scores but significantly lower plasma TNF-alpha protein levels than infliximab-treated animals.
"In the case of rheumatoid arthritis, an RNAi therapeutic would represent a new mechanism of action compared with the existing therapies," noted Dr. Philip J. Mease, M.D., Chief, Rheumatology Clinical Research, Swedish Medical Center and Clinical Professor, University of Washington School of Medicine, Seattle, WA. "I believe this research marks the first demonstration of the successful systemic delivery of an RNAi-based therapeutic in rheumatoid arthritis. RNAi decreases production of the disease-causing H-TNF-alpha, rather than binding the existing H-TNF-alpha or its receptor. Therefore, an RNAi-based therapeutic that actually stops production of H-TNF-alpha may offer similar or potentially superior clinical benefit compared to the current therapies."
In Nastech's studies, conventional infliximab therapy actually increased the levels of detectable H-TNF-alpha in the treated animals by stabilizing it against degradation. The three currently approved RA biologic therapies all bind to and stabilize H-TNF-alpha, and this mechanism may reduce efficacy.
ABOUT RNA INTERFERENCE
RNA interference, or RNAi, is a cellular pathway in which double-stranded RNA molecules can silence a specific gene by degrading its mRNA, which results in a reduction of the amount of the protein the gene produces. RNAi can be used as a research tool to analyze and determine the effectiveness of tight junction proteins affecting drug delivery and as a therapeutic strategy to decrease levels of specific proteins associated with disease. Nastech's RNAi research and development program seeks to enhance the systemic delivery of this potential new class of therapeutics.
ABOUT RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic disease mainly characterized by inflammation of the lining, or synovium, of the joints. RA affects 1 percent of the U.S. population, or 2.1 million Americans. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. Further, RA is a systemic disease, which means it can affect other organs in the body. The disease progresses in three stages: first, the synovial lining swells, causing pain, warmth, stiffness, redness and swelling around the joint; second, the rapid division and growth of cells, or pannus, causes the synovium to thicken; and lastly, the inflamed cells release enzymes that may digest bone and cartilage, often causing the involved joint to lose its shape and alignment and causing more pain and loss of movement.
Currently, the cause of RA is unknown. According to independent sources, drugs regulating TNF-alpha, such as Centocor and Schering-Plough's Remicade®, Amgen/Wyeth's Enbrel®, and Abbott's Humira® are already a multibillion-dollar market. RNAi-based therapeutics could lead to the development of rivals to these products as it affects TNF-alpha through a different pathway, suggesting potential for more efficient treatments. |
