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RNA Interference
OPKO's RNA interference technology is one of the most exciting areas in biomedical research and drug development today. Cited as the Science 2002 "technology of the year," RNAi uses double stranded RNA to "silence" genes with great potency and specificity, stopping production of disease-causing proteins.
RNAi is of potential clinical interest in situations where an over-abundant protein is thought to be the cause of a disease. In such cases, molecules called small interfering RNA (siRNA) may be useful as a direct means to treat the disease by eliminating the production of the pathogenic protein.
RNAi gene silencing may be achieved through the use of siRNAs in order to effectively silence mammalian genes, and the RNAi mechanism of action is illustrated below:
RNAi is a naturally occurring intracellular process, whereby a molecule of siRNA joins with a complex known as RISC, already present in the cell. This active complex is guided to the complementary sequence of the target mRNA. The target mRNA is cleaved by the RISC and subsequently degraded or rendered incapable of translation (the cellular process that builds proteins from mRNA). Each siRNA molecule can inactivate hundreds to thousands of mRNAs. Therefore, siRNA therapeutics have the potential to be more potent than alternative therapies which rely on binding alone.
Synthetic siRNAs can be designed, manufactured and delivered to cells in order to shut down the production of unwanted disease-causing proteins. In order to be used as a drug, the siRNA molecules must be delivered to the relevant cells, must sustain their activity for a sufficient period of time, and must not cause unwanted side effects, among other criteria. OPKO's compound, bevasiranib or Cand5, satisfies these criteria, and is currently in clinical trials.
Bevasiranib or Cand5
Our most advanced therapeutic compound, known as bevasiranib, is expected to enter Phase III clinical trials in the third quarter of fiscal 2007. Bevasiranib will be marketed as a treatment for Wet Age-related Macular Degeneration (referred to as “Wet AMD”). Bevasiranib is an siRNA that works to silence the genes that promote the overgrowth of blood vessels that lead to vision loss in Wet AMD. Bevasiranib is a synthetic double-stranded RNA (dsRNA) oligonucleotide that selectively inhibits the production of all isoforms of VEGF by efficiently and effectively halting the production of VEGF on the mRNA level. VEGF is a protein that has been shown to be the central stimulus in the development of ocular neovascularization. Bevasiranib is administered locally to the eye via an intravitreal injection.
To find out more about bevasiranib please click here
Several OPKO RNAi Targets
- Vascular Endothelial Growth Factor (VEGF)
- Hypoxia Inducible Factor-1 alpha (Hif1-alpha)
- Intracellular Adhesion Molecule-1 (Icam-1)
- Angiopoietin-2 (Ang-2)
Several diseases that OPKO RNAi therapy may be useful in treating:
- Acute Myocardial Infarction
- Cancer
- Diabetic Retinopathy
- Inflammatory Bowel Disease
- Psoriasis
- Rheumatoid arthritis,
- Wet and Dry Age-related Macular Degneration
Autophagy
Proteins must fold into their correct three-dimensional conformation to achieve their biological function. Protein aggregation and misfolding are contributors to many human diseases, such as autosomal dominant retinitis pigmentosa, Alzheimer’s disease, and cystic fibrosis. The loss of vision associated with Dry AMD is thought to be caused by the destructive effects of the misfolded protein and debris aggregates likes lipofuscin. Autophagy is a cellular process by which cellular protein aggregates and dysfunctional organelles like mitochondria are degraded.
OPKO is currently identifying compounds and methods for increasing autophagy in order to, enhance the elimination of misfolded proteins, and eliminate the destructive effects associated with their accumulation. These compounds may mitigate retinal degeneration, particularly retinal and macular degeneration.
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| OPKO currently enrolling Phase 3 trial with Bevasiranib in wet AMD. |
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