RNA interference technology has been offering great promise over the recent years as a potential boon for treatment of all kinds of diseases. The ability to selectively shutdown the expression of a specific gene means that even genetic disorders could be treated in the future. The promise of Small interfering RNAs (siRNA), and to a lesser degree microRNAs (miRNA), has not so far quite matched the expectations of companies that have invested hundreds of millions of dollars in the research. Chemical & Engineering News magazine has just published an overview of the challenges and progress of this technology while profiling the work of some of the big players in the industry.
In the early days, scientists naively thought they could just send naked siRNA strands into patients and knock down a target gene. Except for topical or direct delivery to places like the lung, eye, and the central nervous system, that facile approach hasn’t panned out. Researchers have had to come up with more involved delivery approaches instead.
“Just as all roads lead to Rome, all roads lead to cellular delivery,” says Steven F. Dowdy, Howard Hughes Medical Institute investigator and professor of cellular and molecular medicine at the University of California, San Diego, Medical Center. “Today, everybody in the field recognizes that delivery is the problem to solve, and all other problems, of which there will be numerous ones, pale in comparison.”
Scientists trying to deliver siRNA need to engineer around several troublesome properties. RNA has a molecular weight that is 10 to 20 times that of a traditional small-molecule drug. And because the molecule is highly negatively charged, it typically can’t cross the similarly negatively charged plasma membranes to enter the cell. It’s no wonder naked strands of siRNA didn’t make it as a therapeutic approach.
Delivery systems for siRNA must overcome three major obstacles: getting the drug to its target in the body, coaxing it inside the cell, and releasing it. Even after all that is accomplished, companies then need to worry about safety, a major concern given the power of siRNA to turn off cellular processes.