During the past 10 years researchers have puzzled over how best to deliver small interfering RNA (siRNA) molecules, whose therapeutic value lies in their ability to shut down genes in higher organisms and in pathogens that may cause sexually transmitted infections (STIs).
Lipid-based formulations, the most widely used siRNA delivery vehicles, suffer from certain limitations. In particular, they are unable to provide sustained release of siRNAs that may be required for many applications, and they may be toxic to target tissues.
Now, as reported in Nature Materials in May, Yale scientists have found a safe and effective way of administering siRNA molecules. “We wanted to develop a new strategy of delivering siRNAs with an FDA-approved material,” said lead author Kim Woodrow, Ph.D., a postdoctoral fellow working with W. Mark Saltzman, Ph.D., the Goizueta Foundation Professor of Biomedical Engineering and Chemical Engineering.
For this proof-of-principle work, the researchers designed siRNAs to target a gene expressed widely in the lining of the female mouse reproductive tract. Saltzman and Woodrow used densely loaded nanoparticles made of PLGA, an FDA-approved biodegradable polymer, to create a stable time-release vehicle for delivering siRNAs to mucosal tissue.
To convert an FDA-approved material into an siRNA delivery system, the particles needed to be small enough to penetrate tissue barriers and be taken up by cells. These nano sized particles also required stable incorporation of large quantities of siRNA. Saltzman and Woodrow demonstrated that their siRNA nanoparticles were distributed and retained throughout the female reproductive tissue. They also showed that delivery of siRNA by PLGA nanoparticles resulted in sustained gene silencing in the tissue for up to 14 days.
“Before human clinical testing can begin, our next step in research will be to test this approach directly in disease models—for example in the HIV-model mice that have an immune system genetically identical to that of humans,” said senior author Saltzman.
This approach may lead to antimicrobial treatments that patients can apply themselves. “It is safe and effective, and much easier than getting an injection of vaccine,” Woodrow said.