All in the delivery

Alnylam and MIT discover novel ‘core-shell’ nanoparticles for systemic delivery of RNAi therapeutics

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CAMBRIDGE, Mass.—One of the reasons RNAi therapeutics remain full of promise but still out of reach for clinical viability is the difficulty in delivering the therapies in the first place. However, in a bit of potential breakthrough progress, Alnylam Pharmaceuticals Inc. and its collaborators at the Massachusetts Institute of Technology (MIT) recently announced the publication of new paper describing the discovery of "core-shell" nanoparticles for systemic delivery of RNAi therapeutics.

Generated using what the two organizations call a "high-throughput polymer synthesis strategy" and screened for intracellular delivery applications, including siRNA delivery, the findings related to these nanoparticles saw publication in the Aug. 9 issue of Proceedings of the National Academy of Sciences, According to that article, the Alnylam/MIT-developed process allows for the development of novel nanoparticles that have optimal chemical and physical properties for effective intracellular delivery of RNAi therapeutics.

In conducting the study, Alnylam and MIT evaluated a library of more than 1,500 chemically diverse nanoparticles as drug delivery vehicles, exerting "precise control" over particle size, chemical composition and architecture. As Alnylam and MIT note, the physical and chemical properties of materials can have controlling effects on their utility as nanotherapeutics and the findings of the study suggest that certain chemical functionalities may be advantageous for polymer-based delivery. Reportedly, initial in-vivo studies on one of these novel nanoparticles showed silencing of hepatocyte-specific Factor VII in a preclinical model.

As the two parties note, "The ability to control and modify the chemical nature of the core and shell of the nanoparticle may afford utility of these materials in a wide range of drug delivery applications."

"Continued progress in delivery of RNAi therapeutics requires broad-based efforts around novel lipids, conjugates and polymers. In the current study, core-shell nanoparticles were discovered using combinatorial approaches to identify novel materials for siRNA delivery," said Dr. Kevin Fitzgerald, senior director of research at Alnylam, in the news release about the study. "These findings further expand our systemic delivery platform to achieve the broadest applications of RNAi therapeutics."

This particular work between Alnylam and MIT is, as Dr. Daniel G. Anderson of the David H. Koch Institute for Integrative Research at MIT tells ddn, "not really disease-focused, but rather nanoparticle design-focused and cellular barrier-focused."

Anderson, who is an associate professor of chemical engineering and health sciences and technology at MIT, says the relationship between MIT and Alnylam, which goes back several years, is a productive one, and he explains that this particular effort is in some sense a continuation of ongoing efforts between the two organizations to make progress in the area of RNAi delivery.

"But this effort focuses very specifically on making libraries of new nanoparticles and evaluating their performance to understand some of the structure/function relationships in terms of nanoparticle delivery," he says. "These materials were a discrete class of nano-level polymers that are very promising. We're taking a very broad look at how different chemistries and particles could affect cellular delivery of RNAi, and we continue to be very optimistic that RNAi therapeutics are going to have a really important impact on medicine. The fundamental challenge is delivery—we know the molecules work in animals and cells, but we want to get the broadest possible combination of target tissues."

Barry Greene, president and chief operating officer of Alnylam, echoes Anderson's positive view of the Alnylam-MIT working relationship over the years, and adds that Dr. Phillip A. Sharp, for example, an institute professor at MIT—the highest honor the institution can bestow on a professor—was one of the original scientific founders of Alnylam in 2002.

"MIT is one of the premier institutes in the world when it comes to technologies that are instrumental in biotechnology," Greene tells ddn. "It is the technology and ideas from people like Phil Sharp and his lab that form the basis of our company, along with people like Dr. Robert Langer [also an MIT institute professor], whom we got involved with early on in terms of delivery of sRNA molecules. When you think of the best place to study delivery of these kinds of therapies, you think of the Langer Lab and MIT. We're funding about 10 postdocs at MIT and have a tremendous relationship with them talking about how RNAi works and the various methods of delivery being invented at MIT."

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