Small interfering RNA (siRNA) therapies are a type of RNA-interfering drugs (RNAi) that have shown to be effective at silencing
genes in preclinical and clinical studies. Unlike biologically based gene therapy treatments, synthetic siRNA therapeutics
can be manufactured under completely controlled conditions. They are considered to be large small-molecule therapies and,
therefore, follow the established regulatory pathway for those types of drugs. As clinical trials for siRNA therapies continue
to advance toward approvals for this class of drugs, Pharmaceutical Technology asked leading companies about their work in this emerging field.
Representatives from Alnylam Pharmaceuticals (Cambridge, MA), MDRNA (Bothell, WA), and Quark Pharmaceuticals (Fremont, CA)
discuss their approaches and techniques for developing and delivering siRNA therapeutics, specifically, liposomal and naked
siRNA delivery. Participants in the forum are Mark Tracy, PhD, senior director of pharmaceutical operations at Alnylam Pharmaceuticals;
Michael Houston, vice-president of chemistry and formulations at MDRNA; and James Thompson, vice-president of pharmaceutical
development at Quark Pharmaceuticals.
What novel approaches is your company taking to deliver siRNA therapies?
Dosage forms for systemic delivery of siRNA must meet several important criteria. In particular, they must maintain drug
stability, enable transport of the siRNA through the body to the desired organ and cell type(s) within that organ, and, then,
allow transport of the siRNA to the cytoplasm within the desired target cells.
Novel lipid nanoparticle (LNP) formulations containing specially designed lipids are one of the few siRNA delivery systems
to date that have demonstrated highly potent silencing in vivo of multiple targets in multiple species, including non-human primates. These formulations are able to overcome the delivery
challenges described above.
LNP formulations can be designed to achieve silencing of target genes in a variety of cell types in the liver, tumors, and
immune cells, among other cell types and tissues. LNP formulations that have advanced to the clinic to date are specifically
designed for delivery to cell types in the liver, including hepatocytes and tumor cells.
MDRNA is developing liposome formulations based on its DiLA2 (di-alkylated amino acid) platform. This platform allows MDRNA to create a library of DiLA2 molecules, and subsequent formulations for delivery of siRNA, where key characteristics such as charge, fusogenicity, and
pH responsiveness can be tailored to meet the delivery requirements associated with specific therapeutic indications. MDRNA
has formulations for systemic and local delivery.
Formulations currently in development do not use active targeting moieties, but this is a focused area of our research. The
DiLA2 platform readily enables the incorporation of peptide, protein, and other classes of targeting ligands. MDRNA has developed
a proprietary phage display library based on the [self-folding mini proteins called a Trp cage peptide] as a source of novel,
highly specific targeting agents.
We have not devoted our initial efforts toward liposomal delivery. Quark's strategy has been, with synthetic siRNAs, to evaluate
what cell types take up the siRNAs and where they distribute after various routes of administration. For example, when you
administer our type of siRNAs intravenously, they are rapidly cleared by the kidneys and distribute almost exclusively to
the kidney. Because of this, we are focusing one program on kidney indications. We're basically going where the siRNAs go.
Formulations allow you to change the distribution and to lower the dose of the siRNA to gain more efficient delivery with
certain delivery vehicles. There's always a tradeoff, however, when developing formulations in terms of the cost:benefit ratio.