Systemically Administered siRNA via Targeted Nanoparticles: Initial Phase I Clinical Trial Results

The delivery of siRNA holds promise for targeted gene silencing in the development of potent gene-specific therapeutics against cancer and other diseases. Injection of naked siRNA alone results in poor accumulation within target tissues and can illicit an immune response, so far limiting the utility of siRNA as a systemic therapy.
Mark Davis and colleagues from Caltech have developed a targeted nanoparticle delivery system to shlep siRNA to melanoma patients. The particles contain a cyclodextrin based polymer with polyethylene glycol on the surface of the particle. A transferrin ligand on the surface of the particle is used to target the surface of cancer cells. The authors show dose dependent accumulation of the particles in the tumor and reduction of the mRNA targeted by the siRNA sequence. Results are described for three patients. The clinical effects of the therapy are not yet reported.
From the abstract:

We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

Link to article in Nature: Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Image from Mark Davis lab website…