Nanomedicines for Systemic Delivery of RNAi Therapeutics - RNA Interference from Biology to Therapeutics - page 135

liposomes [ 80 ]. Composed of natural biomaterials, these nanoparticles offer a safe
platform for siRNAs delivery, avoiding cytokine induction and liver damage.
Enabling usage of fairly low siRNA doses (2.5 mg/kg), this system, in addition to
advantages such as high payload capacity (~4,000 siRNA molecules per particle)
and low off-target effects and toxicities, is economically worthy. This strategy was
also used with an LFA-1 antibody decorated particles for the delivery of CCR5-
siRNAs to human lymphocytes and monocytes. This system has been shown to
protect mice from HIV challenge [ 81 ]. LFA-1 I-tsNPs with CCR5-siRNAs did not
induce interferon response or TNF-a (inflammatory cytokine) secretion, hence
strengthens the potential for clinical relevance.

6.5 Future Perspectives

In summary, although there is no clinically approved siRNA delivery system yet, we
are convinced that in the coming years this situation will be changed. Approximately
22 different siRNA/shRNA therapeutics have reached clinical evaluation for the
treatment of at least 16 diseases [ 82 ]. The results from the ongoing ALN-PCS02
and ALN-TTR01 SNALP-based clinical studies will have a major impact on the
RNAi therapeutics era for the next few years. In addition, positive data from the
AtuPLEX-based Atu027 trial have the potential to amplify the SNALP-driven
approach as well as cyclodextrin-based approach that is currently under clinical
evaluation.
Similar to other RNA-based therapeutics, the efficacy of RNAi drugs relies on
maximising targeted delivery while minimising off-target toxicity and degradation.
We are convinced that the delivery efforts currently explored will be successful. We
base this assumption on one of the major advantages of siRNA delivery systems—
the fl exibility to change either the payloads entrapped inside the nanoparticles (by
using different sequences of siRNAs, or with combination to other drugs) or the
targeting agent (by replacing the antibody or the ligand decorating the nanoparti-
cle's surface). This opens new avenues for treating a wide variety of diseases as well
as adjusting the treatment to the unique molecular abnormalities of a specific
patient.

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