Successful Systemic siRNA delivery via Nanoparticles in Humans

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Arrowhead Research Subsidiary, Calando Pharmaceuticals, have provided the first proof of RNA Interference in Humans with a systemically administered siRNA Therapeutic. The clinical trial results were published in Nature

We believe we are nearing the time when siRNA therapeutics can begin to make a historic leap from science to applied medicine, where it can truly make a difference as viable treatments for patients with a variety of prevalent unmet medical needs.

Landmark Caltech-led study shows systemic siRNA delivery, mRNA knockdown, protein knockdown and mRNA cleavage products indicative of RNAi.

This represents a breakthrough for Calando, its proprietary RONDEL™ delivery system, and the field of RNAi. It is thought to be the first ever demonstration in humans of targeted siRNA-containing nanoparticle delivery to tumors using systemic administration, delivery of functional siRNAs, and achievement of specific mRNA and protein reductions via RNAi. Thus far in the trial, no significant drug-related toxicities, known as serious adverse events (SAEs), have been observed that may limit use. Data based on Calando’s study were published in the prestigious journal, Nature, on March 21, 2010 in an advance online edition. The Nature article is titled, “Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.”

RONDEL is a proprietary three part RNAi/Oligonucleotide Nanoparticle Delivery (RONDEL) technology, the foundation of which is their cyclodextrin-containing polymer.


Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. 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

8 pages of supplemental inforamation

RONDEL Delivery

CALAA-01 and the RONDEL™ delivery system widened their lead in the siRNA delivery field with the newly published data, which include:

• Detection of RONDEL siRNA nanoparticles inside cells biopsied from tumors, demonstrating that RONDEL is capable of shuttling siRNA into tumors after being infused into the bloodstream of patients;

• Presence of RONDEL inside tumors in a dose-dependent manner, meaning that the higher a dose administered to a patient, the higher number of nanoparticles reach the intended target;

• Specific reduction in target mRNA (often referred to as “mRNA knockdown”) encoding for the M2 subunit of ribonuceotide reductase (RRM2), a widely-recognized cancer target that CALAA-01 is engineered to decrease;

• Specific reduction in target RRM2 protein levels (often referred to as “protein knockdown”);

• Indication that the mRNA and protein knockdown are mediated by delivered siRNAs and the RNAi mechanism as evidenced by accepted 5’-RACE analysis, proving that RONDEL is capable of enabling RNAi in humans.

Calando Pharma explains how RONDEL works

The benefits of RONDEL

* More Effective Delivery
* Modularity
* Fewer Immune Reactions
* Increased Stability
* Designed to Work With Human Physiology and Cell Biology

Calando’s RONDEL siRNA delivery platform is designed to self-assemble with any siRNA therapeutic and to easily incorporate many different targeting molecules, making the platform potentially applicable to many disease indications beyond cancer. Importantly, the sugar-based system has not shown the immune system activation caused by other lipid-based siRNA delivery systems in pre-clinical and clinical development.

Technology Review Coverage
A specialized nanoparticle filled with an RNA-based cancer therapy can successfully target human cancer cells and silence the target gene, according to results from an early clinical trial.

Since the discovery 12 years ago that double-stranded RNA can silence genes in a targeted manner, researchers have hailed the technique, known as RNA interference (RNAi), as a powerful approach to creating new and potent medicines. Indeed, the mechanism garnered its discoverers, Stanford University’s Andrew Fire and Craig Mello of the University of Massachusetts Medical School, the 2006 Nobel Prize in medicine. The trouble is, getting the therapeutic RNA to the right cells has proven to be a sticky challenge. When injected on their own, so-called small interfering RNAs (siRNAs) are quickly filtered out by the kidneys, and researchers have struggled to design particles that carry their contents to target cells with enough specificity, or that don’t cause toxicity or elicit an immune reaction from the body.


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