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Calando Demos Safe siRNA Delivery in Primates

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Researchers from Calando Pharmaceuticals published data demonstrating that the company’s lead siRNA drug candidate, CALAA-01, can be systemically administered to non-human primates with no adverse effects using a proprietary nanoparticle delivery technology.

Publication of the data, which appeared online in the early edition of the Proceedings of the National Academy of Sciences, comes about five months after Calando first presented some of the findings at last year’s Oligonucleotide Therapeutics Society annual meeting.

But the PNAS paper also includes pharmacokinetic data that were not presented at the meeting.

“The experimental work reported in this paper shows that CALAA-01 can safely be repeatedly administered to large animals,” Calando CSO Jeremy Heidel said in a statement. “We observed a lack of significant immunostimulation and, notably, the absence of complement activation, even at the highest dose administered.”

Based on the study results, Calando is proceeding with full investigational new drug-enabling toxicology studies “as the next step toward commencing what we believe will be the first phase I clinical trial with a targeted, systemic formulation of siRNA by the end of 2007,” CEO John Petrovich added.

A relative newcomer to the RNAi drugs field, Calando is banking on a delivery system that comprises a linear, cyclodextrin-containing polycation capable of binding to the anionic backbone of an siRNA. When mixed together, the polymer and siRNA self-assemble into nanoparticles, roughly 50 nanometers in diameter, that are protected from nuclease degradation in blood serum. 

According to Calando, the cyclodextrin in the polymer allows stabilizing agents to be attached to the surface of the particles. These agents have terminal adamantane groups that form inclusion complexes with cyclodextrin and contain polyethylene glycol, which prevents aggregation while preventing degradation.
— Doug Macron

Short Reads

Bio-Rad received a non-exclusive license from Alnylam Pharmaceuticals to sell RNAi research products. The license includes siRNAs and using them in mammalian cells to mediate RNAi.

Quark Biotech finished an investigational new drug application for its siRNA-based acute renal failure drug, AKli-5, which was licensed from SR Pharma subsidiary Atugen. AKli-5 was designed to temporarily inhibit p53 expression. Quark is also preparing to file another RNAi drug, called AHLi-11, that treats acute hearing loss associated with trauma or ototoxic drugs.
 
Benitec hopes to begin the phase I portion of an AIDS lymphoma therapy study using expressed RNAi technology. Benitec filed an investigational new drug application for this therapy in January, but the US asked for another safety test and more information regarding the reagents used during manufacturing.

RXi Pharmaceuticals, a subsidiary of CytRx, has a deal that gives it a non-exclusive, worldwide license to shRNA technology from Cold Spring Harbor Laboratory.

Generex Biotechnology now has a deal with Beijing Daopei Hospital to carry out clinical trials of the company’s RNAi-based cancer therapy. The therapy uses RNAi-expressing vectors to silence the Ii protein in cancer cells expressing MHC class II molecules and is being tested in patients with acute myelogenous leukemia.

Patents

US application 20070042986. Methods of inhibiting VEGF-C. Inventors: Douglas Trask and Jonathan Bock. Filed: October 24, 2006.

“The present invention provides RNA molecules (e.g., antisense, RNAi, or siRNA) specific for VEGF-C, and further provides methods of reducing expression of VEGF-C in cells (e.g., cancer cells),” according to the patent abstract.

US application 20070049543. RNA interference mediated inhibition of 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD-1) gene expression using short interfering nucleic acid siNA. Inventors: James McSwiggen, Chandra Vargeese, Vasant Jadhav. Filed June 16, 2006.

According to the patent abstract, this invention covers “double stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD-1) gene expression, including cocktails of such small nucleic acid molecules and lipid nanoparticle (LNP) formulations of such small nucleic acid molecules.”

Data Point

100 nanograms

Aglient plans to launch a microarray-based microRNA assay. This assay, the company says, will be able to provide miRNA expression profiling from RNA samples of 100 nanograms.

The Scan

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Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.