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Calando Pharmaceuticals, Tekmira Pharmaceuticals, Protiva Biotherapeutics, Phil Sharp

Calando Doses First Patient in Phase I Study of RNAi-Based Cancer Drug
Calando Pharmaceuticals, a unit of Arrowhead Research, said this week that it has dosed the first patient in a phase I study of its systemically administered, RNAi-based cancer drug CALAA-01.
The drug is a non-modified siRNA targeting the M2 subunit of ribonucleotide reductase and is delivered using a proprietary nanoparticle delivery system. Last year, Calando published data in the Proceedings of the National Academy of Sciences showing that CALAA-01 could be systemically administered to non-human primates with no adverse effects (see RNAi News, 3/22/2007).
According to the company, the study is an open-label, dose-escalation phase I trial in patients with solid tumors that are refractory to standard-of-care therapies. It is being conducted at the UCLA Jonsson Cancer Center and at South Texas Accelerated Research Therapeutics.

Tekmira, Protiva Complete Business Combination
Tekmira Pharmaceuticals and Protiva Biotherapeutics announced this week that they have completed their previously announced merger to form a new company that will retain the Tekmira name.
As previously reported by RNAi News, the companies said in March they would combine their operations. The move effectively ended a protracted dispute between the two over the rights to RNAi delivery technology Protiva developed after being spun out of Tekmira’s former parent company Inex Pharmaceuticals (see RNAi News, 4/3/2008).
Under the terms of the arrangement, Tekmira bought all outstanding equity of privately held Protiva in exchange for 22.8 million shares of newly issued stock, with 1.8 million shares reserved for the exercise of Protiva stock options.
In conjunction with the merger, Alnylam Pharmaceuticals and partner Roche have agreed to each make a $5 million equity investment in the new Tekmira in exchange for access to the combined company’s drug-delivery intellectual property.
Tekmira said it now has working capital of more than $35 million.
"The new Tekmira has a tremendous opportunity to be a leader in the advancement of novel RNAi therapeutic products,” Mark Murray, Tekmira’s president and CEO, said in a statement. “We will also continue to support and build upon our world-class alliance partners as they advance products based on our lipid nanoparticle delivery technology."

MIT’s Sharp Sees miRNAs as Effective Therapeutic Targets
The amount of research into using microRNAs therapeutically has been growing in recent years amid a growing body of data linking the small, non-coding RNAs to various disease states. Still, concerns persist over the possibility that modulating miRNA expression may have unintended effects since they are believed to regulate multiple targets.
But according to Massachusetts Institute of Technology researcher Phil Sharp, this doesn’t necessarily mean that miRNAs won’t prove to be good targets for therapeutic intervention.
Currently, as many as 1,000 miRNAs are believed to be encoded by the human genome. Since miRNAs don’t require perfect complementarity to their mRNA target to trigger inhibition, it has been estimated that they regulate as much as one-third of all genes.
“I think about microRNAs in much the same pattern that I think about transcription factors,” Sharp said during a presentation at the American Society of Gene Therapy meeting in Boston last week. “Transcription factors are known to regulate a few genes critically. … But they interact with hundreds of genes … and we know they have overlapping patterns of expression.”
Despite this, “we’ve been able to use transcription factors for therapeutic targets for a long time,” he said. “All small steroid-based drugs are targeting estrogen receptors and progesterone receptors and others … and regulating genes in transitional states. So I think you could possibly think of microRNAs as [a therapeutic] target either by tuning them up or tuning them down.”
A number of different approaches are being explored to regulate miRNA expression, including the use of antisense-like agents such as antagomirs and locked nucleic acids, as well as miRNA sponges, which are essentially transcripts expressed from strong promoters that contain multiple tandem binding sites to an miRNA of interest.
Thus far, the antisense-type of approach has been one of the most popular in the field, and this week Danish biotech firm Santaris Pharma announced that it had begun a phase I study of an LNA-based drug that inhibits miRNA-122 as a treatment for hepatitis C, marking the first time an miRNA-targeting agent has been tested in humans.
Despite this milestone, the miRNA drug field faces many hurdles, primarily related to delivery.
Even if Santaris’ drug is successful, since it is designed to work in the liver, an organ to which oligonucleotide drugs can easily be delivered, it remains unclear whether miRNA drugs will be effective for diseases affecting other tissues.
“If you think about what’s been done over the last 10 years with antisense … the delivery issue has clearly been not solved,” Sharp said, and whether drugs that either up-regulate or down-regulate miRNAs will be forthcoming “is probably going to take a while to figure out.”

The Scan

Study Links Evolution of Longevity, Social Organization in Mammals

With the help of comparative phylogenetics and transcriptomics, researchers in Nature Communications see ties between lifespan and social organization in mammals.

Tumor Microenvironment Immune Score Provides Immunotherapy Response, Prognostic Insights

Using multiple in situ analyses and RNA sequence data, researchers in eBioMedicine have developed a score associated with immunotherapy response or survival.

CRISPR-Based Method for Finding Cancer-Associated Exosomal MicroRNAs in Blood

A team from China presents in ACS Sensors a liposome-mediated membrane fusion strategy for detecting miRNAs carried in exosomes in the blood with a CRISPR-mediated reporter system.

Drug Response Variants May Be Distinct in Somatic, Germline Samples

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.