Despite all the time and attention RNAi has been receiving from those trying to use it therapeutically, the gene-silencing technology continues to face a fundamental problem: delivery.
But recently published data, based on the work of researchers from Harvard Medical School and the University of Pennsylvania, indicate that the key to overcoming systemic delivery issues may be just around the corner.
In a paper published recently in the online version of Nature Biotechnology, Judy Lieberman, a senior investigator at Harvard’s CBR Institute for Biomedical Research, and colleagues describe how an antibody-mediated siRNA delivery approach can be used to trigger RNAi systemically with high specificity and no off-target effects.
According to the paper, the system comprises a fusion protein designed with the protein-coding sequence of protamine, which nucleates DNA in sperm, linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody.
“Basically, if you mix the fusion protein with siRNA, the siRNA binds by charge and [is] delivered very efficiently into just cells that have the receptor recognized by the antibody,” Lieberman says.
She says the delivery approach was first developed by Wayne Marasco at the Dana- Farber Cancer Institute as a means to deliver plasmid DNA.
The antibody-mediated delivery system “is really efficient,” Lieberman says. “With 100 picomoles, we’re getting silencing equivalent with what you get with transfection — but we can use it to introduce siRNAs into cells that you can’t transfect, like primary lymphocytes.”
She added that “the delivery was very specific — [siRNAs] didn’t go into any cells that didn’t express the receptor. We found no induction of interferon or interferon-response genes, and no obvious inflammation or other kinds of toxicity.”
— Doug Macron
US Patent 6,893,867. Molecular switch for regulating mammalian gene expression. Inventor: Keith Webster. Issued: May 17, 2005.
This patent covers expression vectors entailing “one or more silencer elements and conditionally inducible elements to form silencer-inducible regions and ... promoters in operative linkage upstream of at least one expressed region. The expression vector thereby regulates expression of at least one downstream region by conditional silencing in which an expressed DNA region of a gene is transcribed to produce RNA transcripts, which may or may not be translated to produce polypeptides.”
US patent application 20050107325. Modified iRNA agents. Inventors: Muthiah Manoharan, Venkitasamy Kesavan, Kallanthottathil Rajeev. Filed: August 10, 2004.
“The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose,” according to the abstract. “The invention also relates to methods of making and using such modified iRNA agents.”
Supplier Open Biosystems will distribute the human-based short hairpin RNA library developed by the Broad Institute’s RNAi Consortium. The library was expected to be available as early as last month, and the company says the consortium’s mouse shRNA library will be ready for distribution sometime later.
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The National Cancer Institute and Qiagen plan to co-develop and validate a set of siRNAs for cancer genes. The set, for NCI researchers, would be available to the broader research community after the project.
Isis Pharmaceuticals announced a collaboration with Pfizer. The multiyear effort is aimed at identifying antisense drugs for the treatment of ophthalmic disease. Pfizer will select targets and handle clinical development and commercialization, while Isis will be responsible for using its antisense platform to find drugs against the targets.
Alnylam Pharmaceuticals non-exclusively licensed its siRNA technology patents to Ambion for research products and services. Ambion is the tenth company to license pieces of Alnylam’s patent estate.
People laid off in restructuring at Sirna Therapeutics, according to an SEC filing. The job cuts are expected to save the company $2.1 million in salaries and benefits.