The National Institutes of Health this month announced that it is seeking to out-license a new method that uses RNAi, antisense, or similar technologies to boost the efficacy of an enzyme used to treat cancer.
According to the NIH, the approach builds off of technology developed at the National Cancer Institute by various researchers including Natasha Caplen, head of the institute’s gene-silencing section (see RNAi News, 1/30/2004).
The NIH this month has also issued two RNAi-related grants: one supporting the development of siRNA-based treatments for West Nile and Japanese encephalitis viruses, and one funding the investigation of the role of microRNAs in inflammation.
Both grants are sponsored by the National Institute of Allergy and Infectious Diseases.
Up For Grabs
The technology the NIH wants to license combines RNAi or similar technologies together with L-asparaginase, or L-ASP, an enzyme long used to fight certain kinds of leukemias. Based on new research, the agency believes that L-ASP in combination with protein-suppressing technologies could be used against other malignancies
“Studies show that cancer cells that contain less asparagine synthetase are more susceptible to L-ASP … [and] the response to L-ASP therapy is often better when the expression of ASNS is limited,” the NIH’s Office of Technology Transfer said in a licensing opportunity announcement.
In November, Caplen and colleagues at the NIH published a paper in Molecular Cancer Therapy showing that RNAi-based silencing of ASNS resulted in significant increases in L-ASP sensitivity in certain ovarian cancer cell lines.
Based on this research, the NIH has filed two provisional US patent applications covering the enhancement of L-ASP activity by combining the enzyme with ASNS antagonists such as siRNAs or antisense nucleotides, as well as the use of ASNS as a biomarker to screen for patients who are likely to respond to L-ASP treatment.
The NIH’s OTT said that it is currently looking for parties interested in licensing the technology either exclusively or non-exclusively, and that the NCI’s genomics and bioinformatics group in the laboratory of molecular pharmacology is seeking “statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the combination therapies.”
The NIH has awarded a 1-year, $250,000 grant to Manjunath Swamy and colleagues at Harvard University’s CBR Institute for Biomedical Research to study how siRNA can be applied to treating West Nile and Japanese encephalitis viruses.
The viruses are mosquito-borne flaviviruses that cause a “devastating acute neurological illness” that kill as many as 30 percent of individuals infected with them, and cause “permanent neurological disabilities” in survivors, according to the grant’s abstract. “These are also potential category B bioterrorism agents” for which no effective treatment exists.
Swamy’s team has developed an siRNA that targets a highly conserved sequence in a viral envelope-related gene and protects mice from fatal encephalitis caused by the viruses, the abstract notes.
Though this siRNA is a promising therapeutic candidate, “many strains of viruses exist in nature that may exhibit small differences even within the conserved sequence,” the abstract adds. To address this issue, Swamy proposes to identify two to three additional conserved target sequences that can effectively suppress both JEV and WNV, and then see if multiple siRNAs targeting these sequences can boost the level of protection.
Swamy and his collaborators “will also test the siRNAs for their ability to inhibit multiple viral strains isolated from different geographic locations,” the abstract states.
But as with most RNAi-based therapeutic candidates, delivery remains a challenge.
In the earlier mouse experiments, siRNAs were delivered intracranially at the same site as viral challenge, “and thus the siRNA is unlikely to diffuse enough to protect all brain cells, which would be required for treatment to be effective after the virus has extensively spread at later time points after infection,” according to the abstract.
“In order to realize the siRNA treatment potential in a clinical setting … we will develop methods for better delivery of siRNA across the brain … [such as] pegylated immunoliposomes coated with transferrin receptor antibody [and] polymeric nanoparticles coated with transferrin,” the abstract notes. “Alternatively, we will try siRNA delivery into the cerebrospinal fluid. If these methods do not work, we will also test delivery efficacy using methods that disrupt the blood-brain barrier transiently.”
The grant project, which began this week, is set to run until the end of 2008.
The NIH has also awarded Jiahuai Han and colleagues at the Scripps Research Institute a $1 million, 5-year grant to study how miRNA can be used to treat inflammatory conditions.
Despite significant advances, “the mechanism of pro-inflammatory gene expression is still not fully understood,” the second grant’s abstract states.
“It is known that pro-inflammatory genes such as tumor necrosis factor, interleukin-1, and cyclooxygenase 2 are controlled at multiple levels of gene expression … [and] quick mRNA degradation of these pro-inflammatory genes serves as a mechanism to control the level of pro-inflammatory molecules,” it adds. Meanwhile, AU-rich elements, or AREs, “located in the 3' untranslated region of these short-lived mRNAs dictate their degradation.”
“Studies show that cancer cells that contain less asparagine synthetase are more susceptible to L-ASP … [and] the response to L-ASP therapy is often better when the expression of ASNS is limited.”
In early 2005, Han and colleagues published a paper in Cell showing that Dicer1, Argonaute1, and Argonaute2, which are involved in miRNA processing and function, are also required for the rapid decay of mRNA containing AREs of tumor necrosis factor-alpha. The researchers also found that miR-16, a miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, is required for ARE-RNA turnover.
“The requirement of miR16 in ARE-mRNA decay in resting cells suggests a physiological 'housekeeping' function of miR16 in which it prevents high basal levels of pro-inflammatory gene expression,” the grant’s abstract states.
To further elucidate the role of miRNAs in pro-inflammatory gene expression, the grant project will investigate “how inflammatory stimuli induce stabilization of ARE-mRNA by blocking miRNA-mediated mRNA degradation” and evaluate the overall function of miR16 through genome-wide identification and classification of miR16-targeted genes, the abstract notes.
“The work proposed in this application will contribute to a better understanding of pro-inflammatory gene expression,” it adds. “Understanding the function of miRNA in mRNA stability of pro-inflammatory genes should provide new avenues for developing novel anti-inflammatory agents.”
The grant project, which is worth about $200,000 a year in direct costs, started at the beginning of the month and will run through the end of 2011.