By Doug Macron
The National Institutes of Health has issued a call for project proposals under its Small Business Innovation Research program with the goal of providing $150,000 each to up to three preclinical projects focused on developing systemic shRNA-delivery approaches to treat drug abuse
“There is a critical need to develop effective pharmacotherapies for substance use disorders,” according to the agency. “Currently, effective pharmacotherapies for cocaine and stimulant addiction do not exist and therapies for treating other substance disorders have limited efficacy.”
Nonetheless, current treatments for both legal and illicit substances represent a “huge market,” said Jonathan Pollock, chief of the genetics and molecular neurobiology branch of the National Institute on Drug Abuse, who is overseeing the funding opportunity.
The “emerging technology” of RNAi, he added, has the potential to tap into this market by overcoming the shortcomings of currently available treatment options.
Interest in using RNAi to combat substance abuse stems from the “basic research coming out showing that antisense [agents] seems to work in animal models,” Pollock noted.
For example, in 2005 a team led by Ivan Diamond of the Ernest Gallo Clinic and Research Center published a paper identifying AGS3 as a key player in heroin seeking, and reported that inhibiting it by using antisense oligos could prevent such behavior in rats enabled to self-administer the drug.
But RNAi has advantages over antisense, including its use of “the endogenous enzymatic gene-silencing mechanism instead of interfering with translation,” the NIH said. Furthermore, “lower concentrations of RNAi than antisense RNA are needed to reach the cytoplasm of a cell to prevent the expression of a gene, and [the] short length of RNAi molecules avoids triggering the innate immune system.”
The funding agency acknowledged that when it comes to clinical applications of RNAi, the technology still faces delivery hurdles.
“Systemic administration of naked RNAi is rapidly degraded by serum endonucleases and removed by glomerular filtration,” the NIH said. “The negatively charged properties of RNAi [also] prevent crossing endothelial barriers such as the blood-brain barrier.
If they do cross endothelial barriers, “RNAi molecules must diffuse to target cells where the RNAi molecule is
internalized into endocytic vesicles by endocytosis,” it noted. “These endocytic vesicles fuse with endosomes which eventually become late stage endosomes that merge with lysozome.
“Here most RNAi molecules remain trapped inside the endosome and become degraded in the lyszome, never reaching ... RISC … in the cytoplasm,” the NIH added.
To address these issues, the NIH has issued a call seeking six-month project proposals from small commercial entities developing non-viral, systemic shRNA-delivery approaches.
Specifically, the NIH is seeking to help the companies design and create shRNA vectors that will “silence a gene in a defined cell type in the brain of a rodent model. Delivery may be oral, intranasal, intravenous, or intraperoteneal.”
Candidate projects, whose applications are due by Nov. 7, must also “demonstrate that the selected gene in the chosen cell type … will be silenced in vivo by systemic delivery,” and that an “innate or adaptive immune response” is not triggered by chronic administration of the vector.
Finally, projects must determine the pharmacokinetics, tissue distribution, and excretion of the shRNA vectors.
Pollock said that while AGS3 is of particular interest to the NIDA, other targets are fair game under the funding opportunity. And while these phase I projects are focused on achieving successful systemic delivery of an shRNA vector in general, those that involve substance abuse-related gene targets “would be given higher … priority.”
The funding opportunity envisions a second, two-year phase in which contract recipients will receive up to $1 million to apply their delivery systems against a specific therapeutic target for substance abuse treatment, according to the NIH.
The agency provided some guidelines regarding the phase II work, but stressed that they are only for “informational purposes to assist … with long-term strategic planning.” These include demonstrating in vivo target silencing, avoiding immune responses, and proving therapeutic benefit in rodent and non-human primate models of drug addiction.
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