The National Cancer Institute this month announced that it is looking to award three to five Small Business Innovation Research grants focused on the development of nanoparticle delivery technologies for RNAi-based cancer therapeutics as part of a broader $10 million funding initiative.
Meanwhile, the National Heart, Lung, and Blood Institute has begun soliciting Small Business Innovation Research contract proposals for, among other things, research efforts involving the identification of microRNA biomarkers of myocardial fibrosis.
According to the NCI, despite the growing interest in RNAi-based therapies against targets undruggable by small molecules, the gene-silencing technology remains hamstrung by difficulties in achieving intracellular delivery to specific tissues and organs.
“In particular, cellular uptake of naked RNAi is extremely inefficient owing to its polyanionic nature,” the institute noted. “The majority of intravenously administered RNAi is removed from circulation by hepatic and renal clearance, and the remaining RNAi is subject to degradation by non-specific nucleases in the blood. Moreover, injecting large quantities of RNAi may elicit an immune response, and other off-target effects may result in toxicity.”
Delivery of siRNAs and other RNAi molecules to tumor cells faces these and other challenges, but overcoming them “is expected to facilitate the development of new and highly efficacious anti-cancer agents,” it added. “Nanoparticle-based delivery systems are especially attractive as such strategies afford the opportunity to target specific cell, tissue, and organ types, while also increasing circulation half-life and shielding RNAi from degradation.”
Notably, clinical trials in cancer are already underway with nanoparticle-delivered RNAi drugs, suggesting the approach holds “great promise,” the NCI said. These include Arrowhead Research's phase I CALAA-01, which is delivered with a cyclodextrin-based polymer nanoparticle (GSN 9/11/2011) and Alnylam Pharmaceuticals' phase I ALN-VSP, which is delivered using a lipid-based nanoparticle (GSN 6/7/2012).
To accelerate such work, NCI said it is seeking proposals for the development of “novel, commercially viable nanotechnology-based platforms “ for RNAi cancer drug delivery.
Proposals submitted should involve the design, fabrication, characterization, and preclinical evaluation of novel drug-delivery formulations, the NCI said. “Of particular interest are delivery systems that can achieve targeted delivery of RNAi to tumor cells, favorable pharmacokinetics and circulation times, and efficient uptake of RNAi by tumor cells,” as well as nanotechnologies that minimize RNAi-related immune responses and off-target effects.
The agency noted that it will not only consider proposals related to siRNA and shRNA drugs, but miRNA and antisense ones, as well.
Importantly, the funding is not intended to support basic research into molecular targets for RNAi intervention, studies comparing different delivery nanotechnologies, or the establishment of new animal models, the NCI said. The delivery of DNA, mRNA, or proteins, or viral-based delivery approaches, are also unacceptable under the funding opportunity.
However, proposals that include additional functionalities that enhance novel RNAi nanoparticle technologies will be considered, including constructs that feature novel tumor targeting, RNAi-loading and -releasing schemes, and the combination of RNAi and a conventional, non-nucleic acid chemotherapeutic.
Phase I proposals should seek no more than $200,000 in funding for nine months, and are expected to include a “detailed experimental strategy” for the development and delivery of RNAi-based nanotherapeutics, as well as to identify appropriate cancer indications.
Accepted phase I projects are expected to demonstrate nanoconstruct stability and controlled release of the RNAi payload, as well as quantitate target transcript knockdown with a greater than 70 percent reduction in corresponding protein levels and evaluate correlative endpoints and phenotypic effects in vitro.
Small in vivo efficacy studies are also expected in relevant animal models, the NCI noted.
Phase II proposals should be limited to $1 million in funding over two years, and require a plan and timeline for the completion of preclinical development and investigational new drug application filing, the institute said. In vivo efficacy studies; demonstrations of safety, pharmacokinetics, and pharmacodynamics; and process development of clinical manufacturing are also required.
Proposals must be received by Nov. 13, the NCI added.
Concurrent with the NCI's call for contract proposals, NHLBI has said it is looking to fund up to five projects that will yield new methods to detect and assess myocardial fibrosis — a key marker of adverse cardiac remodeling.
“Research suggests a strong correlation between the extent of myocardial fibrosis and adverse myocardial remodeling that occurs after ischemic injury or during the progression of cardiomyopathies and heart failure,” the NHLBI said. “Diffuse myocardial fibrosis is thought to provide a high-risk substrate for the development of atrial and ventricular arrhythmias.”
Therefore, early detection of myocardial fibrosis may provide early warning for the development of heart failure and increased risk of atrial and ventricular heart rhythm disorders, it added. It may also provide a means of monitoring the efficacy of therapeutic interventions.
The overall goal of the initiative is to accelerate the development of non-invasive myocardial fibrosis detection, imaging, and monitoring approaches. Phase I projects are expected to demonstrate their feasibility in either animal models or human tissue samples.
Among the research projects that will be considered is the identification and validation of serum miRNA biomarkers of myocardial fibrosis, NHLBI said.
The budgets for phase I proposals should be limited to $200,000 for one year, and are also due by Nov. 13.