Although RNA interference (RNAi) provides an efficient, widely-used experimental tool for specific gene silencing, it remains unclear if RNAi-based technologies will catalyze a similar revolution in clinical medicine. One potential type of RNAi-based therapy involves short interfering RNA (siRNA). These short, double- stranded pieces of RNA are used by RNA-induced Silencing Complex (RISC) proteins present in the cytoplasm of cells to recognize and degrade mRNAs that contain complementary sequences. In this way, siRNA is able to effectively silence specific genes at the post-transcriptional level. Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. While there are currently no effective cures for malignant gliomas, siRNA based therapies hold much promise. Recent studies have demonstrated that siRNAs designed to decrease stathmin protein levels can increase the in vitro and in vivo sensitivity of malignant glioma cells to chemotherapeutic agents. This indicates that siRNA against stathmin, co-administered with existing chemotherapeutic agents, may be a valuable treatment for malignant gliomas. A major roadblock to implementation of siRNA therapy is effective drug delivery to the cytoplasm of target cells, because the highly charged nature of siRNA prevents movement across hydrophobic lipid cell membrane. In order to address this challenge, this project focuses on the creation of a polymer mediated delivery system for anti-stathmin siRNA. This delivery system will be designed to enter cells via endocytosis and utilize the naturally occurring acidification of maturing endosomes as a trigger to allow movement of siRNA into the cytoplasm. For this application, a polymer that transitions from non-membrane disruptive at neutral pH to membrane disruptive at slightly acidic pH values will be tested as an agent that increases efficiency of an existing polymer delivery agent. Through successful design of this type of delivery vector, it is hoped that anti-stathmin siRNA can be effectively delivered to cytoplasm of brain tumor cells, resulting in increased effectiveness of chemotherapeutic agents for patients with glioblastomas. Public Health Relevance: siRNAs are extremely promising potential drugs because they can be designed to specifically reduce levels of proteins involved in disease. However, siRNAs alone are unable to effectively reach many diseased tissues. This project focuses on how to deliver siRNAs to the brain, as a new treatment for malignant gliomas, a deadly disease with no current effective cure.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZNS1-SRB-M (64))
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Fountain, Jane W
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Harvard University
United States
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Chen, Rongjun; Khormaee, Sariah; Eccleston, Mark E et al. (2009) The role of hydrophobic amino acid grafts in the enhancement of membrane-disruptive activity of pH-responsive pseudo-peptides. Biomaterials 30:1954-61