The main obstacle to RNA-interference-based inhibitors is delivering them into primary cells that are highly recalcitrant to nucleic acid uptake. As a result suppression of target gene expression within these cells for both biological and therapeutic purposes has been a major issue. In recent years there have been several advances in siRNA-carrier design that have enabled efficient and cell-specific siRNA delivery. However, formulation of these carriers is extremely cumbersome and cost-prohibitive for preliminary laboratory testing. We propose to develop novel, cost-effective, easy-to-formulate and non-immunogenic siRNA carriers for the cell-specific delivery of siRNA in vivo. These carriers will be formulated from two components- (1) a non-immunogenic protein/peptide component that binds the immunoglobulin Fc-region with a high affinity coupled to a siRNA binding domain and (ii) an antibody component capable of recognizing a specific cell-surface receptor and inducing internalization. Simple mixing or incubation of the carrier with the antibody will yield a reagent capable of siRNA delivery to the desired cell type. Importantly, delivery to the target cell type/organ will be achieved through simple intravenous injections. We will generate siRNA carriers to each of the human immune cell subtypes and defined organs/tissues and evaluate siRNA treatment efficacy in relevant murine models of human disease. The successful completion of our research plan is expected to lead to the establishment of easily translatable delivery platforms for the preclinical evaluation of potential siRNA therapeutic candidates.

Public Health Relevance

siRNAs represent the most promising of RNA-based therapeutics advancing into clinical trials but efficient delivery is still an issue. The availability of 'user-friendly'siRNA carriers for delivery into practically any cell type of choice would tremendously expand the applicability of the RNAi technology. Here we propose to develop easy-to-formulate non-immunogenic reagents for the delivery of siRNA specifically into multiple human cells thereby increasing the range of siRNA- amenable cell types for in vivo applications to counter disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI088484-02
Application #
8317539
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2011-08-15
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$207,552
Indirect Cost
$82,552
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520