The siRNA molecule needs better protection from nuclease degradation before it can be effectively used as a therapeutic. AM Biotechnologies (AM) will address this critical issue by developing ribonucleoside thiophosphoramidite (ABz, CBz, GIbu and U) reagents that will enable synthesis of phosphorodithioate siRNA (PS2-siRNA). This synthesized PS2-siRNA will significantly increase siRNA nuclease resistance; lower Tm, which could help the activated RISC unwind siRNA; and enhance the pharmacokinetic properties of siRNA. The PS2-siRNA will also be achiral at phosphorus, which will eliminate the variable biochemical, biophysical, and biological properties of diastereomeric phosphoromonothioate substituted siRNAs (PS-siRNAs). In this Phase I SBIR project, AM will: 1) develop the chemistry and optimize the conditions to produce four ribonucleoside thiophosphoramidites (ABz, CBz, GIbu and U); 2) demonstrate high coupling yield (>97%) in the synthesis of PS2-siRNAs; and 3) evaluate PS2-siRNA gene silencing effect in vitro. In Phase II, AM will perform the research required to (a) scale reagent production up to commercial quantities and purity; (b) optimize a robust protocol for synthesis of PS2-siRNA; (c) systematically evaluate the positional effect of PS2 modification on siRNA activity in mammalian cells; (d) examine the bio-distribution of PS2-siRNA; and (e) fully characterize the pharmacokinetic properties of PS2-siRNA. AM in Phase II may also offer for sale limited quantities of research-grade reagents for market beta testing. Upon successful completion of Phase II, AM will work with its industry partners to commercialize the ribonucleoside thiophosphoramidites (R-thioamidites) and enable the entire life science community to benefit from the use of these unique reagents. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43GM084552-01
Application #
7481422
Study Section
Special Emphasis Panel (ZRG1-GGG-J (10))
Program Officer
Portnoy, Matthew
Project Start
2008-07-01
Project End
2009-12-31
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$99,600
Indirect Cost
Name
Am Biotechnologies, LLC
Department
Type
DUNS #
788679244
City
Houston
State
TX
Country
United States
Zip Code
77034
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