A rationally designed nanoparticle for RNA interference therapy in B-lineage lymphoid malignancies

The purposes of the present study were to further evaluate the biologic significance of the CD22δE12 molecular lesion and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22δE12 genetic defect. We provide unprecedented experimental evidence for a previously unrecognized causal link between CD22δE12 and aggressive biology of BPL cells by demonstrating that siRNA-mediated knockdown of CD22δE12 in primary BPL cells is associatedwith amarked inhibition of their clonogenicity. These findings provide the preclinical proof-of-concept that siRNA-mediated depletion of CD22δE12 may help develop effective treatments for high-risk and relapsed BPL patients who are in urgent need for therapeutic innovations. We also describe a unique polypeptide-based nanoparticle formulation of CD22δE12-siRNA as an RNAi therapeutic candidate targeting CD22δE12 that is capable of delivering its siRNA cargo into the cytoplasmof leukemia cells causing effective CD22δE12 depletion andmarked inhibition of leukemic cell growth. Further development and optimization of this nanoparticle or other nanoformulation platforms for CD22δE12-siRNAmay facilitate the development of an effective therapeutic RNAi strategy against a paradigm shift in therapy of aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.