The Levy Lab is focused on developing new technologies and approaches using nucleic acid aptamers as well as engineered proteins for both diagnostic and therapeutic purposes. I have been working with, synthesizing and engineering aptamers, ribozymes and deoxyribozymes and engineering proteins for more than 16 years. Prior to this, I spent a number of years investigating the prebiotic synthesis and stability of the nucleobases in RNA and DNA. My current lab is focused on developing new methods as well as new aptamers which target cells, engineering aptamer based biosensors and engineering proteins. I was among the first to demonstrate the targeted delivery of cargoes to cells using receptor-specific aptamers during my postdoctoral work, coupling nuclease stabilized aptamers that target the prostate specific membrane antigen (PSMA) to quantum dots for imaging or to the ribosomal toxin gelonin for use as a therapeutic. I continue to seek better and more robust ways to find affinity agents that can specifically target cells. We have developed novels methods to identify RNA molecules which are directly internalized by cells (1) and have also selected aptamers to some therapeutically relevant protein targets including the human transferrin receptor (CD71) (2, 3), a protein over expressed on many cancers and the target receptor for mammarenavirus entry, the dendritic cell receptor DEC205 a potentially important target for the generation of vaccines (4). The lab is now adapting many of these molecules for both diagnostic and therapeutic applications including generating novel imaging agents, aptamer targeted toxins (5), liposomes (2) and engineering oligonucleotide stabilized lipid micelles (6) for the delivery of drugs, siRNA and mRNA. Our focus, however, is not just limited to using aptamers as targeting agents. For example, we recently published a study demonstrating the ability to target siRNA-laden LNPs to DEC205+ DC in mice using an anti-DEC205 single chain antibody (7). Most recently, we have developed an improved means to identify highly stabilized, modified aptamers with enhanced chemical functionality. Importantly, the approach allows us to rapidly generate highly stable ligands to targets that we could not previously hit. This is a very active area in my group in which we are working with other acedemics as well as partnering with industry. Finally, in addition to using aptamers as ‘tools’, my lab has a standing interest in better understanding the unique nature of aptamer-protein interactions. In this respect, we have a number of active projects in which we are using structural approaches (crystallography and NMR) to better understand the unique nature of these non-natural nucleic acid:protein interactions (8).
- Magalhães ML, Byrom M, Yan A, Kelly L, Li N, Furtado R, Palliser D, Ellington AD, Levy M. A general RNA motif for cellular transfection. Mol Ther. 2012 Mar;20(3):616-24. PubMed PMID: 22233578; PubMed Central PMCID: PMC3294222.
- Wilner SE, Wengerter B, Maier K, de Lourdes Borba Magalhães M, Del Amo DS, Pai S, Opazo F, Rizzoli SO, Yan A, Levy M. An RNA alternative to human transferrin: a new tool for targeting human cells. Mol Ther Nucleic Acids. 2012 May 15;1:e21. PubMed PMID: 23344001; PubMed Central PMCID: PMC3390244.
- Maier KE, Jangra RK, Shieh KR, Cureton DK, Xiao H, Snapp EL, Whelan SP, Chandran K, Levy M. A New Transferrin Receptor Aptamer Inhibits New World Hemorrhagic Fever Mammarenavirus Entry. Mol Ther Nucleic Acids. 2016;5:e321. doi: 10.1038/mtna.2016.32; PMCID: PMCID in process.
- Wengerter BC, Katakowski JA, Rosenberg JM, Park CG, Almo SC, Palliser D, Levy M. Aptamer-targeted antigen delivery. Mol Ther. 2014 Jul;22(7):1375-87. PubMed PMID: 24682172; PubMed Central PMCID: PMC4089008.
- Kelly L, Kratschmer C, Maier KE, Yan AC, Levy M. Improved Synthesis and In Vitro Evaluation of an Aptamer Ribosomal Toxin Conjugate. Nucleic Acid Ther. 2016. doi: 10.1089/nat.2015.0599. PubMed PMID: 27228412; PubMed Central PMCID: in progress.
- Wilner SE, Sparks SE, Cowburn D, Girvin ME, Levy M. Controlling lipid micelle stability using oligonucleotide headgroups. J Am Chem Soc. 2015;137(6):2171-4. doi: 10.1021/ja512012m. PubMed PMID: 25634639; PMCID: PMC4861057.
- Katakowski JA, Mukherjee G, Wilner SE, Maier KE, Harrison MT, DiLorenzo TP, Levy M and Palliser D (2016) Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses. Mol Ther 24(1):146-155. PubMed PMID: 26412590; PubMed Central PMCID: PMC4754549.
- Padlan CS, Malashkevich VN, Almo SC, Levy M, Brenowitz M, Girvin ME. An RNA aptamer possessing a novel monovalent cation-mediated fold inhibits lysozyme catalysis by inhibiting the binding of long natural substrates. RNA. 2014 Apr;20(4):447-61. PubMed PMID: 24570482; PubMed Central PMCID: PMC3964907.