P1355: delivery of therapeutic rna to the bone marrow in multiple myeloma using cd38-targeted lipid nanoparticles

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Multiple myeloma (MM) is a cancer of plasma cells that occurs in the bone marrow (BM). Despite the recent advancements in drug development for MM, most patients eventually relapse and there is a constant need for developing new therapeutic options for this disease. RNA-based therapies are an appealing therapeutic approach for cancer, as they hold the potential to manipulate the genetic expression of any gene and cell. However, clinical implementation of RNA therapy is limited due to inefficient systemic delivery of ribonucleotides to cells outside the liver, especially lymphocytes. Aims: We aim to generate a novel RNA-based therapy for MM by silencing the expression of crucial genes in MM cells and therefore lead to the alleviation of the disease. Methods: We utilize lipid nanoparticles (LNPs) as they are currently the most advanced and clinically approved non-viral delivery system of RNA. In this study, we present targeted (t)LNPs designed for delivery of RNA payload to MM cells. The tLNPs consists of a novel ionizable lipid and are coated with an anti-CD38 antibody (αCD38-tLNPs). To explore their therapeutic potential, we use small interference RNA (siRNA) to block the expression of cytoskeleton-associated protein 5 (CKAP5), a protein that regulates centrosomal organization during mitosis. Results: We demonstrate that LNPs encapsulating siRNA-CKAP5 lead to a significant decrease in cell viability upon transfection of MM cells in vitro and primary MM cells ex vivo. Next, since previously described xenograft MM mouse models have poor homing of MM cells to the BM and are therefore not suitable for evaluating the retention of systemically administered drugs to the BM, we establish a novel xenograft MM mouse model. Our new model clinically resembles the human disease as the MM-bearing mice display lytic bone lesion and secretion of monoclonal protein to the serum, and, importantly, demonstrate efficient homing of MM cells to the BM. Using this model, we show the specific delivery of αCD38-tLNPs to BM-residing and disseminated MM cells and the improvement in therapeutic outcome of MM-bearing mice treated with αCD38-tLNPs-siRNA-CKAP5. Summary/Conclusion: These results underscore the potential of RNA therapeutics for the treatment of MM and the importance of developing effective targeted delivery systems and reliable preclinical models.Keywords: Nanoparticle, Multiple myeloma, RNA interference (RNAi), Bone Marrow