RNA-based therapy as a novel therapeutic approach for multiple myeloma

Multiple myeloma (MM) is the second most common hematological malignancy. MM arises of differentiated malignant plasma cells accumulating in the bone marrow. Despite the recent approval of several drugs for MM, most patients eventually relapse, and the disease is considered incurable. Recent approvals of RNA-based therapies for various indications have made them an appealing therapeutic approach for cancer, as they hold the potential ability to manipulate the genetic expression of any gene and cell. The clinical implementation of RNA-based therapies is limited due to inefficient systemic delivery of the nucleic acids to cells beyond the liver, especially to lymphocytes. Our goal is to generate a novel RNA-based therapy for MM to specifically silence the expression of crucial genes in myeloma cells and therefore lead to the alleviation of the disease. For this purpose, we used small interference RNA (siRNA) to block the expression of cytoskeleton-associated protein 5 (CKAP5), a protein that regulates centrosomal organization during mitosis. We utilized lipid nanoparticles (LNPs) as a delivery system for siRNA-CKAP5 to allow specific delivery to myeloma cells, and the LNPs were decorated with an anti-CD38 monoclonal antibody, a targeting ligand that was chosen due to its overexpression and clinical relevancy in MM. Validation of our αCD38-LNPs-siCKAP5 for therapy of MM was examined in-vitro, in-vivo, and ex-vivo in primary MM patient samples. Our data show that silencing CKAP5 results in a significantly decreased cell viability of MM cell lines and primary MM cells. Moreover, since previously described xenograft MM mouse models have poor homing of myeloma cells to the bone marrow and are not suitable for investigation of our therapy, we established a novel xenograft MM mouse model that demonstrates high engraftment of myeloma cells to the bone marrow and high resemblance to the human MM disease. Encouraged by our results, we hope biodistribution and efficacy studies of our αCD38-LNPs-siCKAP5 would lead to positive outcomes and open a new therapeutic opportunity to treat MM.