Antisense oligonucleotides-based approaches for the treatment of multiple myeloma

Multiple myeloma (MM), a hematological malignancy which affects the monoclonal plasma cells in the bone marrow, is in rising incidence around the world, accounting for approximately 2 % of newly diagnosed cancer cases in the US, Australia, and Western Europe. Despite the progress made in the last few years in the available therapeutic options (e.g. proteasome inhibitors, immunomodulatory drugs, tumor cell-targeting monoclonal antibodies, autologous stem cell transplantation, etc.), multiple myeloma is still regarded as incurable, and the prognosis for most patients is poor, as the disease becomes refractory to treatment throughout time. Antisense oligonucleotides (ASOs), designed to be complementary to selected messenger RNA (mRNA) sequences of specific genes involved in the pathogenesis of multiple myeloma (e.g. Bcl-2, Mcl-1, STAT3, IRF4, IL6, ILF2, HK2, cMYC, etc.), represent a promising alternative to conventional treatments, and can be tailored according to the individual requirements of each patient. The main goal of antisense therapy for multiple myeloma consists in silencing the specific genes participating in the proliferation and survival of tumor cells via RNA cleavage or RNA blockage, thus preventing mRNA interactions with ribosomes and altering the process of protein translation. So far, pre-clinical and clinical studies showed promising results when Bcl-2 (Genasense), Mcl-1 (ISIS2048), STAT3 (ISIS345794) and IRF4 (ION251) were targeted using ASOs-based formulations. However, FDA approval has not been obtained yet for these products, mainly due to ethical and financial issues posed by customized therapies and insufficient information regarding their long-term toxicity. This review aims to provide a comprehensive insight into antisense oligonucleotides-based therapies, their potential chemical modifications, the mechanisms involved in ASOs-mediated gene silencing, potential systems for ASOs delivery, and the applications of ASOs in the treatment of multiple myeloma. The relevant genetic targets in ASOs-based MM therapies were described, and the research results obtained in the studies conducted so far were analyzed, with a focus on the ASOs formulations that were already included in clinical trials. In the end, current challenges, and future perspectives of antisense therapy for MM were also discussed.