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Antisense Inhibitors of Long Noncoding RNA as Treatment for Multiple Myeloma
Dana-Farber
Nucleotide
Oncology
Hit To Lead or Lead Optimization
Overview
Researchers at Dana-Farber Cancer Institute have designed antisense oligonucleotides (ASOs) that are proven inhibitors of RROL. By incorporating state-of-the-art chemical modifications, the ASOs demonstrate greater bioavailability and resistance to enzymatic degradation while retaining high selectivity to the RROL target. Two classes of ASOs have been designed to inhibit RROL via two different mechanisms: (i) an RNase-based mechanism where binding of the ASO to its RROL target induces degradation of RROL, or (ii) a “steric block” mechanism in which RROL is masked by binding to the ASO thereby impeding its function without its degradation.
Both classes of modified ASOs show strong anti-proliferative effects(>50% cell growth inhibition) in MM cell lines and patient-derived MM cells, while sparing non-malignant cells. In vivo mouse studies show tumor growth inhibition of >68% in an AMO1-based plasmacytoma xenograft model and >50% in a model of aggressive myeloma. No significant toxicity was observed in any mice after treatment, and both classes of inhibitors produced survival in the mice.
Benefits
• Chemical modifications impart the ASOs with efficient cellular uptake properties and resistance to enzymatic degradation
• The inherent RNA target selectivity of ASOs limit off-target toxicity
• Demonstrated strong tumor growth inhibition
Nikhil Munshi, Eugenio Morelli, Mariateresa Fulciniti
PCT Application Filed
"A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth". Eugenio Morelli et al. Blood. 2023 Jan 26;141(4):391-405
"RROL lncRNA role in multiple myeloma". Agirre, X. Blood 2023
