Nord microsynth3/17/2023 ![]() ![]() Small interfering RNAs (siRNAs) are one of the primary modalities in the field of RNA therapeutics, harnessing the endogenous RNA interference machinery for pharmacological interventions. The relatively straightforward design and predictable pharmacokinetic properties of oligonucleotides have enabled the development of a customized treatment for a single patient in <1 year, delivering on the promise of personalized medicine. A key advantage of this new drug class is its inherent potential to regulate the expression of any gene of interest through the rational design of a complementary oligonucleotide, including disease-causing genes that have been previously considered undruggable. Therapeutic oligonucleotides have emerged as a third pillar of modern pharmacotherapy, expanding the portfolio of traditional small molecule drugs and biologics. Furthermore, Lin28B is a promising target for cancers, and the development of such simplified siRNA analogs, possibly together with novel targeting units, holds potential. ![]() ![]() Despite the lack of a delivery agent-free antitumor effect, we anticipate our study to be a starting point to develop alternative siRNA scaffolds that can be degraded into naturally-occurring metabolites and help alleviate the aforementioned challenges. Liver and kidney were the main sites of accumulation after its subcutaneous administration in mice. We found that its stability in vitro matched that of nanoparticle-free patisiran in serum and surpassed it in liver tritosome extracts, although it did not reach the stability of the fitusiran siRNA core structure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this article, microsynth is described in detail and its application is illustrated using data from a drug market intervention in Seattle, WA.State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. The microsynth procedure includes functionality that enables its user to (1) calculate weights for synthetic control, (2) tabulate results for statistical inferences, and (3) create time series plots of outcomes for treatment and synthetic control. The effect of the intervention on one or more time-varying outcomes is evaluated by determining a synthetic control region that resembles the treatment region across pre-intervention values of the outcome(s) and time-invariant covariates and that is a weighted composite of many untreated comparison regions. The methodology implemented within microsynth is designed to assess the efficacy of a treatment or intervention within a well-defined geographic region that is itself a composite of several smaller regions (where data are available at the more granular level for comparison regions as well). The R package microsynth has been developed for implementation of the synthetic control methodology for comparative case studies involving micro- or meso-level data. ![]()
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