RESUMO
N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.
Assuntos
Doenças Cardiovasculares , Hepatócitos , Humanos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/química , Análise Custo-Benefício , RNA de Cadeia Dupla , Acetilgalactosamina/química , Proteína 3 Semelhante a AngiopoietinaRESUMO
Asthma and diabetes are major chronic conditions in the United States, particularly in the Medicaid population. The majority of care for these diseases occurs at ambulatory practice sites. The New York State Department of Health Office of Health Insurance Programs (OHIP) worked with IPRO, the New York State Medicare quality improvement organization, to develop and implement a quality improvement project (QIP) for these conditions. The approach was based upon the Chronic Care Model and used an iterative academic-detailing methodology. Clinics and community health centers volunteered to participate and used IPRO-collected data with audit and feedback to improve their practices. Several metrics significantly improved for asthma (e.g., use of anti-inflammatory long term controller agents, assessment of asthma severity, use of asthma action plans) and for diabetes (e.g., lipid testing and control, A1c testing). Key organizational elements of success included senior medical leadership commitment and practice site quality improvement team meetings. OHIP has used the QIP experience to begin patient-centered medical home implementation in New York State.