Genome editing holds the potential for curative treatments of human disease, however, clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism, and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model-informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from phase I investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here, we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR-based investigational therapies in the clinic.
Wildfire events in southwestern China resulted in catastrophic loss of property and human life, and the localized wildfire risks show differentiated trends under global warming scenarios. In the case of quantitating climate impacts and localizing wildfire risks, synthesized assessments of wildfire risks of high-incident areas in southwestern China are established and mapped in this article, constituted by three essential elements: hazard, vulnerability, and disaster prevention/mitigation capacity. The hazard group includes vegetation ignitability and fire spreading related to climate and topography factors. Public and economic characteristic elements belong to the vulnerability and disaster prevention/mitigation capacity group based on their functions and influences on wildfire events. Each aspect and group are rated by the historical wildfire site records and weighted by the entropy weight method and analytic hierarchy process. Assessments indicate that most very high wildfire risk girds are distributed in the west of 103°E and the north of 28°N, covering an area of over 26,500 km 2 , mainly in low-altitude suburban regions in basins and valleys with high climate hazards. The highly localized wildfire risk maps specified both stresses of fire prevention/mitigation in each grid cell and general spatial patterns of wildfire risks, thereby enhancing the understanding of both current and future patterns of wildfire risks and thus helping improve suppression and prevention policies.
Background Thyroid cancer is the most common malignant tumor of the endocrine system. Most patients with thyroid cancer have a good prognosis, although a small proportion experience recurrence and metastasis and have a poor prognosis. Ferroptosis is a novel form of regulated cell death (RCD); previous studies have confirmed that ferroptosis was associated with thyroid cancer. The purpose of this study was to investigate the key ferroptosis-related genes in thyroid cancer and their relationship with prognosis and immune cell infiltration. Methods In this study, 497 thyroid cancer RNA expression datasets were downloaded from the cancer genome atlas (TCGA) cohort and a prognostic risk model for eight ferroptosis-related genes (FRGs) was constructed by Lasso-Cox regression. The prognostic value of the risk model and the correlation of prognostic features with immune scores and tumor immune cell infiltration were systematically analyzed. Results The prognostic risk model for eight FRGs ( DPP4 , TYRO3 , TIMP1 , CDKN2A , SNCA , NR4A1 , IL-6 and FABP4 ) were constructed and validated in training and testing cohorts. Kaplan-Meier curve and receiver operating characteristic (ROC) curve analysis confirmed that that the ferroptosis-related eight gene signature had good predictive value for the prognosis of thyroid cancer (THCA) patients. Multivariate regression analysis further showed that the risk score of the prognostic model could be used as an independent prognostic factor for THCA patients. Functional enrichment analysis showed that DEGs in high risk and low risk groups were involved in immune-related biological processes and that there were significant differences in immune cell infiltration between the two risk groups. Conclusion We identified eight key genes related to ferroptosis in THCA patients. Further studies are now needed to investigate the mechanisms involved; these genes may represent clinical diagnostic and prognostic biomarkers.
Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (
BackgroundTransthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR).MethodsIn this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.ResultsA total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.ConclusionsIn this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.)
Recent decades have witnessed accelerated climate changes across the Qinghai-Tibet Plateau (QTP) and elevated socioeconomic exposure to meteorological hazards. The QTP is called the “the third pole”, exerting remarkable impact on environmental changes in its surrounding regions. While few reports are available for addressing multi-hazard risks over the QTP, we develop an integrated indicator system involving multiple meteorological hazards, i.e., droughts, rainstorms, snowstorms and hailstorms, investigating the spatiotemporal patterns of major hazards over the QTP. The hazard zones of droughts and rainstorms are identified in the southern Gangdise Mountains, the South Tibet Valley, the eastern Nyenchen-Tanglha Mountains, the Hengduan Mountains and West Sichuan Basin. Snowstorm hazard zones distribute in the Himalayas, the Bayan Har Mountains and the central Nyenchen-Tanglha Mountains, while hailstorm hazard zones cluster in central part of the QTP. Since the 21st century, intensified rainstorms are detectable in the densely populated cities of Xining and Lhasa and their adjacent areas, while amplified droughts are observed in grain production areas of the South Tibet Valley and the Hengduan Mountains. Snowstorm hazards show large interannual variations and an increase in pastoral areas, although the overall trend is declining slightly. The frequency of hailstorms gradually decreases in human settlements due to thermal and landscape effects. Mapping meteorological hazards regionalization could help to understand climate risks in the QTP, and provide scientific reference for human adaptation to climate changes in highly sensitive areas.
Wildfire events in the southwestern China resulting in catastrophic loss of property and human life, and the localized wildfire risks show differentiated trends under warming scenarios. In case of quantitating climate impacts and localizing wildfire risks, synthesized assessments of wildfire risks of high-incident areas in the southwestern China are established and mapped in this article, which are constituted by three basic elements: hazard, vulnerability and disaster prevention/mitigation capacity. Vegetation ignitability and fire spreading related climate and topography factors are selected and interpolated as the hazard part, public and economic characteristic elements are grouped into vulnerability and disaster prevention/mitigation capacity based on their functions and influences with wildfire events, each factors and groups are rated by the historical wildfire site records and weighted by entropy weight method and analytic hierarchy process. Assessments indicates that most very high wildfire risk girds distribute in the west of 103°E and the north of 28°N, cover an area of over 26500 km 2 , mainly occur in low altitude suburban regions in basins and valleys with high climate hazards. The highly localized wildfire risk maps specified both stresses of fire prevention/mitigation in each grid cells and general spatial patterns of wildfire risks, therefore enhance the understanding of both current and future patterns of wildfire risks, and thus help improve suppression and prevention policies.
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