Gene therapy has recently witnessed accelerated progress as a new therapeutic strategy with the potential to treat a range of inherited and acquired diseases. Billions of dollars have been invested in basic and clinical research on gene medicine, with ongoing clinical trials focused on cancer, monogenic diseases, cardiovascular diseases and other refractory diseases. Advances addressing the inherent challenges of gene therapy, particularly those related to retaining the delivery efficacy and minimizing unwanted immune responses, provide the basis for the widespread clinical application of gene medicine. Several types of genes delivered by viral or non‐viral delivery vectors have demonstrated encouraging results in both animals and humans. As augmented by clinical indications, gene medicine techniques have rapidly become a promising alternative to conventional therapeutic strategies because of their better clinical benefit and lower toxicities. Their application in the clinic has been extensive as a result of the approval of many gene therapy drugs in recent years. In this review, we provide a comprehensive overview of the clinical translation of gene medicine, focusing on the key events and latest progress made regarding clinical gene therapy products. We also discuss the gene types and non‐viral materials with respect to developing gene therapeutics in clinical trials.
Understanding global warming effects on forest ecosystems will help policy-makers and forest managers design forest management and biodiversity conservation strategies. We examined the change in woody plant structural diversity in response to topography-associated thermal gradients in a subtropical forest with diverse abundance patterns. We found that energy distribution in a warming trend across slopes had significant effects on woody plant structural diversity. Except for total basal area of the adult trees, plant structural diversity significantly decreased with the increase of heat load. Heat load is significantly and negatively correlated with number of stems, number of species, and the number of stems of the most abundant species (Nmax) for seedlings, saplings, and individuals of all sizes. For the adult trees, heat load is significantly and positively correlated with number of stems and Nmax, and negatively but not significantly with number of species, indicating that large trees may not be as sensitive as seedlings and saplings to warming. Partial correlation analysis, having controlled for elevation, strengthened those relations in most cases. Our results reveal that warming will increase community productivity by enhancing the growth of large trees, but decrease species diversity and inhibit the regeneration of tree seedlings and saplings.
Purpose: To develop and validate models to predict who will develop myopia in the following year based on cycloplegic refraction or ocular biometry and to identify thresholds of premyopia. Methods: Prospective longitudinal data of nonmyopic children at baseline from the Guangzhou Twins Eye Study and the Guangzhou Outdoor Activity Longitudinal Study were used as the training set, and the Singapore Cohort Study of the Risk factors for Myopia study formed the external validation set. Age, sex, cycloplegic refraction, ocular biometry, uncorrected visual acuity, and parental myopia were integrated into 3 logistic regression models to predict the onset of myopia in the following year. Premyopia cutoffs and an integer risk score system were derived based on the identified risk. Results: In total, 2896 subjects with at least 2 visits were included. Cycloplegic refraction at baseline is a better predictor to identify the children with myopia onset [C-statistic = 0.91, 95% confidence interval (CI), 0.87-0.94; C-statistic = 0.92, 95% CI, 0.92-0.92 for internal and external validation, respectively], comparing to axial length, corneal curvature radius (CR) and anterior chamber depth (C-statistic = 0.81, 95% CI, 0.73-0.88; C-statistic = 0.80, 95% CI, 0.79-0.80, respectively), and axial length/CR (C-statistic = 0.78, 95% CI, 0.71-0.85; C-statistic = 0.76, 95% CI, 0.75-0.76). With a risk of > 70%, the definitions of premyopia indicating approaching myopia onset were 0.00 D for 6-8 years and −0.25 D for ≥ 9 years in children with 2 myopic parents. Conclusions: Either cycloplegic refraction or ocular biometry can predict 1-year risk of myopia. Premyopia can be successfully defined through risk assessments based on children's age and predict who would require more aggressive myopia prophylaxis.
Messenger RNA (mRNA) has come into the spotlight due to its potential for addressing a staggering number of diseases, while the lack of effective and safe carriers for in vivo delivery significantly limits its clinical application. Herein, the potential of lipid‐like nanoparticles (LLNs) containing three new cholesterol derivatives to achieve the liver targeting delivery of mRNA is investigated. The central composite design (CCD) is used to tailor the formulation of LLNs through in vivo optimization of the molar ratios of these cholesterol derivatives required for liver targeting. The optimized LLNs (O‐LLNs) are able to systemically deliver mRNA to the liver of mice with a synergistic action of prolonged systemic circulation, increased liver targeting, and enhanced hepatocyte uptake. The O‐LLNs outperformed DLin‐MC3‐DMA (MC3) in functional delivery of Cre‐recombinase (Cre) and human erythropoietin (hEPO) mRNA. Successful delivery of cytidine base editor mRNA (CBE mRNA) and sgRNA by O‐LLNs achieved more than 8% correction rates in a liver‐related metabolism disorder, phenylketonuria (PKU). In conclusion, the general method above can accelerate in vivo screening and optimization of multicomponent nanoparticle formulations, and the optimized ones demonstrate great potential as delivery vehicles for targeted gene therapy in specific tissues.
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