Journal of pharmaceutical sciences最新文献_第8页

Corrigendum to “Dissolving microneedles patch: A promising approach for advancing transdermal delivery of antischizophrenic drug” Journal of Pharmaceutical Sciences/volume 113, issue 10 (October 2024), pages 3078–3087

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-03 DOI: 10.1016/j.xphs.2025.01.029

Qurat-ul-Ain Umar , Muhammad Imran Khan , Zulcaif Ahmad , Muhammad Furqan Akhtar , Muhammad Farhan Sohail , Asadullah Madni , Alia Erum , Badarqatul Ayesha , Qurat Ul Ain , Aamir Mushtaq

引用次数: 0

A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2025.01.015

Ping Chen , Hongxia Lin , Yongjun Xue , Mark Thomas , Alice Wang , Yan Li , Yiming Cheng

{"title":"A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide","authors":"Ping Chen , Hongxia Lin , Yongjun Xue , Mark Thomas , Alice Wang , Yan Li , Yiming Cheng","doi":"10.1016/j.xphs.2025.01.015","DOIUrl":"10.1016/j.xphs.2025.01.015","url":null,"abstract":"<div><div>Iberdomide, a novel potent cereblon E3 ligase modulator, is under investigation for multiple myeloma. This study assessed how renal impairment (RI) affects iberdomide pharmacokinetics (PK). Twenty-six subjects with varying renal function, including those with severe renal impairment and those requiring intermittent hemodialysis (IHD), received a single oral 1 mg dose of iberdomide. Plasma, urine, and dialysate samples were analyzed to evaluate the PK of iberdomide and its major active metabolite, M12. Data were subsequently pooled with PK data from four other clinical trials involving 354 patients to develop a parent – metabolite population PK model using nonlinear mixed-effects modeling to assess the impact of various degrees of RI on drug exposure. The population PK model effectively described the PK of iberdomide and M12, showing that normal, mild, and moderate RI had no significant impact on iberdomide PK exposure, whereas severe RI reduced total clearance and increased PK exposure of iberdomide and M12. Subjects with kidney failure on IHD had comparable total clearance and PK exposure to those with normal renal function. These findings systematically examined the effects of various degrees of RI on iberdomide PK and provide a basis for informing iberdomide dosing in patients with varying degrees of renal impairment.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1315-1325"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a thermal stabilizer formulation optimized by response surface methodology for Senecavirus A antigen 用响应面法优化塞内卡病毒a抗原热稳定剂配方的研制。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.11.013

Zhenru Hu , Jiankun Huang , Simiao Zhao , Huiying Zhou , Shiqi Sun , Xiaobo Wen , Xuhua Ran

{"title":"Development of a thermal stabilizer formulation optimized by response surface methodology for Senecavirus A antigen","authors":"Zhenru Hu , Jiankun Huang , Simiao Zhao , Huiying Zhou , Shiqi Sun , Xiaobo Wen , Xuhua Ran","doi":"10.1016/j.xphs.2024.11.013","DOIUrl":"10.1016/j.xphs.2024.11.013","url":null,"abstract":"<div><div>Numerous members of the family Picornaviridae, such as the Senecavirus A (SVA) and foot-and-mouth disease virus (FMDV), exhibit thermal instability, resulting in the dissociation of viral particles, which affects the insufficient potency of the vaccine. Based on this characteristic, this study aimed to maintain the thermal stability of SVA by supplementing it with a stabilizer. Excipients, such as sucrose, mannitol, sorbitol, polyethylene glycol (PEG), L-arginine (L-Arg), glutamic acid (Glu), polyvinyl pyrrolidone (PVP), bovine serum albumin (BSA), and potassium chloride (KCl) dissolved in Tris-HCl buffer solution, retained the infectivity of SVA in the thermostability assay. Thermal stability formulations were developed by combining different excipients in disaccharide polyol systems and optimizing formulations using the Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). Three significant factors were studied: sucrose 9.9%, sorbitol 9.9%, and L-Arg 0.06 mol/L against virus titer of thermal-resistance of SVA as a response. The formulation improved the stability of SVA, whose viral infectivity titer decreased by 10<sup>1.0</sup> TCID<sub>50</sub>/mL at 4°C, 25°C, and 37°C, respectively, until it decreased by 10<sup>1.21</sup> TCID<sub>50</sub>/mL at 7 d of incubation at 42°C. The combinational thermal stabilizer generated in this study enabled the stabilization of the SVA, which might contribute to storage and transportation when the cold chain is unavailable, especially in rural areas. Therefore, the thermal stabilizer is an efficient candidate stabilizer for picornavirus formulations, which keep picornavirus infectivity at various temperatures. Further optimization of this approach will provide new opportunities for the generation of stabilizer formulation from different stabilizers.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1024-1034"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hydroxypropyl β cyclodextrins effects on self-assembly of cyclic peptide, lanreotide acetate, in water and subsequent release rate from an in vitro emulator of subcutaneous delivery 羟丙基β环糊精对环肽、醋酸Lanreotide在水中自组装的影响及体外皮下给药模拟器的释放速率

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.11.018

Negar Jafari , Camille Addison , Hao Lou , Michael J. Hageman

{"title":"Hydroxypropyl β cyclodextrins effects on self-assembly of cyclic peptide, lanreotide acetate, in water and subsequent release rate from an in vitro emulator of subcutaneous delivery","authors":"Negar Jafari , Camille Addison , Hao Lou , Michael J. Hageman","doi":"10.1016/j.xphs.2024.11.018","DOIUrl":"10.1016/j.xphs.2024.11.018","url":null,"abstract":"<div><div>Most of the peptide drugs are often delivered subcutaneously. The significant barrier in this type of peptide administration is the high concentration of formulation, which can lead to self-assembly and aggregation. These phenomena can negatively impact the peptide drug's bioavailability, manufacturing, and injectability. This study investigated the self-assembly behavior of Lanreotide acetate at high concentrations in water using Hydroxypropyl β- Cyclodextrins (HPβCyD) to mitigate the self-assembly and enhance release rate during subcutaneous administration. Our finding demonstrated that the lanreotide/ HPβCyD inclusion complex effectively prevents aromatic-aromatic interactions of lanreotide, thereby controlling self-assembly. This complexation also alters the viscosity behavior of lanreotide from non-Newtonian under low shear rates to Newtonian solution. Furthermore, the lanreotide/ HPβCyD inclusion complex reduces interactions with hyaluronic acid in the subcutaneous environment, leading to significant improvement in the release rate of lanreotide acetate at high concentrations (above 3 % w/w in water).</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1068-1076"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Why a complementary analytical toolbox is essential for correct siRNA duplex content determination 为什么一个互补的分析工具箱是必要的正确的siRNA双工含量测定。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.12.009

Laure-Elie Carloni, Tiny Deschrijver, Kirsten Ryvers, Bart Noten, Lukas M. Stratmann, Thomas De Vijlder

{"title":"Why a complementary analytical toolbox is essential for correct siRNA duplex content determination","authors":"Laure-Elie Carloni, Tiny Deschrijver, Kirsten Ryvers, Bart Noten, Lukas M. Stratmann, Thomas De Vijlder","doi":"10.1016/j.xphs.2024.12.009","DOIUrl":"10.1016/j.xphs.2024.12.009","url":null,"abstract":"<div><div>Small interfering RNAs (siRNAs) have emerged as a highly promising class of therapeutics, capable of effectively treating a wide range of indications, including previously challenging targets. To correctly characterize the duplex content of siRNA therapeutics, a careful design of the analytical conditions is required. This is due to the weak interactions governing the duplex formation and thermal stability of these double-stranded oligonucleotides. In this study, we demonstrate that the reliability of duplex content analyses can be compromised by denaturation or hybridization artifacts caused by environmental factors related with sample preparation or with the ‘non-denaturing’ chromatographic analysis method. To address this issue, we propose to characterize the siRNA duplex in various analytical media with unbiased techniques such as circular dichroism spectrophotometry and use the results to evaluate potential artifacts in the ‘non-denaturing’ method, developed to determine the duplex content. Through this approach, one can optimize the sample preparation and develop ‘non-denaturing’ method conditions to minimize the influence of environmental factors on the duplex content, and thereby determine the assay of siRNA duplex with no bias.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1359-1367"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kinetics of human insulin degradation in the solid-state: An investigation of the effects of temperature and humidity 人胰岛素固态降解动力学：温度和湿度影响的研究。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.11.032

Andrew Fagan , Lorraine M. Bateman , Joseph P. O'Shea , Abina M. Crean

{"title":"Kinetics of human insulin degradation in the solid-state: An investigation of the effects of temperature and humidity","authors":"Andrew Fagan , Lorraine M. Bateman , Joseph P. O'Shea , Abina M. Crean","doi":"10.1016/j.xphs.2024.11.032","DOIUrl":"10.1016/j.xphs.2024.11.032","url":null,"abstract":"<div><div>With the increasing development of oral peptide dosage forms, a comprehensive understanding of factors affecting peptide drug stability in the solid-state is critical. This study used human insulin, as a model peptide, to examine the individual and interactive effects of temperature and humidity on its solid-state stability. Insulin was stored at temperature (25 °C, 40 °C, and 6 °C) and humidity (1 %, 33 % and 75 %) over 6 months. Primary degradation pathways were deamidation and covalent aggregation. Degradation product formation rates were determined empirically and modelled using the humidity-corrected Arrhenius equation. Temperature had a major impact on deamidation and covalent aggregation rates, with the reaction rates increasing with temperature. The effect of humidity was temperature dependent. Moisture induced degradation was minimal at 25 °C and 40 °C, but an important factor at 60 °C. Dynamic vapour sorption analysed determined a clear differences in insulin moisture sorption characteristics at 60 °C relative to 25 °C and 40 °C. The findings suggest that the effect of moisture on insulin deamidation and covalent aggregation rates was not a function of water content but the nature of the insulin moisture interaction.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1368-1375"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A cross-species assessment of in silico prediction methods of steady-state volume of distribution using Simcyp simulators 利用Simcyp模拟器对稳态分布体积的计算机预测方法进行跨物种评估。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.12.018

Miaoran Ning , Ma Fang , Kushal Shah , Vaishali Dixit , Devendra Pade , Helen Musther , Sibylle Neuhoff

{"title":"A cross-species assessment of in silico prediction methods of steady-state volume of distribution using Simcyp simulators","authors":"Miaoran Ning , Ma Fang , Kushal Shah , Vaishali Dixit , Devendra Pade , Helen Musther , Sibylle Neuhoff","doi":"10.1016/j.xphs.2024.12.018","DOIUrl":"10.1016/j.xphs.2024.12.018","url":null,"abstract":"<div><div>Predicting steady-state volume of distribution (V<sub>ss</sub>) is a key component of pharmacokinetic predictions and often guided using preclinical data. However, when bottom-up prediction from physiologically-based pharmacokinetic (PBPK) models and observed V<sub>ss</sub> misalign in preclinical species, or predicted V<sub>ss</sub> from different models varies significantly, no consensus exists for selecting models or preclinical species to improve the prediction. Through systematic analysis of V<sub>ss</sub> prediction across rat, dog, monkey, and human, using common methods, a practical strategy for predicting human V<sub>ss</sub>, with or without integration of preclinical PK information is warranted. In this analysis, we curated a dataset of 57 diverse compounds with measured physicochemical and protein binding data, together with observed V<sub>ss</sub> in these species. Using a bottom-up approach, prediction performance was consistent across species for each method. Although no method consistently outperformed others for all compound types and across species, M2 (Rodgers-Rowland method) performed marginally better for acids. Comparable compound-specific global tissue Kp scalars were needed to match observed V<sub>ss</sub> for both, human and preclinical species. Consequently, application of geometric mean values of preclinical Kp scalar to human V<sub>ss</sub> prediction improved accuracy. We propose a decision tree for human V<sub>ss</sub> prediction using PBPK methods with or without integrating preclinical PK information.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1410-1422"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of lacosamide-loaded in-situ gels through experimental design for evaluation of ocular irritation in vitro and in vivo 通过实验设计开发lacosamide负载原位凝胶用于体外和体内眼部刺激评价。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.11.027

Özlem Çoban , Sıla Gülbağ Pınar , Heybet Kerem Polat , Gülşah Gedik , Nasıf Fatih Karakuyu , Esra Pezik , Sedat Ünal , Behzad Mokhtare , Aleyna Akşit

{"title":"Development of lacosamide-loaded in-situ gels through experimental design for evaluation of ocular irritation in vitro and in vivo","authors":"Özlem Çoban , Sıla Gülbağ Pınar , Heybet Kerem Polat , Gülşah Gedik , Nasıf Fatih Karakuyu , Esra Pezik , Sedat Ünal , Behzad Mokhtare , Aleyna Akşit","doi":"10.1016/j.xphs.2024.11.027","DOIUrl":"10.1016/j.xphs.2024.11.027","url":null,"abstract":"<div><div>Lacosamide (LCM) selectively increases the slow inactivation of voltage-gated sodium channels (VGSCs) and is a N-methyl <span>d</span>-aspartate acid (NMDA) receptor glycine site antagonist. Therefore, it can be used in dryness-related hyperexcitability of corneal cold receptor nerve terminals. Ocular <em>in-situ</em> gels remain in liquid form until they reach the target site, where they undergo a sol-gel transformation in response to specific stimuli. They can show mucoadhesive properties related to the polymer used and increase the residence time of the drug in the mucosa. In the presented study, ocular <em>in-situ</em> gel formulation of LCM, which has potential for use in ocular diseases and consists of hyaluronic acid and poloxamer 407 as polymers, was developed using cold method. The effect of formulation components on target product properties (pH, gelation temperature and viscosity) was evaluated by design of experiments (DoE) design. The optimized LCM-loaded <em>in-situ</em> gel had a pH value of 6.90 ± 0.01, showed pseudo-plastic flow with a viscosity of 562 ± 58 cP at 25 °C, gelled at 33 ± 0.47 °C, and released drugs via the Peppas-Sahlin mechanism. Ocular safety was confirmed via <em>in vitro</em> tests using two different cell lines (L929 and Arpe-19), along with <em>in vivo</em> Draize tests, histological examinations, and Hen's Egg Chario-Allontioc-Membrane (HET-CAM) analysis. <em>In vitro</em> studies confirmed the optimized LCM-loaded <em>in-situ</em> gel's suitability for ocular use, demonstrating long-acting effects through controlled release. In addition, ocular irritation and histological studies have supported that it will not show any toxic effect on the eye tissue.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1342-1350"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant 速释口服固体制剂的生物豁免专论：Lemborexant.

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.10.030

Kristian Beran , Bertil Abrahamsson , Naseem Charoo , Rodrigo Cristofoletti , René Holm , Atsushi Kambayashi , Peter Langguth , Mehul Mehta , Alan Parr , James E. Polli , Vinod P. Shah , Jennifer Dressman

{"title":"Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant","authors":"Kristian Beran , Bertil Abrahamsson , Naseem Charoo , Rodrigo Cristofoletti , René Holm , Atsushi Kambayashi , Peter Langguth , Mehul Mehta , Alan Parr , James E. Polli , Vinod P. Shah , Jennifer Dressman","doi":"10.1016/j.xphs.2024.10.030","DOIUrl":"10.1016/j.xphs.2024.10.030","url":null,"abstract":"<div><div>Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their <em>in vitro</em> dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 644-659"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of the correlation between nuclear localization levels and genome editing efficiencies of Cas12a fused with nuclear localization signals 评估与核定位信号融合的 Cas12a 的核定位水平与基因组编辑效率之间的相关性。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2025-02-01 DOI: 10.1016/j.xphs.2024.10.029

Tomohito Tsukamoto , Haruna Mizuta , Eiko Sakai , Fuminori Sakurai , Hiroyuki Mizuguchi

{"title":"Evaluation of the correlation between nuclear localization levels and genome editing efficiencies of Cas12a fused with nuclear localization signals","authors":"Tomohito Tsukamoto , Haruna Mizuta , Eiko Sakai , Fuminori Sakurai , Hiroyuki Mizuguchi","doi":"10.1016/j.xphs.2024.10.029","DOIUrl":"10.1016/j.xphs.2024.10.029","url":null,"abstract":"<div><div>Genome editing technology using the CRISPR-Cas system is attracting much attention not only as a promising experimental tool for analysis of genome functions, but also as a novel therapeutic approach for genetic disorders. Among the various types of Cas proteins, Cas12a is expected to be a promising gene editing tool due to its unique properties, including low off-target effects. As Cas proteins are of prokaryotic origin, they need to be fused with appropriate localization signals to perform their function in eukaryotic cells. Cas12a proteins fused with a nuclear localization signal (NLS) have been developed so far, but the relation between the nuclear localization activity and the genome editing efficiency has not been fully elucidated. Here, utilizing two Cas12a orthologs, AsCas12a and LbCas12a, with various number of NLSs derived from various origins, we revealed that the improved nuclear localization resulted in increased genome editing efficiencies when expressed using adenovirus (Ad) vector in cultured cells. However, when they were expressed in mouse liver, the improvement of the nuclear localization activity was not necessarily required to achieve the maximum genome editing efficiency four weeks after Ad vector administration. These data indicated that the optimized NLS modification of Cas12a proteins <em>in vitro</em> situations differed from that <em>in vivo</em>.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 841-848"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0