Applications and developments of gene therapy drug delivery systems for genetic diseases

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.

Transcatheter closure for decompression sickness with a patent foramen ovale:A case report

A patent foramen ovale is one of the predisposing factors of neurotic decompression sickness.Transcatheter closure of a patent foramen ovale is effective in the secondary prevention of decompression sickness associated with intracardiac shunt.The size of the umbrella should not be limited to the diagnosis of a patent foramen ovale or an atrial septal defect but should be determined by the supporting force of the soft margin of the atrial septum.The surgical method of patent foramen ovale closure is the same as that of the closure of an atrial septal defect,but the closure umbrella of a patent foramen ovale is different from that of the closure umbrella of an atrial septal defect.The size of the umbrella of the right atrium is larger than that of the left atrium,and it is better to close the atrial septum.

Editing function of type Ⅱ thioesterases in the biosynthesis of fungal polyketides

Polyketide synthases(PKSs)are megasynthases with multiple autonomously folding domains,which operate cooperatively in the PKS assemblies to synthesize specific polyketide scaffolds.Any nonreactive intermediates tethered to acyl carrier protein(ACP)domain in the PKS will block the elongation process of polyketide chains.In this study,we systematically elucidate the editing function of fungal typeⅡthioesterases(TEIIs)to hydrolyze ACP domain-bounded nonreactive acyl groups,which are uploaded by substrate promiscuous fungal phosphopantetheinyl transferase.Thereof,the TEIIs encoded in gene clusters of nonreducing PKS with reductase domain exhibit universal editing function.Besides,editing function was also found for TEIIs encoded in gene clusters of highly-reducing PKS with condensation domain.Hence,the editing TEIIs with function of recovery PKS are applied to improve the yield of the fungal polyketides in vivo.Our study provides valuable insights into the editing process of fungal PKSs,highlights the crucial role of TEIIs in enhancing polyketide production and introduces a novel metabolic engineering strategy for fungal polyketide biosynthesis by leveraging the editing function of TEIIs.

植物来源药用天然产物的合成生物学研究进展

大多数药用天然产物在植物中含量低微,提取分离困难;而且这些化合物一般结构复杂,化学合成难度大,还容易造成环境污染。基于合成生物学技术获得药用天然产物具有绿色环保和可持续发展等优点。文中以药用萜类化合物人参皂苷、紫杉醇、青蒿素、丹参酮,生物碱类化合物长春新碱、吗啡以及黄酮类化合物灯盏花素为例,总结了植物来源药用萜类、生物碱类和黄酮类化合物的生物合成途径及合成生物学研究进展,介绍了药用天然产物合成生物学研究的关键技术与方法,并展望了合成生物学技术在药用天然产物研究与开发方面的应用前景。

Metabolic engineering of yeasts for green and sustainable production of bioactive ginsenosides F2 and 3β,20S-Di-O-Glc-DM

Both natural ginsenoside F2 and unnatural ginsenoside 3β,20S-Di-O-Glc-DM were reported to exhibit anti-tumor activity.Traditional approaches for producing them rely on direct extraction from Panax ginseng,enzymatic catalysis or chemical synthesis,all of which result in low yield and high cost.Metabolic engineering of microbes has been recognized as a green and sustainable biotechnology to produce natural and unnatural products.Hence we engineered the complete biosynthetic pathways of F2 and 3β,20S-Di-OGlc-DM in Saccharomyces cerevisiae via the CRISPR/Cas9 system.The titers of F2 and 3β,20S-Di-O-GlcDM were increased from 1.2 to 21.0 mg/L and from 82.0 to 346.1 mg/L at shake flask level,respectively,by multistep metabolic engineering strategies.Additionally,pharmacological evaluation showed that both F2and 3β,20S-Di-O-Glc-DM exhibited anti-pancreatic cancer activity and the activity of 3β,20S-Di-O-GlcDM was even better.Furthermore,the titer of 3β,20S-Di-O-Glc-DM reached 2.6 g/L by fed-batch fermentation in a 3 L bioreactor.To our knowledge,this is the first report on demonstrating the anti-pancreatic cancer activity of F2 and 3β,20S-Di-O-Glc-DM,and achieving their de novo biosynthesis by the engineered yeasts.Our work presents an alternative approach to produce F2 and 3β,20S-Di-O-Glc-DM from renewable biomass,which lays a foundation for drug research and development.