心脏再生, 3D类脑器官, 器官芯片, 疾病模型, 细胞与基因治疗 | 全球再生医学研发创新与类器官研究峰会 2024 重磅更新

Abstract: 

Brain organoids are 3D tissue cultures that resemble cell type diversity, tissue architecture and developmental trajectory of the native human brain tissues. Rapid advances in the stem cell technologies have led to human pluripotent stem cell-derived brain organoids that mimic the development and properties of different regions of the developing human brain. In parallel, brain organoids have been generated from patient surgical tissues, such as glioblastoma, that can maintain inter- and intra-tumor heterogeneity as well as the tumor microenvironment. I will review recent development of brain organoid technologies and provide examples for therapeutic applications of these human stem cell-derived brain organoids, such as applications during the past two global pandemics (Zika virus and SARS-Cov2). I will also discuss technologies of tumor organoids and their applications in the personized medicine. Finally, I will discuss challenges ahead.   

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Organs-on-chip technology are ideally suited for the development of assays for disease modeling and drug testing, because they can recapitulate many key aspects of the human tissue microenvironment and can be used to simulate high-level tissue and organ-level physiology. In this talk, I will present the properties and functions of human organs on chips and microphysiological system we developed for the purpose of tissue engineering, disease modeling and drug testing. The design processes with attention of the particular device, cell types and materials used are also presented. This technology has great value to advance the understanding of organ physiology/pathology, drug metabolism and disease etiology in a physiologically relevant manner, providing a unique platform for drug development , advanced therapy and precision medicine. 

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Critical limb ischemia (CLI) is a severe obstruction of the arteries which markedly reduces blood flow to the limbs and has progressed to the point of severe pain, ulcer and even amputation. Therapeutic angiogenesis using implanted vascular cells has been widely investigated to treat the CLI, however, the therapeutic outcome is quite mixed. Since the vasculogenesis potential and paracrine effect of the transplanted vascular cells are the two major driving forces for enhancing the local neovascularization, we hypothesized that stem cell derived vascular organoids (VO) could be the ideal cell sources.

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Attrition in the therapeutic pipeline can often be attributed to a lack of translational efficacy from the pre-clinical phase to the clinic. Organoids show great promise as a game-changer in disease modeling and drug screening. However, challenges such as assay complexity, reproducibility, high throughput screening and the ability to scale up have limited their widespread adoption in drug discovery. To alleviate the bottlenecks, we developed the CellXpress.ai Automated Cell Culture System. This revolutionary solution automates the entire organoid culture process with machine learning-assisted monitoring, feeding, imaging, and scheduling. Combination of processes automation, machine learning decision-making and high content imaging has incredible potential to bring 3D biology to next level, allowing for increased throughput and reproducibility.

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礼升生物  创始人

北京大学生命科学华东院

礼升器官再生X实验室

Abstract: 

We have established a unique organoid system rich in autologous blood vessels and immune microenvironment. Organoids, innovative three-dimensional in vitro models, have rapidly gained attention in the scientific community for their transformative potential in medical research. Single cell sequencing and organoid drug sensitivity screening from tumor patients provide essential information to guide clinical decisions and personalized medicine. We successfully established around 200 organoid samples from 5 different types of tumors, such as ICC (intrahepatic cholangiocarcinoma) Organoids, Colorectal cancer organoid, Ovarian cancer organoid, Glioma organoid and Skin cancer organoids. Single cell RNA-sequencing analysis confirmed that our unique organoids system maintained the tumor immune microenvironment from individual tumor patients. We also proved the consistency between the tumor tissue and our organoids. After that, we used this system to performed the drug sensitivity screening. Significant heterogeneity was noticed among tumor patients. The analysis of association between individual differences and organoid single cell portions provided potential explanation of drug mechanism. Single cell assisted analysis of tumor organ cell populations, construction of self-assembled tumor organs with immune microenvironment provided precise treatment strategies and drug response mechanisms for individual tumor patients.

Abstract: 

Organoids and organ-on-a-chips have broad application prospects in the fields of new drug research and development, disease model, personalized medicine and manned aerospace medicine. We have constructed a series of multi-organ on a chip that simulating the microphysiological structure of vascularized organs, such as splenic blood sinus, microvascular tumor and blood-retinal-barrier, ect.. We also constructed three-dimensional (3D) vascularized brain organoids and fused organoids using induced pluripotent stem cells and reproduced powerful physiological and functional coupling between nerves and target tissues (blood vessels, muscles and myocardium) or target organs that combined with optogenetics. We are aiming at the problem of organ scaling, innervation and sensor integration by integrating the multiple laminar- flow microfluidic method, 3D bioprinting, structural color material barcode sensing, the fabricated organ-on-a-chips are used to construct in vitro models of neurovascular units, neuromuscular junctions and neuromyocardial junctions, and intergreted with sensors, electrophysiological stimulation and on-line monitoring for high-throughput drug screening application.

Horst Ruppach

Abstract: 

Cell and Gene Therapy (CGT) products comprises diverse product modalities like viral vectors, oncolytic viruses, genetically modified cell therapy products of different origins (donor PPMCs, stem cells, iPSCs), etc.. The viral risk profile of these types of products can be much different but is frequently higher compared to standard Biologics like CHO derived recombinants (e. g monoclonal antibodies). The presentation will give an overview on the different risk profiles, the tools to mitigate the risk and how Next Generation Sequencing (NGS) technology will impact future testing strategies. The importance of this technology for viral safety testing and the regulatory acceptance will be discussed.

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CD99 CAR-T cell therapy treats sarcoma, T cell leukemia/lymphoma, and acute myeloid leukemia, which constitutively overexpress membrane protein CD99. A pilot IIT study showed CR in 4 patients with sarcoma, CR in 3 AML and PR in 1 AML, and CR in 3 T-ALL and PR in 1 T-ALL. Moreover, none CRS/ICNAS/CRES over grade 3 was observed. The promising safety and efficacy of CD99 CAR-T cell therapy promote its an ideal treatment, and currently undergo Investigational New Drug (IND) application.

Abstract: 

Cell and gene therapies are undeniably one of game-changing medical innovations of this century with the potential to provide effective cures in a variety of disease previously thought to be incurable or untreatable. However, it is increasing clearly that the high cost and potential safety issues prevent its further widely application and full potential. Efficacious, safe yet affordable therapy is key to the future of sustainable gene and cell therapy. To achieve these goals, innovative technologies have to be developed to solve the underneath fundamental challenges on the way. Here I will review two such innovative technologies 1) targeted insertion of large gene fragment into genome; 2) non-viral gene delivery for in vivo therapy. These two technologies are important for achieving 1) safer GCT therapies; 2) complex cell engineering with multiple components for better efficacy; 3) replacement of large-sized genes which cannot be delivered with conventional vehicles; 4) affordable CGT. Lastly, I will present our proprietary nonviral -based genetic engineering and polymer-based gene delivery technologies for treatment of rare genetic disease and cancer cell therapy. We apply our technology platforms to Recessive Dystrophic Epidermolysis Bullosa (RDEB), a rare genetic disorder of which an 8.9Kb gene is malfunctional with limited therapeutic options.  Our nonviral-based genetic engineering also enables multiplexed-engineering of NK cells to enable the potential best-in-class immuno-cell therapy.

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Fabry disease is an X-linked lysosomal storage disease due to a deficiency of α-galactosidase A (α-Gla A) with the prevalence around 1 in 40,000.There are two clinical subtypes of Fabry disease, classic (type I) and late-onset (type II), depending on the amount of enzyme function patients have lost. A typical characteristics of this disease is the progressive and systemic accumulation of sphingolipids such as globotriaosylceramide (Gb3) and its derivative, globotriaosylsphingosine (lyso-Gb3), in the lysosomes of vascular endothelial cells. The standard treatment for the patients is enzyme replacement therapy which is a lifelong burden and a considerable proportion of type I males eventually produce neutralizing antibodies. The overexpression of α-Gla A in the liver by rAAV gene therapy is believed to be a more lasting and effective treatment. So, we proposed that the use an α-Gla A gene with enhanced secretion capacity compared the wild type could have better treatment efficiency. To achieve this goal, the signal peptide of α-Gla was replaced by 22 heterogenous ones and the constructed plasmids were transfected in HepG2 cells individually. The supernatants were collected and used for ELISA and enzymatic assay. By such a screening, four signal peptides were found to have 1.5-3 folds higher expression levels and enzyme activities than the wild type. The best one sp21 were further evaluated in vivo using Fabry mice. A codon optimized α-Gla A with sp21 under the control of a novel liver specific promoter were packaged in a self-complementary rAAV vector with the serotype AAV8. Two doses of vectors, 2x1012 and 5x1012 vg/kg, were administrated by tail vein injection. α-Gla A activity levels measured in plasma sampled at 0, 2, 4, 6, and 8 weeks. Expression levels were stable since week 2 and could be up to 1678 nmol/h/mL. The mice were sacrificed at 6 or 14 week to quantify lyso-Gb3 level in plasma by LC-MS/MS. It was showed that the lyso-Gb3 was largely cleared in the plasma and the amounts were less than 1%. It was also evidenced by IHC that the expressing levels of α-Gla A in the liver, heart, spleen, and kidney at week 14 were significantly higher than the negative control.