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About Gempharmatech About GemPharmatech GemPharmatech Co., LTD. is a high-tech biotechnology enterprise specialized in the development of humanized mouse model and drug screening technology. "Innovation research institute of humanized model and drug screening technology " aimed at keeping establishing novel humanized animal models for medical research and drug development, improving the success rate of the drug screening for biological medicine industry and providing strong support and guarantee. GemPharmatech is one of the first entities entitled “novel research and development institution” in Nanjing. GemPharmatech has developed a series of severe immune deficiency mouse strains with intellectual property rights, a full set of single and double target immune checkpoint humanized mouse on both C57BL/6 and BALB/c backgrounds. With support of Jiangsu provincial institute of industry & technology and Jiangbei new area, based on the original resources and technologies of Nanjing university-Nanjing biomedical research institute, GemPharmatech will keep moving on with professional teams and human-oriented animal model innovation technology. Three core technology platforms: ·Platform of generating humanized animal models; ·Drug screening service platform based on humanized animal models ·R&D platform of humanized antibody derived drugs. History National Resource AAALAC international certification Center for Mutant Mice Nanjing Biomedical Research Institute of Nanjing University IMPC Model Animal Establish Cas9 technology GemPharmatech Asian Mouse Mutagenesis National Laboratory Animal International Mouse Research Center platform Co.,Ltd Resource Association Center Phenotyping Consortium 2002 2006 2010 2011 2013 2017 Resource Technology Scale World Fourth of Mouse Disease Model World Third of Mouse Model Innovation 80000 IVC cages in 10000 m2 SPF Resources capability facility Unique member in China of International The world’s leading CRISPR/Cas9 >600 new strains developed per year Mouse Phenotyping Consortium (IMPC) technology platform China’s largest lab mouse supplier Qualification First and four consecutive times Export Animal Enterprise Laboratory animal production accredited by AAALAC in China Registration certificate and use certificate The only national genetic engineering mouse center certificated by National Ministry of Science and Technology Utility Model Patents Approval by ICLAS Quality With the strict quality control of veterinarians, GemPharmatech provides high-quality laboratory Control animals in line with international standards. The health check passes 41 items (containing 33 national standard items) including pathology, microbiology, parasitology, etc. Genetic To prevent genetic contamination, genetic drift or genetic mutations, GemPharmatech uses SNP Control (Single Nucleotide Polymorphism) method to conduct genetic monitoring annually for background of inbred and genetically engineered mice. Dalmatian Mouse Action Covering >20000 genes CKO/KO mice models resource center Dalmatian Mouse Action（DMA） Phase I ： Over 1200 CKO strains,only $9900/strain Over 1800 KO strains,only $4900/strain As fast as 90 days Hot gene spots selected covering research areas of tumor, metabolism,immune response, developmental biology, DNA and protein modification etc Rich selection 3000 Strains available ,more strains will Lower price be added in the future. CKO only $9900/strain,KO only $4900/strain Faster delivery More convinient Fastest delivery cycle is 90 days. All you have to do is online shopping. www.gempharmatech.com/en Emice: [email protected] - 2 - 2019 Resources and services Genetic engineering mouse service With experienced CRISPR / Cas9, ZFN and TALEN gene targeting technologies, GemPharmatech has constructed many knock-out / knock-in models, with a wide range of applications. GemPharmatech has currently accomplished over 1000 gene modified rat and mouse models via CRISPR/Cas9, and has the capability to generate over 1000 models annually. CRISPR/ Multiple Cas9 Targeting KO/CKO/KI H11/Rosa26 Locus Transgenic One-stop service KO first ES Cell KO/CKO/KI Experienced Promising service Efficient & stable project techniques management Professional R & D Advanced team equipments Resources and services 2019 - 3 - CRISPR/Cas9 technology The CRISPR/Cas9 system is a prokaryotic immune system that confers resistance to foreign genetic elements, such as plasmids and phages and provides a form of acquired immunity.The double strand complex, formed by crRNA and TracrRNA via base complementary, direct Cas9 protein to cleave target DNA sequences matching the crRNA. The HNH domain and RuvC-like domain of Cas9 protein will introduce DSB (Double strand break) at the target locus, DSB will be repaired by NHEJ(Non- homologous end joining) and random bases will be inserted or deleted. Frame- shift caused by the In-del mutation can destroy the target gene product. China’s first single/ multiple gene Cas9 KO mouse [1] [2] [3] [4] [5] China’s first Cas9 CKO mouse China's first CKO rat model World’s first Cas9 KO dog World’s first Cas9 KO monkey Advantages Quality Cas9 KO projects with 100% success rate Guarantee Cas9 CKO/KI projects with 100% success rate Zero off- Independent modifications on Cas9 system [6] target ZERO off-target reported Longest flox region of 210 Kbp Flexible Largest deleted fragment of 23 Mbps Strategy 5 genes deleted simuntaneously Design Largest KI Fragment of 12 Kbps Multiple Background C57BL/6JGpt, C57BL/6NGpt, NOD/LTJ, BABL/CGpt, etc. Choices Price GemPharmatech TG/KO pricing Service Cost（USD） Turnaround Time （Months） CRISPR/Cas9 CKO & KI 17000 6-8 CRISPR/Cas9 point mutation 16000 6-8 Mouse Super-TG 14000 6-8 CRISPR/Cas9 KO 5500 5-6 Conventional ES targeting CKO/KI 27500 10-12 Transgenic 5000 3-4 Bac Transgenic 8000 3-5 Rat CRISPR/Cas9 KO 12000 6-8 - 4 - 2019 Resources and services CRISPR/Cas9 technology ■ Cas9 KO/CKO ▲CRISPR/Cas9 KO strategy diagram ▲CRISPR/Cas9 CKO strategy diagram ■ Cas9-KI/TM ▲ CRISPR/Cas9 KI strategy diagram ▲ CRISPR/Cas9 TM strategy diagram ■ Cas9-cTM ▲ CRISPR/Cas9 cTM strategy diagram Resources and services 2019 - 5 - ES technology ES targeting is a molecular biological technology based on homologous recombination of DNA and embryonic stem cell science. Homologous recombination takes place when exogeneous DNA fragment with high homology with host DNA sequence swaps with host DNA. Advantages Independent self-deletion Save 3 months at most technique Modified Bac Targeting system Accomplished 300 Kbp fragment KI Accomplished first CKO model of China in 2005 Professional teams >700 models successfully generated Multiple background choices 129S6/SvEvTac，C57BL/6N，C57BL/6J ■ KO ▲Knock out strategy diagram - 6 - 2019 Resources and services ES technology ■ CKO ▲CKO strategy diagram ■ KO first ▲KO first strategy diagram ■ KI ▲Knock in strategy diagram Resources and services 2019 - 7 - Transgenic technology Advantages High success rate, 100% BAC transgenic technology to generate models with >300 Kbp fragment inserted Multiple background available: C57BL/6JGpt, NOD/LTJ, FVB, BABL/CJ, C57BL/ 6NGpt, etc. TG： TG TG Vector Promoter Gene ORF pA Release for injection 转基因 ▲Schematic diagram of TG strategy ▲ H11/Rosa26 KI strategy diagram The comparison between transgenic and Super-TG (H11/Rosa26 site insertion): ■ Transgenic Technology: ■ H11/Rosa26 site insertion: Different expression levels Precise copy number Risk of random insertion Precise insertion site Expression not guaranteed Guaranteed expression Risk of affecting endogenous genes Avoid affecting endogenous genes Breeding/screening of lines needed Used directly Poor genetic stability High genetic stability Short Turnaround Time (<3 months) Long turnaround time (4-5 months) Reference: [1 ]Shen, B., et al. (2013). "Generation of gene-modified mice via Cas9/RNA-mediated gene targeting." Cell Res 23(5): 720-723. [2] Zhou, J., et al. (2014). "One-step generation of different immunodeficient mice with multiple gene modifications by CRISPR/Cas9 mediated genome engineering." Int J Biochem Cell Biol 46: 49-55. [3] Ma, Y., et al. (2014). "Generating rats with conditional alleles using CRISPR/Cas9." Cell Res 24(1): 122-125. [4] Zou, Q., et al. (2015). "Generation of gene-target dogs using CRISPR/Cas9 system." J Mol Cell Biol 7(6): 580-583. [5] Niu, Y., et al. (2014). "Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos." Cell 156(4): 836-843. [6] Shen, B., et al. (2014). "Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects." Nat Methods 11(4): 399-402. - 8 - 2019 Resources and services Other mouse models ■ Table 1. Cre lines Research area Strain number Strain name Application Broad spectrum expresssion emCin(CAG-Cre) Broad spectrum expression cre Cre T004055 B6-H11 /Gpt Nervous system expression em1Cin(Nes-Cre) Specific expression of the central and peripheral nervous system Cre T003763 B6-H11 /Gpt em1Cin(Tek-Cre) Endothelial cells expression Cre Endothelial expression Cre T003764 B6-H11 /Gpt em1Cin(icre) Hepatic specific expression Cre T003814 B6-Alb /Gpt em1Cin(cre/ERT2) Small intestine specific expression, homozygous death T003768 B6-Lgr5 /Gpt Others em1Cin(iCre) Myeloid cells expression Cre T003822 B6-Lyz2 /Gpt em1Cin(P2A-iCre) B cell specific expression Cre T003785 B6-Cd19 /Gpt ■ Table 2. Tool mice Research area Strain number Strain name Application FLPo recombinant enzyme whole-body expressed in high em1Cin(CAG-FLPo) expression strain FLP-FRT System T002183 B6-H11 /Gpt T003856 DBA/1-tdTomato/Gpt
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