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BIOPHARMANALYSES
Trend Chart oN
GENE EDITING

BioPharmAnalyses is happy to announce
 the release of the first issue of its
 “BRIEFING ON CART-T CELLS TRIALS”
NEW: "BRIEFING ON CART-T CELLS TRIALS”

 This publication provides you with an accurate overview to explore the latest trials in this hot and rapidly evolging field.  

More than 20 diseases, mainly hematological cancers
and solid tumors...
 47 trials and 33 sponsors in Asia, Europa and USA...
  
 More than 12 antigens targeted by clinical trials registered
on Clinicaltrials.gov from 01/01/2017 to 01/10/2018...
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● To get an example of a technical datasheet 
●  To receive this report, fill in the subscription form
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contents
November 2018, 22nd

FEATURE STORY
●    CRISPR/Cas9 for cancer therapy: hopes and challenges 
GENE THERAPY  
● Gene correction of HBB mutations in CD34+ hematopoietic stem cells using Cas9 mRNA and ssODN donors 
● From molecules to medicines: the dawn of targeted therapies for genetic epilepsies 
● CRISPR-Cas biology and infectious diseases applications 
● Ribonucleoproteins mediated efficient in vivo gene editing in skin stem cells
MODELS
● Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line
DISRUPTIVE TECHNOLOGIES
●   In vivo cell type-specific CRISPR gene editing for sleep research 
● Orthogonal Cas9-Cas9 chimeras provide a versatile platform for genome editing 
MISCELLANEOUS
● Human germline editing: Insights to future clinical treatment of diseases
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FEATURE STORY
CRISPR/Cas9 for cancer therapy: hopes and challenges
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment. Moreover, CRISPR-Cas9 can be employed to rapidly engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Perhaps more importantly, the ability of CRISPR-Cas9 to accurately edit genes, not only in cell culture models and model organisms but also in humans, allows its use in therapeutic explorations.
The review appeared in November 12th online issue of Biomedicines  
Related Informations/Publications
*Nature . 2018 Nov 7. Predictable and precise template-free CRISPR editing of pathogenic variants. Shen MW et al. Massachusetts Institute of Technology, Cambridge, MA, USA
Link: Abstract 
*Genome Biol . 2018 Nov 6;19(1):185. CRISPR/Cas9 offers a new tool for studying the role of chromatin architecture in disease pathogenesis. Guo X & Dean A. National Institutes of Health, Bethesda, MD, 20892, USA
Link: Abstract - Full Text
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GENE THERAPY
Gene correction of HBB mutations in CD34+ hematopoietic stem cells using Cas9 mRNA and ssODN donors
β-Thalassemia is an inherited hematological disorder caused by mutations in the human hemoglobin beta (HBB) gene that reduce or abrogate β-globin expression. Although lentiviral-mediated expression of β-globin and autologous transplantation is a promising therapeutic approach, the risk of insertional mutagenesis or low transgene expression is apparent. However, targeted gene correction of HBB mutations with programmable nucleases such as CRISPR/Cas9, TALENs, and ZFNs with non-viral repair templates ensures a higher safety profile and endogenous expression control. The results exhibited that indel frequency of CRISPR/Cas9 was superior to TALENs and ZFNs.
The results appeared in November 14th online issue of Mol Cell Pediatr
Related Informations / Publications  
* Hum Gene Ther. 2018 Oct;29(10):1106-1113. Gene Therapy for Hemoglobinopathies. Cavazzana M & Mavilio F. IMAGINE Institute, Paris, France; and University of Modena and Reggio Emilia , Modena, Italy
Results / Comments : Gene-editing technology may provide a therapeutic alternative overcoming some of these limitations, though proving its safety and efficacy will most likely require extensive clinical investigation
Link: Abstract - Full Text  
* Blood Cells Mol Dis . 2018 May;70:87-101. Gene therapy and gene editing strategies for hemoglobinopathies. Lidonnici MR & Ferrari G. San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy
Results / Comments : This review discusses the current status of gene therapy for β-thalassemia and sickle cell disease with a perspective towards the improvements necessary in the context of clinical translation
Link: Abstract
From molecules to medicines: the dawn of targeted therapies for genetic epilepsies
Precision medicine is the treatment of patients with therapy targeted to their specific pathophysiology. This lofty ideal currently has limited application in clinical practice. However, new technological advances in epilepsy models and genomics suggest that the precision medicine revolution is closer than ever before. We are gaining an improved understanding of the true complexity underlying the pathophysiology of genetic epilepsies and the sources of phenotypic variation that continue to frustrate efforts at genotype-phenotype correlation. Conventional experimental models of epilepsy, such as mouse models and heterologous expression systems, have provided many of the advances in our understanding of genetic epilepsies, but fail to account for some of these complexities. Novel high-throughput models of epilepsy such as zebrafish and induced pluripotent stems cells can be combined with CRISPR-Cas9 gene editing techniques to explore the pathogenesis of a specific gene change and rapidly screen drug libraries for potential therapeutics. The knowledge gained from these models must be combined with thorough natural history studies to determine appropriate patient populations for pragmatic clinical trials.
The review appeared in November 17th online issue of Nat Rev Neurol
Related Informations / Publications
* Hum Mol Genet . 2018 Oct 16. CRISPR/Cas9-mediated disruption of SHANK3 in monkey leads to drug-treatable autism-like symptoms. Tu Z et al. Jinan University, Guangzhou, 510632, China
Link: Abstract
*Front Mol Neurosci . 2018 Aug 29;11:294. Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future. Sakai C et al. Yale University, New Haven, CT, United States
Results / Comments : This review article focuses on studies that have harnessed these advantages of the zebrafish system for the functional analysis of genes that are strongly associated with the following neurodevelopmental disorders: autism spectrum disorders (ASD), epilepsy, intellectual disability (ID) and schizophrenia
Link: Abstract 
CRISPR-Cas biology and infectious diseases applications
Infectious diseases remain a global threat contributing to excess morbidity and mortality annually with persistent potential for destabilizing pandemics. Improved understanding of the pathogenesis of bacteria, viruses, fungi, and parasites, along with rapid diagnosis and treatment of human infections are essential to improving infectious diseases outcomes worldwide. Genomic loci in bacteria and archea, termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) proteins, function as an adaptive immune system for prokaryotes protecting against foreign invaders. CRISPR-Cas9 is now routinely applied for efficient gene editing contributing to advances in biomedical science. In the past decade improved understanding of other diverse CRISPR-Cas systems has expanded CRISPR applications, including in the field of infectious diseases.
The review appeared in November 14th online issue of J Clin Microbiol  
Related Informations / Publications
* PLoS One . 2018 Feb 15;13(2):e0192602. Multiplex CRISPR/Cas9 system impairs HCMV replication by excising an essential viral gene. Gergen J et al. INSERM, Université de Nantes, Nantes, France
Results /Comments : In conclusion, the multiplex anti-UL122/123 CRISPR/Cas9 system can target the viral genome efficiently enough to significantly prevent viral replication
Link: Abstract - Full Text
* Rev Med Virol. 2018 Sep 27:e2009. Harnessing CRISPR/Cas 9 System for manipulation of DNA virus genome. Ebrahimi S et al. Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Results / Comments : The researchers here systematically review recent applications of the CRISPR/Cas9 system for manipulation of DNA virus genomics and discuss the therapeutic potential of the system to treat viral diseases
Link: Abstract 
Ribonucleoproteins mediated efficient in vivo gene editing in skin stem cells
The clustered regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system functions like an adaptive immune system in a variety of microbes and has recently been engineered as a powerful tool for manipulating genomic sequences in a huge variety of cell types. In mammals, CRISPR/Cas9 has the potential to bring curative therapies to patients with genetic diseases, although it remained unknown whether suitable in vivo methods for its use are feasible. It is now appreciated that the efficient delivery of these genome-editing tools into most tissue types, including skin, remains a major challenge. Chinese researchers recentyl described a detailed protocol for performing in vivo gene editing of genomic sequences in mouse skin stem cells using Cas9/sgRNAs ribonucleoproteins in combination with electrotransfer technology. They present all of the required methods needed for the protocol, including molecular cloning, in vitro sgRNA expression and sgRNA purification, Cas9 protein purification, and in vivo delivery of cas9 ribonucleoproteins.
The results appeared in November 14th online issue of Methods Mol Biol   
Related Informations / Publications
 * Mol Ther Nucleic Acids . 2018 Sep 7;12:554-567. Ex Vivo COL7A1 Correction for Recessive Dystrophic Epidermolysis Bullosa Using CRISPR/Cas9 and Homology-Directed Repair. Izmiryan A et al. Imagine Institute, 24 bd du Montparnasse, Paris, France
Results / Comments: The study provides evidence that precise genome editing in primary RDEB cells is a relevant strategy to genetically correct COL7A1 mutations for the development of future ex vivo clinical applications
Link: Abstract -  Full Text  
*Mol Ther. 2018 Nov 7;26(11):2592-2603. CRISPR/Cas9-Mediated In Situ Correction of LAMB3 Gene in Keratinocytes Derived from a Junctional Epidermolysis Bullosa Patient. Benati et al. University of Modena and Reggio Emilia, Modena, Italy
Results / Comments: This study provides evidence for efficient CRISPR/Cas9-mediated in situ restoration of LAMB3 expression, paving the way for ex vivo clinical application of this strategy to laminin 332 deficiency
Link: Abstract
* Methods Mol Biol. 2018; 1828:31-55. An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Rodrigues M & Yokota T. University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada
Link : Abstract 
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MODELS
Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line
Malignant pleural mesothelioma (MPM), a highly refractory tumor, is currently incurable due to the lack of an early diagnosis method and medication, both of which are urgently needed to improve the survival and/or quality of life of patients. NF2 is a tumor suppressor gene and is frequently mutated in MPM. Using a CRISPR/Cas9 system, Japanese researchers have recently generated an NF2-knockout human mesothelial cell line, MeT-5A (NF2-KO). In NF2-KO cell clones, cell growth, clonogenic activity, migration activity, and invasion activity significantly increased compared with those in NF2-WT cell clones. cDNA microarray analysis clearly revealed the differences in global gene expression profile between NF2-WT and NF2-KO cell clones. Quantitative PCR analysis and western blot analysis showed that the upregulation of FGFR2 was concomitant with the increases in phosphorylation levels of JNK, c-Jun, and Rb in NF2-KO cell clones. These increases were all abrogated by the exogenous expression of NF2 in the NF2-KO clone.
The results appeared in November 12th online issue of Cancer Sci ( Abstrac t - Full Text )
Related Informations / Publications
* F1000Res . 2018 Oct 22;7. pii: F1000 Faculty Rev-1681. Multimodality treatment of malignant pleural mesothelioma. Berzenji L & Van Schil P. Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem (Antwerp), Belgium
Link : Abstract -  Full Text 
* Front Oncol . 2018 Oct 10;8:429. Next-Generation in vivo Modeling of Human Cancers. Gargiulo G. Max Delbrück Center for Molecular Medicine, Berlin, Germany
Results / Comments : The review highlights the use of glioma models in dissecting mechanisms of tumor initiation, in the retrospective identification of tumor cell-of-origin, in understanding tumor heterogeneity and in testing the potential of immuno-oncology.
Link : Abstract - Full Text  
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DISRUPTIVE TECHNOLOGIES
In vivo cell type-specific CRISPR gene editing for sleep research
Sleep is an innate behavior conserved in all animals and, in vertebrates, is regulated by neuronal circuits in the brain. The conventional techniques of forward and reverse genetics have enabled researchers to investigate the molecular mechanisms that regulate sleep and arousal. However, functional interrogation of genes in specific cell subtypes in the brain remains a challenge. American researchers recently reviewed the background of newly developed gene-editing technologies using engineered CRISPR/Cas9 system and describe the application to interrogate gene functions within genetically-defined brain cell populations in sleep research.
The review appeared in November 15th online issue of J Neurosci Methods 
Related Informations / Publications
* Cell Rep . 2018 Jun 26;23(13):3776-3786. MicroRNAs Regulate Sleep and Sleep Homeostasis in Drosophila. Goodwin PR et al. Brandeis University, Waltham, MA 02454-9110, USA.
Results / Comments : This screen sets the stage for understanding the role of miRNAs in sleep
Link: Abstract
* J Med Genet . 2018 Mar;55(3):143-149. Gene editing as a promising approach for respiratory diseases. Bai Y et al. Xinxiang Medical University, Xinxiang, China
Link: Abstract  
Orthogonal Cas9-Cas9 chimeras provide a versatile platform for genome editing 
The development of robust, versatile and accurate toolsets is critical to facilitate therapeutic genome editing applications. Researchers have established RNA-programmable Cas9-Cas9 chimeras, in single- and dual-nuclease formats, as versatile genome engineering systems. In both of these formats, Cas9-Cas9 fusions display an expanded targeting repertoire and achieve highly specific genome editing. Dual-nuclease Cas9-Cas9 chimeras have distinct advantages over monomeric Cas9s including higher target site activity and the generation of predictable precise deletion products between their target sites. At a therapeutically relevant site within the BCL11A erythroid enhancer, Cas9-Cas9 nucleases produced precise deletions that comprised up to 97% of all sequence alterations.
The review appeared in November 19th online issue of Nat Comm   
Related Informations / Publications
* Nat Chem Biol. 2018 Mar;14(3):311-316. Partial DNA-guided Cas9 enables genome editing with reduced off-target activity. Yin H et al. Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Results / Comments : Cas9 guided by a DNA-RNA chimera may provide a generalized strategy to reduce both the cost and the off-target genome editing in human cells
Link : Abstract -  Full Text  
* Nucleic Acids Res . 2017 Aug 21;45(14):8411-8422. Comparative analysis of chimeric ZFP-, TALE- and Cas9-piggyBac transposases for integration into a single locus in human cells. Luo W et al. Vanderbilt University Medical Center, Nashville, TN 37232, USA
Link : Abstract - Full Text 
* Mol Ther Nucleic Acids . 2018 Sep 13;13:256-274. Transient Retrovirus-Based CRISPR/Cas9 All-in-One Particles for Efficient, Targeted Gene Knockout. Knopp Y et al. Hannover Medical School, Hannover 30625, Germany
Link : Abstract  
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miscellaneous
Human germline editing: Insights to future clinical treatment of diseases
Last year, the first attempt to genetically modify human embryos in the United States was reported and sparked a huge debate. Although the first human germline modification was only performed two years ago, the study showed that rapid advances in technology has allowed the rate of off-target effects and mosaicism to be reduced considerably. Recently, Vertex  and CRISPR Therapeutics collaborated and developed CTX001, the first CRISPR/Cas9-based therapy, targeting patients with β-thalassemia  and have begun phase 1/2 clinical trials. With policies and technologies regarding genome editing both developing rapidly, explorations into the possibility of clinical gene editing for hundreds of hereditary diseases are starting to become achievable.
The analysis appeared in November 14th online issue of Protein Cell 
Related Informations / Publications
* iScience . 2018 Nov 2;9:286-297. Intra-embryo Gene Cassette Knockin by CRISPR/Cas9-Mediated Genome Editing with Adeno-Associated Viral Vector. Mizuno N et al. University of Tokyo, Minato-ku, Tokyo 1088639, Japan
Link: Abstract 
* Sci Eng Ethics . 2018 Oct 24. Will CRISPR Germline Engineering Close the Door to an Open Future? Mintz RL et al. Columbia University, 500 West 120th Street, New York, NY, 10027, USA
Results / Comments : Germline engineering in many instances is objectionable considering Feinberg's open future theory
Link: Abstract
*OCT 2018 : CRISPR Therapeutics and Vertex Announce FDA Has Lifted the Clinical Hold on the Investigational New Drug Application for CTX001 for the Treatment of Sickle Cell Disease
Link: Press Release 
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CHALLENGE US

I nnovative Biotherapies, Artificial Intelligence,
 Cell and Gene Therapies, Microbiome, MicroRNA,
 Gene Editing, Orphan Drugs, Orphan Diseases,
 Emerging diseases, Synthetic Biology.... and Whatever...

WE'LL BUILD FOR YOU TOOLS TAILORED
TO YOUR NEEDS.

Don't hesitate to get in touch with us
 Anne-Lise Berthier
(alb@biopharmanalyses.fr - 33(0)686 683 220)
 http://biopharmanalyses.fr
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