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The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes

In this article, Merienne et al. designed a smart lentiviral vector system to improve the safety for genome editing of CNS disease gene. They characterized their CRISPR self-inactivating system (KamiCas9) for permanent disruption of huntingtin gene in the context of Huntington’s disease (HD).

The potency of LV-KamiCas9 was demonstrated in mouse primary neuronal/glial cultures, in the striatum of mice, and in patient-specific iPSC neuronal derivatives. They showed that the kinetics of Cas9 expression shortly followed by self-inactivation provided high on-target editing while progressively inactivating the nuclease, therefore preventing further on- and off-target activities.

R&D GEG Tech team works for providing high performance lentiviral vector systems with smart designs for CRISPR:  inducible systems, self-inactivating systems, non-integrating LVs, RNA LVs (LV which remains in RNA form), multiple gRNAs expression, specific pseudotypes etc…

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Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. In a first study, the authors developed a lentiviral vector (LV) expressing a shRNA to downregulated HTT and observed a reduction of pathology in an HD rodent model.

In this new study, they modified the design of the LV for preclinical development by using a tat independent third-generation LV (pCCL) backbone and removing the original reporter genes. They tested the efficiency of their new LV shHTT6 in vitrowith Striatal Neurons Derived from HD-iPSCs and in vivo by LV injection in the striatum of adult mice. They also investigated several parameters concerning the biosafety:

  • Inappropriate synthesis and processing of the shRNA
  • Preferential incorporation of the passenger versus guide strand in the RNA-induced silencing complex (RISC)
  • Off-target effects caused by partial homology of the guide RNA with other transcripts or pairing between the hexamer seed region and the 30 UTR of transcripts (miRNA-like effects)
  • Saturation of the endogenous cellular machinery
  • Inflammatory/immune responses

Their results demonstrated the reduction of two major pathological hallmarks for HD, a minimal inflammatory response in the brain, proper cellular processing of the shRNA, and a highly favorable on/off-target profile.

These preclinical data suggest that this new shRNA vector fulfills primary biosafety and efficiency requirements for further development in the clinic as a cure for HD.

GEG Tech provides a large range of fully customizable LV to express your favorite transgenes, including for shRNA.  By the way, GEG Tech is born in a laboratory of neurology, the first laboratory which done gene transfers in the brain. Consequently, GEG has a high expertise in the design of gene transfer tools in this field and offers solutions allowing to have specific and/or inducible expression in astrocytes, microglia cells, neurons and in some cases in some subpopulations of neurons.

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To know more about shRNA LV

The CRISPR/Cas9 systems have revolutionized the field of genome editing by providing unprecedented control over gene sequences and gene expression in many species, including humans. Lentiviral vectors (LVs) are an important means of delivering CRISPR/Cas9 components due to their ability to accommodate large DNA payloads and efficiently transduce a wide range of dividing and non-dividing cells.

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The scientific team of GEG Tech is proud to be a part of it, designing advanced vectorization systems required by this promising research.

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Lentiviral vectors have evolved over the last decade as powerful and reliable gene transfer tools for dividing and non-dividing cells because they possess a large packaging capacity, weak immunogenesis, and a high flexible of design. However, in some cases, the integrating feature of lentiviral vectors may cause unbalanced gene expression, gene silencing and insertional mutagenesis. The sMARt design of non-integrating lentiviral vectors (NILV) can avoid these problems because they do not integrate into the cell genome.

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Over the last years, new genetic engineering technologies have emerged and undoubtedly show up game-changing. Genome engineering is since a long time explored and used because there is a lot at stake here in many fields

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A significant recent advance in genome engineering is the development of the CRISPR/Cas9 system for nuclease based genome editing. However, several cell types are not easily transfected and in vivo delivery of the CRISPR system remains challenging.

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Recombinant proteins of therapeutic use are ideally produced in human cells to ensure appropriate co- and post-translational modifications. 

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If you have been living in a cave (without a connection to Labiotech.eu) during the last few months, you may not know what a CAR-T therapy is. Let me explain!

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Lentiviral vectors are commonly pseudotyped with the heterologous envelope VSV-G due to its broad host tropism and stability conferred.

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