This technology is expected to fundamentally treat cancer

Introduction

It is well known that in vivo gene editing can treat diseases that were previously considered incurable, such as genetic diseases and cancer, through gene editing of target cells in vivo, knocking out disease-causing genes or inserting functional genes

Gene editing technology could fundamentally treat cancer

Gene editing technology is mostly used for gene function research and disease treatment.

Table 1 Comparison of three gene editing technologies

Data source: [1]Table: Bio-Exploration editorial team

The CRISPR/Cas system widely exists in the innate immune system of bacteria and most archaea , and is mainly composed of two parts: the gene encoding the Cas protein and the CRISPR sequence consisting of a leader sequence, discontinuous repeat sequences, and spacer sequences of similar length

• Class 1 system is a complex composed of a variety of different effector proteins, usually forming a multi-subunit protein crRNA (CRISPR RNA) effector complex, including three types I, III and IV and 12 subtypes;
• Type 2 systems only have a single effector protein (Cas9, Cas12, Cas13) to interfere with target genes, accounting for about 10% of CRISPR/Cas systems, including types II, V and VI and 9 subtypes, except for cutting DNA, type 2 systems Cas13a (C2c2) in ssRNA can be targeted to cleave ssRNA (Single-stranded Ribonucleic Acid)
  
  

  Figure 1 Classification of CRISPR/Cas systems (Source: [1])

  Figure 1 Classification of CRISPR/Cas systems (Source: [1])

  The mechanism of action of the CRISPR/Cas system is divided into three stages (Figure 2):

  The mechanism of action of the CRISPR/Cas system is divided into three stages (Figure 2):

  (1) Adaptation: intake of foreign genetic material

  (1) Adaptation: intake of foreign genetic material

  After the invasion of exogenous genetic material, the CRISPR/Cas system recognizes the PAM sequence of the exogenous gene, and obtains part of the exogenous fragment from the vicinity of the PAM sequence to form a spacer sequence, which is integrated into the CRISPR repeats from the 5' end to make it "memory".

  
  Infect

  (2) Expression: expression and maturation of crRNA

  (2) Expression: expression and maturation of crRNA

  The CRISPR region is first transcribed into pre-crRNA, which is then cleaved into mature crRNA containing a spacer sequence and part of the repeat sequence, directly or further processed and combined with Cas protein to form an "effector" or "interference" complex with specificity Endonuclease activity

  
  

  (3) Interference: cleavage of foreign genetic material

  (3) Interference: cleavage of foreign genetic material

  The complex scans along the exogenous genetic material under the guidance of crRNA.

  
  

  Cas9 is a type 2 type II CRISPR system, and has become the most widely used genome editing tool since it was validated in human cells in 2013.

  
  

  Figure 2 Schematic diagram of the mechanism of action of CRISPR/Cas (Source: [1])

  Figure 2 Schematic diagram of the mechanism of action of CRISPR/Cas (Source: [1])

  Tumors are formed by the accumulation of somatic mutations, and there are different mutated genes and mutation sites depending on the type of cancer

  
  It can be used for homology-directed repair, gene knockout, insertion, chromosomal translocation, chromatin recombination, disease diagnosis
  
  Table 2 Basic research of CRISPR/Cas9 in tumor therapy

  Data source: [1]Table: Bio-Exploration editorial team

  Data source: [1]Table: Bio-Exploration editorial team

  Table 3 CRISPR/Cas9-mediated tumor biotherapy

  Table 3 CRISPR/Cas9-mediated tumor biotherapy

  Data source: [1]Table: Bio-Exploration editorial team

  Data source: [1]Table: Bio-Exploration editorial team

  The advantages of CRISPR technology are outstanding, how is the clinical application?

  The advantages of CRISPR technology are outstanding, how is the clinical application?

  On June 17, 2021, The New England Journal of Medicine (NEJM) reported the world's first clinical data supporting the safety and efficacy of CRISPR gene editing in vivo (Figure 3)

  
  

  Figure 3 Research results (Source: NEJM)

  Figure 3 Research results (Source: NEJM)

  Transthyretin amyloidosis (ATTR) is a life-threatening disease characterized by the progressive accumulation of misfolded transthyretin (TTR) proteins primarily in the nerves and heart

  
  

  Figure 4 Mechanism of action of NTLA-2001 (Source: NEJM)

  Figure 4 Mechanism of action of NTLA-2001 (Source: NEJM)

  Interim clinical data published in this study included 6 ATTR patients treated in a Phase 1 clinical trial, 3 of whom received NTLA-2001 at a dose of 0.

  
  

  1.

  
  1.
  
  2.
  On the 28th day of NTLA-2001 treatment, NTLA-2001 showed good safety, and no serious adverse events and liver problems were found
  .
  All adverse events were mild adverse events (grade 1);

  3.
  The therapeutic dose of NTLA-2001 did not produce "off-target effects"
  .
  

  3.
  The therapeutic dose of NTLA-2001 did not produce "off-target effects"
  .
  

  "The first-ever in vivo gene editing clinical data show that a single intravenous infusion of the CRISPR system allows precise editing of target cells in a patient's body to treat genetic disorders, " said John Leonard, Ph.
  Disease
  .
  NTLA-2001 interim results validate hypothesis with the potential to abort and reverse ATTR with a single dose
  .
  Addressing the challenges of targeted delivery of the CRISPR/Cas9 system to the liver also provides potential for therapeutics based on our technology platform Other genetic diseases have opened doors, and we plan to rapidly advance and expand our R&D pipeline
  .
  These data give us confidence that we are truly opening up a new era of medicine
  .
  "

  precise

   

  Source of the title map: Spotlight Therapeutics official website, only for academic exchange
  .
  

  Source of the title map: Spotlight Therapeutics official website, only for academic exchange
  .
  

   

  References:

  References:

  [1] Ma Mengdan, Yang Yubin, Chen Yanping, et al.
  CRISPR/Cas9 technology and its application in tumor research and treatment [J] Life Science, 2021, 33(11): 1370-1381.
  DOI: 10.
  13376/j.
  cbls/ 2021153.
  

  [1] Ma Mengdan, Yang Yubin, Chen Yanping, et al.
  CRISPR/Cas9 technology and its application in tumor research and treatment [J] Life Science, 2021, 33(11): 1370-1381.
  DOI: 10.
  13376/j.
  cbls/ 2021153.
  

  [2] Gillmore JD, Gane E, Taubel J, et al.
  CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
  N Engl J Med.
  2021 Aug 5;385(6):493-502.
  doi:10.
  1056/NEJMoa2107454.
  Epub 2021 Jun 26.
  PMID: 34215024.
  

  [2] Gillmore JD, Gane E, Taubel J, et al.
  CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
  N Engl J Med.
  2021 Aug 5;385(6):493-502.
  doi:10.
  1056/NEJMoa2107454.
  Epub 2021 Jun 26.
  PMID: 34215024.
  

  [3] https:// https://
  
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