Silk worm (Bombyx Mori) protein, have been considered as potential materials for a variety of advanced engineering and biomedical applications for decades. Recently, silkworm silk has gained significant importance in research attention mainly because of its remarkable and exceptional mechanical properties. Silk has already been shown to have unique interactions with cells in tissues through bio-recognition units. The natural silk contains fibroin and sericin and has been used in various tissues of the human body (skin, bone, nerve, and so on). Besides, silk also still has anti-cancer, anti-tyrosinase, anti-coagulant, anti-oxidant, anti-bacterial, and antidiabetic properties. This article is supposed to describe the diverse biomedical capabilities of B. Mori silk as the appropriate biomaterial among the assorted natural and artificial polymers that are presently accessible, and ideal for usage in regenerative medicine fields.
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32The field of gene therapy has been galvanized by the discovery of the highly efficient and 33 adaptable site-specific nuclease system CRISPR/Cas9 from bacteria. 1,2 Immunity against 34 therapeutic gene vectors or gene-modifying cargo nullifies the effect of a possible curative 35 treatment and may pose significant safety issues. [3][4][5] Immunocompetent mice treated with 36 CRISPR/Cas9-encoding vectors exhibit humoral and cellular immune responses against the 37 Cas9 protein, that impact the efficacy of treatment and can cause tissue damage. 5,6 Most 38 applications aim to temporarily express the Cas9 nuclease in or deliver the protein directly into 39 the target cell. Thus, a putative humoral antibody response may be negligible. 5 However, 40 intracellular protein degradation processes lead to peptide presentation of Cas9 fragments on 41 the cellular surface of gene-edited cells that may be recognized by T cells. While a primary T 42 cell response could be prevented or delayed, a pre-existing memory would have major impact.
43Here, we show the presence of a ubiquitous memory/effector T cell response directed towards 44 the most popular Cas9 homolog from Streptococcus pyogenes (SpCas9) within healthy human 45 subjects. We have characterized SpCas9-reactive memory/effector T cells (TEFF) within the 46 CD4/CD8 compartments for multi-effector potency and lineage determination. Intriguingly,
47SpCas9-specific regulatory T cells (TREG) profoundly contribute to the pre-existing SpCas9-48 directed T cell immunity. The frequency of SpCas9-reactive TREG cells inversely correlates with 49 the magnitude of the respective TEFF response. SpCas9-specific TREG may be harnessed to 50 ensure the success of SpCas9-mediated gene therapy by combating undesired TEFF response 51 in vivo. Furthermore, the equilibrium of Cas9-specific TEFF and TREG cells may have greater 52 importance in Streptococcus pyogenes-associated diseases. Our results shed light on the T 53 cell mediated immunity towards the much-praised gene scissor SpCas9 and offer a possible 54 solution to overcome the problem of pre-existing immunity.
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56SpCas9 was the first Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) 57 associated nuclease hijacked to introduce DNA double-strand breaks at specific DNA sequences. 1
58Through the ease of target adaption and the remarkable efficacy, it advanced to the most popular 59 tool for re-writing genes in research and potential clinical applications. The major concern for 60 clinical translation of CRISPR/Cas9 technology is the risk for off-target activity causing potentially 61 harmful mutations or chromosomal aberrations. 2,7 High-fidelity Cas9 enzymes were developed to 62 reduce the probability of these events. 8 Furthermore, novel Cas9-based fusion proteins allow base 63 editing or specific epigenetic reprogramming without inducing breaks in the DNA. 9,10 Most 64 approaches are based on the original SpCas9 enzyme that originates in the facultatively 65 2 pathogenic bacterium Streptococcus ...
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