The most widely used homologs of the Cas9 protein are derived from the bacteria Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). Based on the fact that these two bacterial species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureus homolog of Cas9) and SpCas9 (S. pyogenes homolog of Cas9)...[Our results] demonstrate[s] that there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials. [Italics added for Linnaean emphasis.]If humans, and, presumably, other mammals, possess potent immune responses to the Cas protein component of this powerful gene editing system, the therapeutic prospects for CRISPR-Cas9 may dim considerably beyond applications in isolated cells or tissues or patients having immature or suppressed immune responses. After many more than two steps forward, therapeutic gene editing may be about to take at least one substantial step backward.
Thursday, January 11, 2018
The Cas Against CRISPR
The realization that some diseases have genetic etiologies long inspired the hope that "correcting" mutant DNA sequences in patients could cure their diseases. Recent progress in gene therapy has made this tantalizing possibility seem achievable, and precise and efficient gene editing methods using tools like CRISPR-Cas9 have accelerated progress considerably. However, an important preprint article, entitled "Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans", published by Charlesworth et al. on
bioRχiv,
has now cast a shadow on the efficacy of CRISPR-Cas9 in humans. The Matt Porteus' research team, based at Stanford Medical School, appear to have discovered an immune response to CRISPR-Cas9:
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