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Targeting and detection of cancer fusion oncogenes using CRISPR/Cas13

P Puig-Serra(1) M Martínez-Lage(1) M C Casado-Rosas(1) B Olalla-Sastre(2) S Míguez Amil(1) M López Valls(2) J Díaz-Martín(3) E De Álava(3,4) B Sot Sanz(2) R Fernández Leiro(1) R Torres-Ruiz(1,2) S Rodríguez-Perales(1)

1:Centro Nacional de Investigaciones Oncológicas; 2:CIEMAT-CIBERER; 3:Instituto de Biomedicina de Sevilla-IBiS; 4:Universidad de Sevilla

Studies over the past decades have demonstrated the presence of specific fusion oncogenes (FOs) in almost 20% of human cancer. FOs provide unique diagnostic and therapeutic advantages because of their tumor-specific expression.

FO targeting diagnosis: Traditional diagnostic methods such as qRT-PCR, FISH, or NGS are routine in the clinic. However, those techniques are expensive, time-consuming, and contain multiple steps, requiring dedicated equipment and personnel.

FO targeted therapy: Many therapies currently used are non-selective, leading to severe side effects responsible for prolonged recovery, often followed by relapses.

In this sense, the identification of type II Cas13 nuclease, an RNA-targeting CRISPR enzyme, has opened up the possibility of selective cleavage of FO transcripts that could be used to develop new directed-therapies and highly-sensitive diagnostic options. Cell-based RNA targeting with Cas13 does not modify the DNA, like CRISPR/Cas9 system, and is associated with reversible and temporally controllable changes. Moreover, CRISPR/Cas13 system is correlated with high knockdown efficiencies and no off-target effects, contrary to shRNAs, offering unique advantages when used for therapeutic purposes. Diagnostic methods based on CRISPR/Cas13 provide rapid RNA detection with attomolar sensitivity and single-base mismatch specificity. We show our results in i) the set-up of a Cas13 system for selective degradation of FO RNA inducing efficient elimination of cancer cells, and ii) the development of a platform for highly-sensitive, specific, affordable, and instrument-free diagnostic test for FO detection by Cas13.

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