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Research Field Cell & gene therapy, Neuroscience

Fresher and CRISPR

As the basis of ‘genome editing,’ CRISPR (clustered regularly interspaced short palindromic repeats) and CRISPR-associated systems (Cas) are attracting intense interest. In CRISPR-Cas gene modification, a guide RNA (gRNA) directs nuclease to recognize and cut a matching DNA sequence (for example, an unwanted mutation). At the same time, a replacement (therapeutic) DNA sequence is provided for the DNA repair machinery to insert at the break site.

Part of the strength of CRISPR-Cas is its specificity – but this is also its weakness. Consider a disease arising from any one of many mutations in a given gene: conventional genome editing would require multiple therapies to be developed, trialed, approved and marketed for each mutation. Retinitis pigmentosa (RP) is a prime example: over 150 mutations are involved in the rhodopsin-dependent form of the disease. Even if a disease is relatively common – which RP is not – each mutation may only represent a very small group of patients. The economics of drug development simply don’t allow the development of expensive therapies for small populations. So is CRISPR-Cas doomed to fail in genetically heterogeneous disease?

Not necessarily: a team led by Stephen Tsang at the University of Columbia, New York, USA, have reported a potential new approach. Rather than correcting individual mutations in a defective gene, Tsang advocates ‘destroying’ all expression of the endogenous gene, while simultaneously providing cells with non-defective replacement sequences.

It makes sense – but can it make patients better? In mice, at least, the results are encouraging.  Applying this ‘ablate-and-replace’ approach in two murine models of rhodopsin-dependent RP (1), subretinal injection of Tsang’s therapy resulted in outer nuclear layers (ONLs) 17–36 percent thicker than controls (mice that had received therapeutic DNA without ablation of the dominant mutant Rho gene). Electroretinography data also showed the preservation of a and b waves was significantly improved (P<0.001) in treated mice compared with controls in both mouse models. This stabilization of retinal structure and function in two models of rhodopsin-dependent RP indicates that ‘ablate-and-replace’ may extend the promise of CRISPR-Cas to genetically heterogeneous disease. What might this mean for the future? Said Tsang: “Genome surgery is coming, and ophthalmology will see genome surgery before the rest of medicine” (2).

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  1. Y Tsai, et al., “Clustered regularly interspaced short palindromic repeats-based genome surgery for the treatment of autosomal dominant retinitis pigmentosa”, Ophthalmology, [Eub ahead of print], (2018).
  2. American Academy of Ophthalmology. “Genome surgery for eye disease moves closer to reality”. Available at: bit.ly/tsangCRISPR. Accessed: May 17, 2017.
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