Tunable, proteolytic dosage control of CRISPR-Cas systems enables precise gene therapy for dosage sensitive disorders

Proteolytic control of CRISPR-Cas systems achieves precise, tunable gene expression with reduced variability, enabling improved gene therapy for dosage-sensitive disorders.

• Why it matters: Variability in gene delivery hampers the precision of gene therapy, especially for conditions requiring tightly regulated gene expression, such as autism-related syndromes.
• What they did: A modular incoherent feedforward loop was developed to control Cas protein levels through proteolytic cleavage, allowing post-delivery tuning of gene activation and repression in human and mouse cells.
• The result: This system provides consistent gene expression, demonstrated by dosage-controlled activation of RAI1 in patient-derived cells and neurons, paving the way for more accurate and effective gene therapies.