Background:

Advancements in gene editing have primarily focused on DNA—offering powerful tools for permanent genomic modification. However, significant therapeutic opportunities lie in precisely controlling RNA (transcriptome) rather than DNA (genome), allowing for reversible and more nuanced control over gene expression, such as temporary knockdown, or editing. Traditional RNA editing tools, such as in vivo base editors, generally lack the capacity for precise deletions or insertions and often act through single-nucleotide changes. There remains an unmet need for systems enabling sequence-specific, programmable editing of RNA, especially for therapies, functional genomics, or sophisticated manipulation of RNA viruses and transcripts that require more than just a permanent gene knockout.

Solution:

MSU researchers have created an innovative RNA editing platform that goes beyond knockouts by allowing targeted excision and precise re-ligation of RNA, providing tools to address challenges across medicine and biotechnology. The MSU invention allows precise manipulation of RNA. In vitro, these tools enable both precise excisions, or insertions, while in vivo applications are currently restricted to robust knockdowns and short excisions. Proof of concept has been demonstrated in human tissue culture (Science 2024), showing how this technology is capable of removing premature stop codons from a clinical mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), resulting in the expression of the full length protein. 

Benefits:

  • Safer: By transiently modifying short-lived RNA without altering DNA, this approach offers a reversible therapeutic option with a lower regulatory burden and streamlined approval compared to permanent genome editing.  
  • Specificity: Targeted RNA excisions at precise, user-defined sites deliver greater specificity, dramatically reducing off-target effects compared to traditional RNA editing techniques.
  • Lower manufacturing costs: The invention reduces manufacturing costs by eliminating the need for extensive safety checks and complex processes required for permanent DNA modification. Additionally, leveraging the cell’s own enzymatic machinery for RNA repair minimizes dependency on expensive external reagents and reduces the complexity of manufacturing steps. 

Potential Applications:

  • Restoring Protein Function in Genetic Disease with Nonsense Mutations: The majority of genetic diseases are caused by mutations that result in a premature stop codon, which triggers non-sense mediated decade of the mRNA, and no protein production (e.g., cystic fibrosis, CFTR W1282X mutation). CRISPR mediated excision of the premature stop codon and RTCB mediated ligation of the RNA can restore translation of the full length functional protein, potentially eliminating the disease without permanently altering the patient’s genome.
  • Therapeutic Excision of Pathogenic RNA Expansions: In disorders such as Huntington’s or certain ataxias, disease-causing transcripts contain harmful trinucleotide expansions. Excision of these repeats followed by RNA re-ligation can restore functional RNA, decreasing the production of toxic proteins without eliminating the transcript entirely.
  • Programmable Viral RNA Editing for Attenuation or Functional Study: Targeted excision and re-ligation in viral RNA genomes can remove or swap functional domains within viral transcripts enabling the generation of attenuated variants for vaccines and broader medical applications. For example, this could include disabling viral replication genes in infected cells as an antiviral strategy, or rapidly prototyping attenuated variants of emerging pathogens. In research, this can also allow the study of domain-specific viral function without destroying the whole viral RNA. 

Opportunity:

Contact:

Daniel Juliano
406‐994‐7483
daniel.juliano@montana.edu