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. Current RNA knockdown approaches (e.g. RNAi and ASOs) can only degrade transcripts-they cannot repair and restore protein function. Further, traditional RNA editing tools (e.g. ADAR and Cas13), including in vivo base editors, generally lack the capacity for precise deletions or insertions and often act through single-nucleotide changes. There is a critical unmet need for systems capable of sequence-specific, programmable RNA editing, particularly for genetic medicine applications requiring precise excision, insertion, or repair.

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 based on a type III CRISPR system for RNA editing, enabling programmable RNA excision, insertion, and repair. Proof of concept has been demonstrated in primary human bronchial epithelial (HBE) cells (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. This proof-of-concept demonstrates the platform's potential to address high-impact genetic diseases with no approved therapies. Pathways for improved ligation efficiency and corresponding protein restoration have recently been identified as well. 

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. 
  • Platform versatility: This technology enables both therapeutic and research applications, offering a powerful tool for biopharma and biotechnology organizations.

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. This approach is broadly applicable to genetic diseases caused by nonsense mutations, which represent a significant portion of inherited disorders.
  • 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:

The patents related to the invention are available for licensing and commercialization:

Contact:

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