STITCHR harnesses the power of retrotransposons, genetic elements often called "jumping genes" due to their ability to move and insert themselves within the genome12. These retrotransposons use a copy-and-paste mechanism, which the researchers ingeniously repurposed for targeted gene editing1. The STITCHR system combines a carefully selected retrotransposon candidate with the nickase enzyme from CRISPR to seamlessly insert genes at specific locations2. This innovative approach leverages the natural capabilities of retrotransposons to overcome limitations of existing gene editing technologies, potentially offering a more versatile and efficient method for treating genetic disorders31.

STITCHR's ability to insert entire genes opens up possibilities for single-step treatments that can address multiple mutations simultaneously, a significant advancement over current gene editing technologies12. This approach is particularly promising for diseases like cystic fibrosis, where thousands of genetic errors can undermine normal function2. By replacing entire faulty genes with functional copies, STITCHR offers a potential "one-and-done" solution for complex genetic disorders3. This contrasts with CRISPR, which is typically programmed to correct individual mutations and may require multiple interventions for diseases with multiple genetic defects23.

• STITCHR can target a wider range of genomic locations compared to CRISPR2

• The system is formulated entirely as RNA, simplifying delivery compared to traditional RNA-DNA systems23

• This approach could potentially slow down or stop disease progression in various genetic disorders4

• STITCHR's versatility may extend its applications beyond rare diseases to more common conditions like Alzheimer's or Parkinson's disease4

Recent advancements in RNA-based delivery systems have revolutionized the field of gene therapy, offering new possibilities for treating a wide range of diseases. Nanoparticle-based RNA delivery has shown significant progress, with the approval of mRNA vaccines for SARS-CoV-2 and liver-targeted siRNA therapies1. These innovations have paved the way for more efficient and targeted delivery of therapeutic RNA to various organs and cell types.

Key developments in RNA-based delivery include:

• Improved cargo design, such as RNA circularization and data-driven untranslated region optimization, enhancing mRNA expression1

• Novel materials for extrahepatic targeting, enabling better delivery to organs like the lung and splenic immune cells1

• Conjugation of small molecule ligands, antibodies, or peptides to RNA delivery nanoparticles for specific cell targeting1

• Advancements in controlling immune responses to RNA delivery systems, crucial for both vaccine development and gene therapies1

• Exploration of intranasal mRNA vaccination for respiratory infections, potentially providing sterilizing immunity against seasonal and pandemic illnesses1

These innovations are expanding the therapeutic potential of RNA-based treatments, addressing limitations of current gene editing technologies and offering more precise and versatile approaches to genetic medicine2.