Triplex Gene Editing

Triplex gene editing uses peptide nucleic acid (PNA) oligomers and DNA correction sequences to edit genomic DNA by harnessing a cell’s own DNA repair machinery. Our development candidates are comprised of a proprietary triplex-forming PNA oligomer and a DNA correction sequence, encapsulated in a nanoparticle that assures that both components of our drug (PNA and DNA) reach the gene targeted for correction.

Triplex-forming PNA

DNA Correction Sequence

Nanoparticle Delivery

 
Using the cell’s own high-fidelity DNA repair mechanisms 

Nanoparticles delivered by intravenous injection into systemic circulation are able to reach the target organ, are endocytosed by cells, and both oligomers (PNA and DNA) are released inside the cell. The triplex-forming PNA oligomer has high sequence selectivity and forms a PNA-DNA-PNA triplex with the targeted single DNA strand. This binding event forms an altered helical structure near the disease-related mutation that induces natural, endogenous DNA repair mechanisms that substitute the DNA correction sequence for the mutation.

Genomic DNA with Corrected Mutation

Recombination & Repair

Genomic DNA with Disease-Related Mutation

Intravenously delivered PNA-containing nanoparticles edit in vivo

 

Our collaborators at Yale have pioneered triplex gene editing using intravenously delivered PNA and DNA correction sequence-containing nanoparticles. Peter Glazer, MD, PhD; Mark Saltzman, PhD; and Marie Egan, MD showed that miniPEG gamma PNAs loaded into biodegradable polymer nanoparticles with DNA correction sequences induce much higher levels of gene editing than classical PNAs. They injected PNA and DNA correction sequence-loaded nanoparticles intravenously into ß-thalassemic mice, durably reversing the disease phenotype by achieving gene correction in bone marrow derived hematopoietic stem cells[1]. This was the first in vivo demonstration that PNAs might effectively translate into a clinically practical platform for human gene correction.

Our proprietary, enabling chemistry repairs genes naturally

We are the first company developing these proprietary PNA oligomers for human therapeutics and have established a broad-based intellectual property portfolio that encompasses foundational patent filings in this new space. Trucode has determined key design rules that allow for improved generation of effective PNA sequences. Triplex gene editing has a number of potential advantages compared to other gene editing techniques, where challenges with specificity, safety, delivery and manufacturing potentially introduce significant risks and costs to patients and might limit routine clinical use.

Advantages of triplex gene editing
  • No viral vectors, reducing concerns over engraftment, durability, safety, oncogenicity, immunogenicity, and manufacturing

  • No endonucleases, reducing the need to control double stranded breaks and potential for off-target effects

  • No bone marrow transplant or immunosuppression required

  • Fully synthetic manufacturing

  • Intravenous delivery

  • Repeat dosing may be feasible for treatment optimization

  • Exclusive IP protects composition of matter and use

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© 2019 Trucode Gene Repair, Inc.