Expanding the Genetic Code to Create Impossible Proteins
Nature’s genetic code uses 20 standard amino acids to build all proteins. Tiragena’s proprietary technology expands this code, enabling us to incorporate non-canonical amino acids (ncAAs) with novel properties—creating therapeutic proteins impossible to achieve in nature.
Genetic Code Expansion (GCE): Rewriting Biology’s Rules
The foundation
Every protein in your body is built from just 20 amino acids, dictated by the universal genetic code. These building blocks have served life for billions of years—but they have limitations. They can be oxidized, they can aggregate, they can fail under stress. Tiragena’s proprietary GCE platform breaks these limitations.
How it works
Our orthogonal translation system (OTS) introduces additional genetic “codes” that cells can use to incorporate non-canonical amino acids (ncAAs)—building blocks with properties nature never evolved:
- Oxidation-resistant amino acids that withstand reactive oxygen species
- Aggregation-blocking amino acids that prevent toxic protein clumping
- Photo-stable amino acids immune to light-induced damage
- Enhanced stability amino acids that maintain protein structure
Key components
- Engineered tRNA–synthetase pairs: Orthogonal systems that don’t interfere with natural cellular machinery.
- Non-canonical amino acids (ncAAs): Over 50 validated ncAAs in our library, each with unique properties.
- Precision site selection: Computational tools to identify optimal modification sites.
- Genetic firewall: Biosafety measures ensuring controlled production.
Delivery platforms
VLP/LNP technology: Getting proteins where they’re needed
Virus-like particles (VLPs)
Our engineered VLPs package all necessary machinery for in vivo protein modification:
- Gag-based protein scaffolding for cargo loading
- Fusogenic proteins for tissue-specific targeting
- TNA-templated RNA patching systems
- Orthogonal translation components
Capabilities:
- CNS penetration (crosses blood-brain barrier)
- Tissue-specific tropism
- High cargo capacity
- Proven safety profile
Lipid nanoparticles (LNPs)
Leveraging mRNA delivery technology validated by COVID-19 vaccines:
- Ionizable lipid formulations for cellular uptake
- Pseudouridine-modified mRNA for reduced immunogenicity
- Scalable GMP manufacturing
- Established regulatory pathway
Targeting strategies:
- CNS: Ionizable lipids, RVG peptides
- Liver: ASGPR-targeted envelopes
- Retina: Transferrin receptor targeting
- Muscle: AAV9-pseudotyped VLPs
Breakthrough innovation: TNA-templated RNA patching
Traditional RNA editing (ADAR-based) can only create UAG codons at existing CAG (glutamine) sites. Most disease-critical sites lack these codons—making them inaccessible. Threose nucleic acid (TNA) serves as a bio-orthogonal scaffold that resists degradation (immune to cellular RNases), evades RNase H (won’t destroy target mRNA), enables precise ligation (inserts UAG codons anywhere), and allows unrestricted ncAA incorporation at any disease-relevant position.
Mechanism: (1) Cas13 locates target mRNA (RADARS-gated for cell specificity). (2) TNA splint hybridizes to mRNA site. (3) MS2-recruited ligase stitches in UAG codon. (4) Orthogonal ribosome incorporates ncAA. (5) Modified protein resists aggregation/oxidation.
Three mechanisms of protein protection
1. Aggregation prevention. Proteins like tau, α-synuclein, and SOD1 misfold and clump together, forming toxic aggregates that kill neurons. Strategic ncAA placement at aggregation interfaces uses bulky aromatic ncAAs (steric clashes blocking β-sheet formation), charged ncAAs (disrupt hydrophobic interactions), and cross-linking ncAAs (stabilize native conformations). Example: Tau PHF6 motifs (residues 275–280, 306–311)—aggregation-blocking ncAAs at these positions.
2. Oxidative damage resistance. ROS modify proteins—nitrating tyrosines, oxidizing cysteines—triggering misfolding. Replace vulnerable residues with oxidation-resistant ncAAs (e.g., meta-fluorotyrosine; selenocysteine analogs; photo-stable tyrosine variants). Example: α-synuclein—three critical tyrosines (Tyr39, Tyr125, Tyr133); nitration accelerates Parkinson’s progression; replace with nitration-proof analogs.
3. Structural stabilization. Age-related protein instability leads to loss of function and toxic conformations. Conformationally rigid ncAAs lock proteins into functional states—proline analogs, fluorinated amino acids for core packing, metal-chelating ncAAs for active sites. Example: Mutant SOD1 in ALS—metal-chelating ncAAs to restore stability and prevent aggregation.
Safety & advantages: why protein editing is superior to gene editing
Transient, not permanent: mRNA-based delivery (naturally degrades); no genomic integration; fully reversible; stop treatment if needed.
Dose-controllable: Adjust frequency based on response; titratable therapeutic effect; flexible administration schedules.
Reduced off-target risk: No DNA cutting; no permanent mutations; RADARS gating ensures cell-specific activity.
Regulatory precedent: mRNA therapeutics validated (COVID vaccines); established manufacturing pathways; known safety profile.
Validated science
Built on decades of research
- 100+ peer-reviewed publications by our founders
- 20+ years of GCE platform development
- 50+ validated ncAAs in our proprietary library
- Proven in vitro & in vivo efficacy in disease models
Key publications
Our scientific foundation includes peer-reviewed work across genetic code expansion, non-canonical amino acid incorporation, and translational protein engineering. A curated publications list is maintained for partners and due-diligence review.
Collaborations
We actively collaborate with academic laboratories, clinical experts, and industry development partners to accelerate target validation, delivery optimization, and translational readiness.
How we compare at a glance
Illustrative comparison of protein-level editing versus permanent genomic change—not a claim of superiority for every patient in every setting.
Protein editing (Tiragena) vs. in vivo gene therapy (typical patterns)
Pipeline and programs: