Therapeutic Strategy

an Upregulation Antisense Oligonucleotide “ASO”

Our development strategy follows a structured, data-driven progression from initial screening to clinical readiness:

1. Lead Identification
A diverse pool of ASO sequences was designed to target regulatory regions of the NAA15 gene and screened for upregulation activity.

2. Screening and Prioritization (La Jolla Labs)
High-throughput screening identified multiple candidates with:

  • Significant mRNA upregulation (>150–200% vs baseline)

  • Reproducible activity across experiments

  • Early evidence of corresponding protein increase

Top-performing sequences were advanced based on concordant RNA and protein signals.

3. Dose-Response and Protein Validation
Leading candidates were further evaluated to confirm:

  • Dose-dependent increases in gene expression

  • Translation of mRNA signal into measurable NAA15 protein

  • Consistency across experimental conditions

This stage represents a key translational milestone: demonstrating that gene upregulation leads to protein production.

4. Validation in Patient-Derived Cells (iXcells)
Top candidates are now being tested in GG’s patient-derived iPSC neurons, including:

  • Glutamatergic and GABAergic neuronal subtypes

  • Measurement of gene and protein expression in a disease-relevant system

  • Ongoing evaluation of functional neuronal activity

5. Candidate Selection and Advancement
Based on the totality of evidence—RNA activity, protein translation, and performance in patient-derived cells—2–3 lead candidates will advance to early in vivo safety studies.

Key Findings to Date

  • Multiple ASO candidates achieve >150–200% mRNA upregulation

  • Protein-level increases have been confirmed across multiple candidates

  • Dose-response relationships are consistent and reproducible

  • Early data supports true biological translation, not isolated transcriptional effects

What This Means

This integrated approach enables:

  • Selection of candidates with demonstrated mechanistic activity

  • Increased confidence in translational relevance to human biology

  • A focused path toward IND-enabling studies and clinical readiness