Therapeutic Strategy

Development of a NAA15 Upregulation Antisense Oligonucleotide (ASO)

Sweet Geej Foundation is developing a mutation-agnostic antisense oligonucleotide (ASO) designed to increase expression of the NAA15 gene. Rather than replacing the gene, our ASO is designed to enhance production of the body's own NAA15 protein.

Our development strategy follows a rigorous, data-driven translational pathway used throughout biotechnology: identify active molecules, confirm protein production, validate activity in disease-relevant human models, and advance the strongest candidates into preclinical safety studies.

1. Lead Discovery

A large library of ASO sequences was rationally designed to target regulatory regions of the NAA15 transcript with the goal of increasing endogenous NAA15 expression.

Initial screening identified multiple active candidates capable of significantly increasing NAA15 mRNA expression. The most promising sequences were selected for additional validation based on potency, reproducibility, and overall performance.

2. RNA and Protein Validation

Lead candidates were advanced through increasingly rigorous laboratory testing at La Jolla Labs.

Each candidate was evaluated for:

  • NAA15 mRNA upregulation

  • NAA15 protein production

  • Dose-response characteristics

  • Experimental reproducibility

Importantly, several lead candidates demonstrated reproducible increases in NAA15 protein, confirming that increased gene expression translated into meaningful protein production.

This represents a major translational milestone for the program. While many discovery programs identify compounds that increase RNA, demonstrating corresponding increases in protein provides much stronger evidence that the therapeutic mechanism is functioning as intended.

3. CRISPR Disease Model Validation

The program has now advanced into a CRISPR-engineered human cell model carrying GG's NAA15 mutation.

Twelve lead ASO candidates are currently being evaluated in this disease-relevant model to determine which molecules most effectively restore NAA15 expression.

Each candidate is being assessed for:

  • NAA15 mRNA restoration

  • NAA15 protein restoration

  • Dose-response characteristics

  • Reproducibility across experiments

  • Relative performance across all lead candidates

This stage represents one of the most important decision points in the development program, allowing us to compare multiple candidate ASOs in a human model of NAA15 haploinsufficiency before advancing into patient-derived neurons.

4. Validation in Patient-Derived Neurons

Following completion of the CRISPR disease model studies, the top-performing ASOs will be evaluated in GG's patient-derived induced pluripotent stem cell (iPSC) neurons.

Testing will include:

  • Glutamatergic neurons

  • GABAergic neurons

  • NAA15 gene expression

  • NAA15 protein production

  • Functional neuronal activity

These studies will provide critical evidence that the selected ASOs remain effective in neurons derived directly from a patient with NAA15 haploinsufficiency.

5. Lead Candidate Selection and Preclinical Advancement

The strongest candidates will be selected using the complete body of evidence generated throughout the program, including:

  • Gene upregulation

  • Protein restoration

  • Performance in the CRISPR disease model

  • Performance in patient-derived neurons

  • Functional neuronal activity

  • Early in vivo tolerability

The lead candidate(s) will then advance into IND-enabling preclinical development, including formal safety, toxicology, pharmacology, and manufacturing activities required to support a first-in-human clinical trial.

Progress to Date

The program has successfully achieved several key milestones:

  • A large library of ASOs has been designed and screened.

  • Multiple candidates demonstrated robust NAA15 mRNA upregulation.

  • Several lead candidates produced reproducible increases in NAA15 protein.

  • Dose-response relationships have been confirmed across leading candidates.

  • Twelve lead ASOs have advanced into a CRISPR-engineered human disease model of NAA15 haploinsufficiency.

  • Patient-derived neuronal studies are planned following selection of the highest-performing candidates from the CRISPR model.

Why This Matters

Developing a precision therapy for a rare genetic disorder requires demonstrating that laboratory findings translate into meaningful biological activity.

Our program has progressed beyond simple gene-expression screening by demonstrating reproducible increases in NAA15 protein and advancing into disease-relevant human cellular models. Each stage is designed to reduce risk and build confidence that the lead ASO has the greatest potential to become a safe and effective therapy for individuals living with NAA15 haploinsufficiency.

By following this stepwise translational strategy—from discovery, to protein validation, to human disease models, to patient-derived neurons, and ultimately preclinical safety studies—we are building a strong scientific foundation for future clinical development.