DLG4 SHINE Syndrome is caused by a mutation in just one copy of the DLG4 gene, meaning the body still has one working copy—but not enough to produce sufficient PSD-95 protein, a critical molecule for healthy brain communication and synapse function.

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Gene therapy offers a powerful solution for this type of disorder. By delivering a functional copy of the DLG4 gene directly to brain cells, gene therapy has the potential to restore normal PSD-95 protein levels and improve key neurological functions such as cognition, communication, and motor skills.

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Our Research Thus Far

Our preclinical research provides strong reason for optimism.

 

Through funding provided to UC San Diego ($495K) and Hebrew University ($90K), researchers have successfully created an AAV9-DLG4 vector designed to restore PSD-95 expression in cells affected by DLG4 SHINE.

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Research to date has shown that the AAV9-DLG4 approach can restore PSD-95 in human brain organoids and DLG4 patient-derived cells. These results provide important evidence that DLG4 gene replacement has therapeutic potential.

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Click below to learn more about these findings:

UC San Diego Research Update
Hebrew University Research Update

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The Next Step: Getting the Vector Right

We are now at an important transition point. The question is no longer simply “Can gene therapy restore PSD-95?” Our research suggests that it can.

 

The next question is:

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“Which version of gene therapy is the safest and most effective version to take into humans?”

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Before moving into expensive GMP manufacturing and formal FDA-enabling toxicology studies, we need to finalize the clinical version of the AAV9-DLG4 vector.

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One important question is whether the vector should include a specific component in the vector that would boost DLG4/PSD-95 protein expression. Because PSD-95 plays an important role in regulating brain activity, we need to make sure we restore enough protein to be therapeutic without producing too much and potentially causing abnormal neuronal activity.

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To answer these questions, we are going to fund a focused $200K research program that will:

• Compare AAV9-DLG4 vectors with and without WPRE at different doses.

• Test the vectors in DLG4 patient-derived neurons to confirm restoration of PSD-95 and improvement in disease-related cellular and synaptic abnormalities.

• Evaluate neuronal activity to look for signs of hyperexcitability or other potential safety concerns.

• Conduct a focused mouse study to evaluate brain expression, distribution, behavior and electrical activity.

 

This additional work is important because we want to finalize the right vector and dose before making the much larger investment required for manufacturing and clinical development.

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Think of it as finalizing the recipe before we start mass-producing it. We want to make sure we have the right version and the right dose before moving into the next stage.

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What Comes After This?

Once we have selected and locked the clinical vector, the program can move into the next major stage:

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GMP manufacturing → FDA/Pre-IND discussions → Formal safety and biodistribution studies → IND preparation → Clinical trial

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Our ultimate goal is to raise approximately $5 million to support the manufacturing, regulatory and IND-enabling work needed to advance AAV9-DLG4 toward a first-in-human clinical trial.

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We Are Getting Closer

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The path from a promising research finding to a treatment is long and requires careful testing at every stage. But we have already taken important steps.

We now have evidence that DLG4 gene replacement can restore PSD-95. Our focus is on making sure we take the safest and most effective version of that therapy into the next stage.

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With the continued support of the DLG4 SHINE community, our goal is to move from promising preclinical research toward a clinical-ready gene therapy and, ultimately, a treatment for our children.