Learn more about this rare disease, how it affects our families, and how we're helping to find treatment.
DLG4 Research-Treatment Options
In just a few short years, there have been great advancements in research on DLG4, PSD-95, and DLG4 SHINE. Teams of doctors and researchers from around the world are working on unraveling the natural history of DLG4 Synaptopathy, its effects on patients, and development and testing of treatments. This section highlights some of the current and future research initiatives, existing articles, and introduces some of the many researchers involved in the community.
Our Research Partners
Gene Therapy for DLG4 SHINE Syndrome
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.
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.
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. Both laboratories have confirmed that applying this vector to human brain organoids—miniature, lab-grown models of the brain—successfully restores PSD-95 protein levels.
Click the links below to learn more about these groundbreaking findings:
UC San Diego Research Update
Hebrew University Research Update
These early results give us real confidence that gene therapy could meaningfully alter the course of DLG4 SHINE Syndrome.
The next steps are clear—and urgent. To advance toward clinical trial readiness, we aim to raise $5 million to:
1. Manufacture the AAV-DLG4 vector under GMP conditions,
2. Initiate pre-IND discussions with the FDA, and
3. Conduct safety and efficacy studies in large animal models to prepare for a future clinical trial.
With your support, in 3-5 years we can bring this promising therapy one step closer to the children and families who need it most.
Drug Repurposing Screens
The DLG4 SHINE Foundation is proud to fund participation in a groundbreaking Population Repurposing Research Study led by Unravel Biosciences in partnership with COMBINED Brain. Using Unravel’s rareSHIFT™ technology, researchers collect RNA from DLG4 SHINE patients through a simple, non-invasive nasal swab to capture brain-relevant gene activity. This data is analyzed through Unravel’s powerful BioNAV™ platform to identify existing FDA-approved or GRAS compounds that may help restore healthy PSD-95 protein pathways disrupted in DLG4 SHINE Syndrome. By studying DLG4 SHINE patients alongside other rare neurodevelopmental disorders, this project will reveal shared biological mechanisms, accelerate drug repurposing opportunities, and prioritize potential treatments for future testing. The total cost of this project is approximately $60,000 and will provide critical insights to guide a broader drug repurposing screen planned with the Broad Institute in 2026.
At the Broad Institute, researchers will use DLG4 iPSC (induced pluripotent stem cell) models to develop cell-based assays and test a library of existing drugs to identify compounds that may increase PSD-95 protein levels. We aim to fund $150,000 over one year to support this effort and identify promising therapeutic candidates for the DLG4 community.
In addition, earlier work at CHEO (Children’s Hospital of Eastern Ontario) using two DLG4 cell lines found that high concentrations of DHA could increase PSD-95 expression—an encouraging early signal for potential intervention. These findings can be viewed here: CHEO Research Findings.
Antisense Oligonucleotide (ASO) Therapy Development – Johns Hopkins University
The DLG4 SHINE Foundation is funding an innovative preclinical research project at Johns Hopkins University (JHU), in partnership with COMBINEDBrain, to explore a novel antisense oligonucleotide (ASO) therapy for DLG4 SHINE Syndrome. This approach aims to design 3–5 ASOs—special molecules that attach a “tail” to the DLG4 gene near the mutation site. Unlike mutation-specific therapies, this “tail” strategy could potentially work across all types of DLG4 mutations, making it a broadly applicable treatment approach.
These ASOs are designed to restore the DLG4 gene’s normal function so the brain can produce healthy levels of PSD-95, a critical protein for synaptic signaling and brain development. If successful, this therapy could improve key neurological functions and reduce symptoms such as seizures, speech delays, and low muscle tone.
The project will be conducted under a formal research agreement with COMBINEDBrain, ensuring rigorous scientific standards, open-access publication of results, and clear ownership and licensing terms that prioritize patient access.
Research Phases, Timeline, and Funding Needs:
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Phase 1: Initial preclinical research – $37,500, duration 1 year
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Phase 2: Testing in each desired cell line – $15,000 per line (anticipated 4–5 lines), duration 6–8 months
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Phase 3: Preclinical work aligned with gene therapy development, including FDA engagement and testing in large animal models – approx. $5 million, timeline TBD
This project represents a critical step toward developing a mutation-independent, precision therapy for children living with DLG4 SHINE Syndrome.
Splice Site Mutation Research – TWU & UTSA
The DLG4 SHINE Foundation is also funding research at Texas Woman’s University (TWU) and the University of Texas at San Antonio (UTSA) to study a specific type of DLG4 mutation called a splice site mutation. Research at UCSD has shown that one type of DLG4 splice site mutation may cause a gain-of-function, which means the gene not only fails to produce enough PSD-95 but also produces abnormal protein that can cause additional harm. Because of this, we are funding UTSA and TWU to study another type of splice mutation to see if it also behaves as a gain-of-function mutation.
Researchers are using patient-derived stem cells to grow brain cells and mini-brains in the lab. This allows them to study how the mutation affects cell growth, development, and electrical activity.
This research will help scientists understand how different DLG4 splice mutations affect the brain, which is a key first step toward developing future treatments for gain of function mutations. The total seed funding for this work is $133,000, and the project is expected to take about 12 months.
Poly(A)-Tail mRNA Booster Therapeutic Development – Johns Hopkins University
The DLG4 SHINE Foundation is funding an innovative preclinical research project at Johns Hopkins University (JHU), in partnership with COMBINEDBrain, to explore a novel RNA-based therapeutic approach for DLG4 SHINE Syndrome. Rather than designing mutation-specific antisense oligonucleotides, this project focuses on mRNA booster, which are small poly(A)-tail mimetic molecules that can increase expression of the DLG4 gene regardless of the mutation type. This makes the strategy potentially applicable across the full spectrum of DLG4 variants.
These poly(A)-tail mimetics are designed to stabilize the DLG4 messenger RNA so the cell can produce higher, more normal levels of PSD-95, a critical protein for synaptic signaling and brain development. If successful, this approach could help support key neurological functions and reduce symptoms associated with DLG4 SHINE Syndrome.
The project will be conducted under a formal research agreement with COMBINEDBrain, ensuring rigorous scientific standards, open-access publication of results, and clear ownership and licensing terms that prioritize patient access.
Research Phases, Timeline, and Funding Needs:
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Step 1: Develop reporter cell lines, design and test candidate poly(A)-tail mimetics, and identify the most effective booster for increasing PSD-95 expression. Estimated cost: $37,500 (shared across participating foundations); duration: ~1 year.
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Step 2: Testing the selected booster candidates in desired patient-derived or engineered cell lines. Estimated cost: $15,000 per line (anticipated 4–5 lines); duration: 6–8 months.
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Step 3: Preclinical development aligned with future therapeutic advancement, including FDA engagement and potential large-animal studies. Estimated cost: approx. $5 million; timeline TBD.
This project represents a critical step toward developing a mutation-independent, precision therapy for children living with DLG4 SHINE Syndrome.
Walt Lab Extracellular Vesicle Biomarker Project
The DLG4 SHINE Foundation is supporting an advanced biomarker discovery project in the Walt Lab at the Wyss Institute at Harvard University. The team is studying extracellular vesicles (EVs)—tiny particles released by brain cells into the bloodstream that carry proteins, RNA, and other molecular cargo. Because EVs reflect the state of the cells that produce them, they offer a rare, noninvasive way to study brain biology in living patients.
For DLG4/SHINE Syndrome, the central focus is PSD-95, the synaptic scaffolding protein made by the DLG4 gene. Mutations in DLG4 reduce or alter PSD-95, disrupting synaptic signaling. The Walt Lab is developing highly sensitive assays capable of detecting PSD-95 and related synaptic markers in EVs and plasma. They will also study how neurons and glia respond when PSD-95 is deficient, providing insight into the effects of different mutation classes.
This work has two major goals:
• Understanding disease biology. EVs can reveal how neurons, astrocytes, microglia, and oligodendrocytes behave when PSD-95 is altered, helping define the biological signature of DLG4-related synaptopathy.
• Preparing for clinical trials. As gene therapy and RNA-based strategies advance, sensitive biomarkers will be essential to measure whether treatments restore PSD-95 and normalize neuronal signaling.
Why Biomarkers Matter for DLG4
DLG4 variants lead to a wide range of symptoms—including developmental delay, motor challenges, epilepsy, sensory issues, and sleep disturbances—but there has never been a way to measure what is happening at the synapse in real time. Biomarkers will allow clinicians to track PSD-95 levels over time, assess whether treatments reach the brain, identify early signs of therapeutic effect, and stratify patients for future trials. EV-based biomarkers are one of the most promising paths forward.
Research Strategy and Phases
Phase 1: Mass Spectrometry of EVs
The team will isolate EVs from DLG4 patient plasma and from patient-derived iPSC neurons. Using high-resolution mass spectrometry, they will:
• map PSD-95 isoforms present in EVs
• identify protein changes associated with different mutation types
• evaluate cellular stress responses and altered pathways
• compare EV cargo from patient-derived and control neurons
This deep proteomic dataset will guide biomarker development and highlight potential therapeutic targets.
Phase 2: Development of High-Sensitivity PSD-95 Simoa Assays
The Walt Lab will build multiple Single Molecule Array (Simoa) assays targeting different regions of PSD-95, enabling detection of truncated or variant forms. After rigorous analytical validation, the assays will:
• quantify PSD-95 levels in plasma and EV fractions
• distinguish EV-associated PSD-95 from free protein
• compare protein localization and EV production across mutation types
This work will lay the foundation for the first blood-based biomarker for DLG4.
Future Directions
Next steps include isolating EVs from specific brain cell types to directly measure how neurons and glia respond to DLG4 mutations and to emerging genetic therapies. These insights will support clinical trial readiness, improve therapeutic design, and help ensure that children with DLG4/SHINE Syndrome receive the most effective future treatments.
Be Part of the Breakthrough
Families living with DLG4 SHINE Syndrome are waiting for answers and research is the only path forward. Every donation fuels groundbreaking studies, accelerates the search for biomarkers, and opens the door to potential treatment options that could transform lives.
Your gift isn’t just support—it’s partnership in discovery. Together, we can move science from possibility to progress, and from progress to hope.