Gene Therapy Restores Neuronal Function in a Rare Disorder

Introduction: the WWOX gene, a vital switch for the developing brain

An eight-month-old who changes the story of gene medicine

On June 8, 2026, an eight-month-old baby became the first human being in the world to receive an experimental gene therapy directly targeting the WWOX gene, injected into the spinal canal at Schneider Children's Medical Center in Israel. The child suffered from WOREE syndrome, an extremely rare and often fatal epileptic encephalopathy that typically claims children before the age of four.

This procedure, carried out in under an hour, is not a miracle out of nowhere. It is the culmination of more than a decade of research led by Professor Rami Aqeilan's lab at the Hebrew University of Jerusalem, in collaboration with the Human Technopole in Milan and the University of Haifa.

Why this obscure gene deserves your attention

The WWOX gene — short for WW domain-containing oxidoreductase — has nothing catchy about its name. Yet its loss of function triggers one of the most devastating known neurodevelopmental diseases: WOREE syndrome (WWOX-related epileptic encephalopathy), marked by drug-resistant seizures, profound developmental delay, and a shortened life expectancy.

A milder form, SCAR12 (spinocerebellar ataxia type 12), occurs when the mutations only partially destroy the protein. Both diseases are ultra-rare, but studying them illuminates fundamental mechanisms of brain development that reach far beyond this single gene.

The hidden mechanism behind the neurological chaos

Brain organoids to crack the mystery

To understand why the absence of WWOX causes such devastation, the team led by Rami Aqeilan, with Daniel J. Steinberg and José Davila-Velderrain, built brain organoids — tiny clumps of brain tissue grown in the lab from induced pluripotent stem cells. Four lines were compared: normal cells, WWOX-KO cells (the gene fully disabled via CRISPR), cells from WOREE patients, and cells from SCAR12 patients.

The team then sequenced the RNA of more than 28,000 individual cells, a technique called single-cell sequencing, published in the journal Brain on July 3, 2026. This extreme resolution pinpointed exactly where the system goes off the rails.

Radial glial cells, ground zero of the disaster

The verdict: it is the radial glial cells, the stem cells that give rise to most of the cortex's neurons, that suffer the most. Without WWOX, their cell cycle goes haywire, piling up abnormally in the G2/M and S phases, while the MYC gene — a proto-oncogene well known in cancer research — becomes excessively active.

The concrete result: less neurogenesis, a slowed and unbalanced production of neurons. Organoids derived from patients, less severely affected than the full WWOX-KO line, instead showed neuronal hyperexcitability and delayed maturation — consistent with the variable clinical severity seen in real children.

Gene therapy tested in the lab before reaching a human patient

A viral vector as messenger

The tested solution relies on an adeno-associated viral vector called AAV9, carrying a functional copy of the WWOX gene under control of the Synapsin I promoter, which specifically targets mature neurons. This same delivery vehicle is used in several gene therapies already approved elsewhere in the world, which lends some reassurance about its relative safety profile.

Injected into the organoids at week ten of culture, then observed for six more weeks, the treatment normalized neuronal hyperexcitability, restored near-normal electrical activity, and boosted expression of neuronal maturation markers such as CTIP2 and SATB2 — without disrupting the radial glial cell population, an encouraging sign for long-term safety.

Mice before organoids, organoids before the child

This organoid study builds on a lineage of earlier work, including a study published in EMBO Molecular Medicine back in 2021, where a single injection of AAV9-SynI-WWOX in Wwox-null mice had already reversed seizures, myelination defects, and early mortality. A more recent study, posted on bioRxiv in March 2026, pinned down the optimal therapeutic window: between days 1 and 5 after birth in mice, for a lasting effect.

The leap to the first human patient

A compassionate-use program, not a standard clinical trial

The treatment given in June 2026 to the child at Schneider Children's Medical Center was not part of a formal clinical trial, but a compassionate-use program, set up by Drs. Naama Orenstein and Dror Kraus after extensive regulatory preparation. The product was developed by the company Mahzi Therapeutics, led by Dr. Yael Weiss, under license from Yissum, the technology transfer company of the Hebrew University.

One month after the injection, the child remained clinically stable, with no recurrence of the severe seizures that had previously threatened his development. Professor Aqeilan himself tempered the enthusiasm, noting that long-term follow-up is still needed to judge the treatment's real safety and effectiveness.

A therapy candidate already under regulatory review

According to the WWOX Foundation, a patient organization that funded part of the initial research, the drug candidate — designated MZ-9138 by the California-based CIRM — was, as of late 2023-2024, in the final stages of safety and efficacy testing before a phase 1-2 clinical trial application. To date, there is no approved treatment for WOREE syndrome.

What this breakthrough really means for families

A disease where every month counts

For families affected by WOREE syndrome, the lack of an approved treatment is not a statistical abstraction. It is a race against a genetic disease that, in its most severe form, takes children before the age of four. Every published advance, even a preliminary one, is one more variable in an equation where time is the main enemy.

Researchers stress that the intervention window appears more favorable early in life, which pushes for early genetic diagnosis — a challenge in itself for a disease this rare and often poorly identified in the first months.

A proof of concept that extends beyond one gene

Beyond WWOX, this neuron-specific AAV9 vector approach confirms a broader trend in pediatric gene medicine: targeting the central nervous system directly for rare monogenic diseases, rather than merely treating symptoms. Other genes, such as SLC6A1, are the subject of similar efforts, with results that are just as cautious and incremental.

The quiet role of patient organizations in this race

Funding science when industry hesitates

Behind this breakthrough also lies the stubborn work of family associations, such as the WWOX Foundation, which contributed roughly 200,000 Australian dollars to Professor Aqeilan's lab between 2020 and 2021 to fund the early stages of gene therapy research. Without this kind of community funding, diseases as rare as WOREE syndrome often struggle to attract the attention of major pharmaceutical funders.

Another grant, awarded in February 2024 by the Children's Medical Research Institute in Sydney, helped explore complementary avenues, such as repurposing existing drugs capable of forcing a readthrough of certain nonsense mutations in the WWOX gene.

A parallel path: repurposing existing drugs

This drug repurposing strategy aims to identify compounds already approved for other uses but capable of inducing partial production of the WWOX protein in patients carrying nonsense mutations. The goal: offer an option that becomes accessible faster than a complex gene therapy, while the latter works its way through every regulatory step.

These efforts illustrate a less glamorous reality of rare-disease research: several therapeutic approaches advance in parallel, with no guarantee that any single one will end up becoming the standard treatment.

What comes next: clinical trials and regulatory caution

The long road still ahead to approval

According to the California-based CIRM, the therapy candidate designated MZ-9138 is heading toward a phase 1-2 clinical trial, the pivotal step that will test safety and efficacy in a larger group of patients with WOREE syndrome. No official timeline for market approval has been announced, and it would be irresponsible to promise one.

Regulatory authorities, notably in the United States and Israel, will need to assess not only the treatment's effectiveness but also its long-term safety, since injecting a viral vector directly into the central nervous system is never a trivial act.

Why scientific transparency matters more here than elsewhere

In a field where families' hope can easily be exploited, the transparency of researchers — who publish their data, own their uncertainties, and refuse premature victory laps — is the best safeguard against overreach. That rigor, more than any splashy headline, deserves recognition.

Comparing WWOX to other recent gene breakthroughs

A growing family of neuron-specific therapies

The AAV9 vector targeting mature neurons via the Synapsin I promoter is not an isolated invention. Similar approaches are being tested for other genes responsible for rare neurodevelopmental diseases, such as SLC6A1, whose mutations cause epilepsy and autism spectrum disorders. These parallel research efforts share a common lesson: the timing of the intervention, very early in brain development, appears decisive for treatment efficacy.

This methodological convergence among several research teams, often competing but sometimes collaborating, is accelerating the collective understanding of what makes a brain gene therapy succeed or fail.

The hidden cost of innovation for ultra-rare diseases

A persistent challenge remains: developing treatments for diseases affecting only a few hundred families worldwide struggles to attract the massive investment of traditional pharmaceutical industry players. That is why mixed funding, spanning patient foundations, public grants such as those from California's CIRM, and specialized companies like Mahzi Therapeutics, remains the dominant model for this kind of research.

This economic reality takes nothing away from the scientific value of the discovery, but it is a reminder that future access to this treatment, should its efficacy be confirmed, will also depend on industrial and regulatory choices that extend well beyond the lab itself.

Conclusion: a real advance, measured hope

What we know, what we still don't

What we know: a gene therapy targeting the WWOX gene normalized neuronal abnormalities in human brain organoids, before being administered for the first time to a real child in June 2026, with encouraging clinical signs after one month. What we still don't know: whether this effect will hold over time, whether long-term safety will be confirmed, and whether a structured clinical trial will one day validate this approach for the full population of patients with WOREE syndrome and SCAR12.

A lesson in scientific patience

The story of WWOX illustrates a simple but often forgotten truth: between the discovery of a molecular mechanism and a treatment available to all, more than a decade of methodical work usually passes, from mice to organoids, from organoids to a compassionate-use program. That is frustrating for families who are waiting. It is also the only path that protects patients from false hope.

By Maxime Marquette, columnist

Columnist's transparency note

Who I am, my acknowledged biases

I am neither a physician nor a geneticist. I am a columnist who translates real scientific publications for a non-specialist audience, with the conviction that science deserves to be told without grandstanding or cynicism. My acknowledged bias: I choose to highlight medical advances that carry concrete hope, while categorically refusing any unproven promise of a cure.

What I don't know, and my method

I do not know whether the treatment given to the Israeli child will produce a lasting benefit beyond the one month of follow-up reported publicly. My method: I rely solely on peer-reviewed scientific publications, verifiable institutional statements, and direct declarations from the researchers involved, setting aside any uncorroborated source.

Sources

Primary sources

Hebrew University of Jerusalem, statement on the first WWOX gene therapy administered to a child — June 8, 2026

Steinberg et al., "WWOX deficiency impairs neurogenesis and neuronal function in human organoids," bioRxiv, republished in Brain — July 3, 2026

Repudi et al., "Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes," EMBO Molecular Medicine — 2021

Secondary sources

The Jerusalem Post, "World's first WWOX gene therapy performed on infant in Israel" — June 9, 2026

"Neuron-Specific WWOX Gene Therapy Produces Dose-Dependent, Durable Rescue," bioRxiv — March 2026

The WWOX Foundation, research page on the development of candidate MZ-9138 by Mahzi Therapeutics