A Historic Milestone in Personalized Genetic Medicine: Israel’s First Individualized RNA Therapy for a Rare Neurodevelopmental Disorder

In a groundbreaking achievement for precision medicine in Israel — and one of the very few such cases worldwide — a multidisciplinary team at Sheba Medical Center has developed and administered a fully personalized RNA-based therapy for an 8-year-old girl named Ayla, who suffers from a rare and devastating GNAO1-related neurodevelopmental disorder.

The treatment, built on antisense oligonucleotide (ASO) technology, is designed to selectively silence the pathogenic allele of the GNAO1 gene while preserving the function of the healthy copy — effectively restoring cellular balance at the molecular level.

A Devastating Diagnosis with No Existing Treatment

Ayla was diagnosed in infancy with GNAO1-neurodevelopmental disorder, a monogenic condition first described in 2013. Mutations in the GNAO1 gene — which encodes the Gαo subunit of heterotrimeric G-proteins critical for neuronal signaling — lead to severe developmental delay, early-onset epilepsy, intractable dyskinesia, dystonia, and profound motor and communication impairment. Ayla is wheelchair-bound, non-verbal, and experiences constant pain and discomfort despite intensive symptomatic management.

The mutation in Ayla’s case is a de novo dominant gain-of-function variant affecting only one allele. Importantly, the mutant allele is not loss-of-function but rather produces a toxic protein that interferes with the normal allele’s activity. This pathomechanism makes the condition an ideal candidate for allele-specific silencing strategies.

From Bench to Bedside in Three Years: The Power of ASO Technology

Led by Dr. Nofar Mor (head of Sheba’s RNA Therapeutics Research Group), Prof. Gidi Rechavi, Prof. Bruria Ben-Zeev, Dr. Dan Dominissini, and colleagues, the team designed dozens of ASOs and screened them in patient-derived cellular models (induced neurons generated from skin biopsy fibroblasts). The lead candidate demonstrated up to 75% selective knockdown of the mutant GNAO1 transcript, with concomitant restoration of normal neuronal signaling markers.

Preclinical validation was further strengthened in a custom knock-in animal model recapitulating Ayla’s exact mutation, where the ASO similarly improved phenotypic and molecular outcomes. Following Good Manufacturing Practice (GMP) production and extensive toxicology studies confirming an excellent safety profile, the Israeli Ministry of Health granted compassionate-use approval.

Last week, Ayla received her first intrathecal injection of the bespoke medicine — the first time an Israeli hospital has developed and administered a truly n-of-1 genetic therapy.

Dr. Dominissini emphasizes the broader implications:

“ASO therapies are rationally designed, can be developed far more rapidly and at lower cost than traditional small-molecule or biologic drugs, and exhibit fewer off-target effects. This makes them uniquely suited for ultra-rare disorders that pharmaceutical companies traditionally consider economically unviable.”

Hope, Realism, and a Vision for the Future

While the extent of clinical reversibility at age 8 remains uncertain, the team is optimistic that improvements in movement, seizure control, and possibly communication may emerge over months to years. Ayla’s mother, Orit, encapsulates the family’s perspective:

“We had nothing to lose. Giving her a chance at a different life — even if uncertain — was the greatest gift we could offer.”

Sheba has already launched a dedicated program for personalized genetic medicines, with more than ten additional n-of-1 projects in progress. Families from around the world have begun contacting the center, recognizing that a confirmed genetic diagnosis can now be transformed — in select cases — into a actionable therapeutic opportunity.

For parents facing similar rare diagnoses, Orit’s message is clear:

“Never lose hope and never give up on them. These children teach us the true beauty of the world, and they deserve every effort we can give.”

This case represents not only a potential turning point for one remarkable child, but a powerful proof-of-concept that the era of truly individualized genomic medicine has arrived — even for the rarest of the rare.

Source: Original article published on Ynet.co.il | https://www.ynet.co.il/health/article/skd8qdu1we