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RNA-Based Drug Restores Calcium Signaling in Hybrid Model of Timothy Syndrome

RNA-Based Drug Restores Calcium Signaling
RNA-Based Drug Restores Calcium Signaling

Researchers have developed an RNA drug that successfully restores calcium signaling in a hybrid model involving rats with human neurons. This breakthrough treatment for Timothy syndrome shows potential for clinical trials as early as next year.


A groundbreaking study published today in Nature introduces an RNA-based drug that successfully reverses neuronal defects in children with Timothy Syndrome. The compound, tested in rats implanted with human neurons, is poised for clinical trials as early as next year, according to the researchers.

Timothy syndrome is a rare and severe genetic disorder characterized by cardiac issues, seizures, and autism, linked to a mutation in the CACNA1C gene responsible for encoding a vital calcium channel. This mutation disrupts calcium signaling, leading to neurons with shortened dendrites, abnormal firing patterns, and impaired brain circuit formation during development.

Using stem cells from children with Timothy Syndrome, researchers have created neuron clusters that exhibit these defective features. However, these abnormalities can be corrected with antisense oligonucleotides (ASOs)—short RNA strands designed to target and silence specific DNA sequences, thereby muting the CACNA1C mutation.

"ASOs intervene in the genetic process, eliminating the mutant RNA within days," explains Sergiu Pasca, the lead researcher and a professor of psychiatry and behavioral sciences at Stanford University. "This action nearly reverses the myriad of defects we've cataloged over the past 15 years."

In their latest experiments, Pasca's team transplanted organoids with Timothy syndrome neurons into rat brains and administered ASOs via the cerebrospinal fluid. Within 7 to 10 days, treated neurons displayed normalized dendrites and calcium signaling.

"This method shows significant potential for treating neurological disorders," comments Silvia Velasco, head of the neural stem cells research group at the Murdoch Children’s Research Institute, who was not involved in the study but commented on it in a related Nature article.

Despite its promise, the technique is invasive and might require bi-monthly repetitions for affected children, posing a significant limitation, Velasco adds.


The new study is an extension of pioneering work initiated by Sergiu Pasca in 2009, which involved deriving neurons from the skin cells of a child with Timothy syndrome. Pasca's team later cultivated these cells in organoids and assembloids, complex structures that mimic different brain regions to study the disorder more intricately.

Timothy syndrome is caused by mutations in the CACNA1C gene, specifically in a segment known as exon 8, which presents in two forms: one active during brain development and the other post-development. During the critical developmental phase, the mutant form is active in individuals with Timothy syndrome. To counteract this, Pasca and his team developed an antisense oligonucleotide (ASO) to promote the expression of the healthy exon.

"We're not altering the mutation at the DNA level; rather, we're capitalizing on a natural physiological process to shift expression towards the healthy exon, thus diverting from the disease pathology," Pasca explains. "And the results were remarkable."

The effectiveness of the ASO was proven in assembloids, but applying this approach in vivo presented additional hurdles. To overcome these, the team transplanted the human neuron-containing organoids into rat brains, where they integrated and maintained the same defects observed in vitro. This setup allowed the researchers to observe the impact of ASOs delivered directly into the cerebrospinal fluid surrounding the brain.

Timothy syndrome is generally diagnosed shortly after birth due to associated heart complications, providing a crucial window for early intervention. Although this timing may be too late to correct issues with neuron migration and circuit formation entirely, it allows for mitigating severe neurological symptoms, like seizures, notes Hongjun Song, a neuroscience professor at the University of Pennsylvania’s Perelman School of Medicine. "This study marks a significant advancement, demonstrating the feasibility of using an in-vivo model to explore human disorders and evaluate potential treatments," Song adds.

The findings also hold broader implications for other genetic conditions characterized by alternative splicing. "This research offers a blueprint for analyzing exon splicing variations in genes and their impact on neuronal structure and function using human neurons," states Mustafa Sahin, director of the Translational Neuroscience Center at Boston Children’s Hospital and professor of neurology at Harvard Medical School. He cautions, however, that there are still many challenges to overcome before such treatments can be deemed safe and effective in clinical trials.

Building on this groundwork, another team is currently investigating ASOs in children with Dravet syndrome, a neurological disorder that also features seizures and autism, using a similar strategy to suppress the mutant exon.

Looking forward, Pasca and his team are preparing to assess the safety of their Timothy syndrome ASO approach in nonhuman primates, with plans to initiate a clinical trial at Stanford shortly thereafter.

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