Have you heard of antisense oligonucleotides (ASOs)? These short, synthetic strands of nucleic acids are designed to bind specifically to the mRNA transcripts of genes, blocking the production of disease-causing proteins. This cutting-edge approach holds promise for treating a range of conditions from viral infections and cancers to genetic disorders by silencing malfunctioning or harmful genes at their source. By interfering with the genetic instructions within cells, ASOs can effectively reduce or eliminate the expression of target proteins, offering a novel and highly targeted therapeutic strategy.

In late April 2024, the NIH/National Institute of Mental Health shared that a research team had successfully shown the effectiveness of a potential ASO therapy for a rare disorder called Timothy syndrome. The proof-of-concept study used cells taken from three controls and three individuals with Timothy syndrome to develop brain organoids and tissue assemblies. If you’re not familiar with organoids, they’re miniature, simplified versions of organs created in vitro from stem cells that replicate the structure and function of real organs, providing valuable models for studying human development, disease, and drug responses.

The study, the results of which were published in Nature, explored the CACNA1C gene mutation. In the Nature article, the researchers explain that:

Timothy syndrome type 1 is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8a, as opposed to its counterpart exon 8…we discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids.

Essentially, by intrathecally administering ASO once to these organoids, the ASO therapy improved the defects in brain cells grown from patients and helped with cell movement in brain models. These results were similarly observed when analyzing organoids transferred into murine models. Additionally, the effects from the treatment lasted for at least 90 days (approx. 3 months) or more.

Moving forward, the research team hopes to continue advancing their understanding of ASOs as a potential Timothy syndrome treatment and advancing their research into the clinical setting.

About Timothy Syndrome

Also known as: Long QT syndrome type 8

Timothy syndrome is a rare genetic disorder caused by CACNA1C mutations. While it primarily affects the heart, it can also affect other areas of the body such as the nervous system, skeleton, brain, and immune system. The main feature of Timothy syndrome is long QT syndrome; this means that the heart muscle takes longer than it should to recharge between beats, leading to heart rhythm arrhythmias and even, in some cases, sudden death. The most common cause of death in Timothy syndrome is ventricular tachycardia. Other characteristics and manifestations of Timothy syndrome include:

• Cardiomyopathy
• Hypotonia (low muscle tone)
• Frequent or recurrent infections
• Delayed speech and language development
• Thickening of the cardiac walls
• Webbed or fused skin between the fingers and toes (cutaneous syndactyly)
• A flat nasal bridge, low-set ears, thin upper lip, and smaller upper jaw with small, misplaced teeth or frequent cavities
• Hypothermia (low body temperature)
• ADHD
• Intellectual disability
• Hypoglycemia (low blood sugar)
• Seizures that may or may not be triggered by flashing lights

Learn more about Timothy syndrome here.