Calcium signaling is crucial for the proper functioning of neurons. When mutations disrupt this process, it can lead to various neurological disorders. For instance, in Timothy syndrome (TS), a specific mutation in the CACNA1C gene causes calcium channels to stay open longer, resulting in increased calcium levels inside neurons. This disrupts neuron activity and affects their development, including dendrite growth.
In a recent study published in Nature, neuroscientist Sergiu Paşca from Stanford University explored a potential treatment for this mutation using antisense oligonucleotides. These are short sequences of nucleotides that can target specific RNA molecules. The study showed promising results in restoring the function of the CACNA1C channel, paving the way for clinical trials.
Paşca and his team have been studying TS for over 15 years, gradually deepening their understanding of the disease. By creating neuronal stem cell models and 3D brain organoids from patient cells, they gained valuable insights into the biology of TS, which led to the development of potential therapies.
One specific type of TS involves a mutation in exon eight A of the CACNA1C gene. Normally, cells switch from using exon eight A to exon eight during development, but neurons from TS patients continue to use the mutated exon. Paşca’s team investigated whether inhibiting the splicing of this mutated exon could encourage the use of the intact variant and improve neuron function.
Using antisense oligonucleotides, the researchers were able to reduce the expression of the mutated exon in neurons and organoids derived from patient cells. This resulted in improved function of the calcium channel and restored neuron migration in 3D brain organoids.
To further validate their finding
s, the team conducted experiments in live animals, transplanting brain organoids into rats and treating them with antisense oligonucleotides. The treatment successfully reduced the expression of the mutated exon and improved neuron function in the transplanted organoids.
Although these results are promising, it’s important to note that the study was conducted in laboratory settings, and further research is needed to determine the effectiveness of this treatment in humans. Nonetheless, the study represents a significant step towards developing a therapy for TS using antisense oligonucleotides to target specific genetic mutations.
