Take home message
Targeting poison exons can restore protein abundance and ameliorate the outcomes of genetic disorders and others, an approach that open the doors to the fine tuning of the levels of critical proteins as therapeutic strategy.
Background
As is often the case, certain biological processes fundamental for proper cellular functioning may incur malfunctions that cause irreversible pathological conditions, such as genetic disorders, some of the most challenging conditions to treat. Just as often, to counteract a cellular malfunction it turns out to be necessary exploiting a physiological process that may be helpful in reversing what is pathological. Among the all known biological phenomenon the inclusion of poison exons into mRNA transcripts is an evolutionarily conserved form of cell self-regulation critical in all eukaryotic organisms.
Poison exons are small exons with premature stop codons that, if and when present, dictate the signal for mRNA degradation, thus poisoning the mRNA transcript. In other words, the presence of poison exons can influence the well-known mechanism of alternative splicing, and can help in removing faulty mRNA molecules from the transcriptome, but also in regulating and shaping protein abundance in the cell.
Summary of the findings
In this scenario, a promising molecule is the STK-001, an antisense oligonucleotide that acts by steric blocking to prevent inclusion of a poison exon containing a premature stop codon in SCN1A mRNA and boost production of intact sodium channel type 1 subunit-α protein.
The Stoke Therapeutics with STK-001 is one of the first to exploit this biological phenomenon in the treatment of the Dravet syndrome, a form of genetic refractory epilepsy due to a mutation on the SCN1A gene which encodes the α-subunit of the voltage-gated sodium channel protein NaV1.1, inducing ion channel malfunctioning and disrupting synaptic function.
Coming to the poison exon, individuals who only have one healthy SCN1A allele are unable to produce enough protein to support normal neuronal functions because the poison exon is involved in the regulation of NaV1.1 protein abundance.
The Stoke have indeed started a clinical trial, and STK-001 is now in phase 2. The results are promising, indeed STK-001 reduced seizures of 50 % in about 80% of patients, and even more interestingly is that these effects were maintained for up to three months after the last dose, and even six months after receiving the final dose of STK-001, the median reduction in seizure frequency was still 74%.
Novelty of the results in the field/whether and how these results advance knowledge in the field
Except from the promising effects in seizure reduction magnitude by STK-001, a great discover was also its ability to ameliorate patients’ cognition and behavior, indeed Stoke now plans to run a pivotal phase 3 trial with STK-001.
The Stroke set the stage for the development of similar approaches indeed other companies are now working for the generation of novel drugs able to target poison exons to modulate protein abundance and ameliorate different pathological conditions. In fact, even though most poison-exon-based agents now in development are focused on targeting genetic conditions or cancer, their application might be wider, for instance in immunology-mediated disease. “Up to 1.6 million potential poison exons have been found in the human genome, thus there’s an ocean of opportunity in that space”.
By: Francesca Mottarlini
Link: https://www.nature.com/articles/s41587-024-02355-4#citeas