240819 A new class of mRNA drugs targets poison exons. Nat Biotechnol (2024)

논문 

 

Sheridan, C. A new class of mRNA drugs targets poison exons. Nat Biotechnol 42, 1159–1161 (2024). https://doi.org/10.1038/s41587-024-02355-4

 

요약 

 

Dravet’s syndrome이라는 뇌전증 질환을 Antisense Oligonucleotide로 치료하려는 시도가 있으며, 환자에게 임상 실험 결과 가능성을 보였다는 최신 연구 결과를 소개하는 내용. 그러면서 최근에 premature stop codon을 읽는 방식을 modulate 해서 환자를 치료하려는 시도들에 대해 전반적으로 소개하는 글이다. 

 

In an early study testing a new class of therapeutic targeting toxic or poison exons, people with Dravet’s syndrome, a severe genetic form of epilepsy, showed improvements that were unexpected and substantial. STK-001, an antisense agent developed by Stoke Therapeutics

Dravet syndrome is usually caused by haploinsufficiency in a sodium channel gene. Over 80% of people with the disease carry only one functional copy of the SCN1A gene, which encodes the α-subunit of the voltage-gated sodium channel protein NaV1.1.  

 

 

흥미로웠던 부분 

 

머신러닝을 적용한 결과 poison exon (premature stop codon?)을 이전에 알려진 것보다 훨씬 많이 찾아낼 수 있었고, 따라서 생각보다 훨씬 다양한 질병에 적용할 수 있을 것 같다. 

이 부분에 대해 어떻게 찾았고, 어떤 종류를 찾았는지 궁금해서 관련 논문을 보고 싶은데 논문을 못 찾겠다. 

So far, most poison-exon-based agents in development are focused on genetic conditions or cancer, given the tight coupling between gene expression and disease biology in each of these areas. But the potential applications may be much wider. “We think this could be replicated across a spectrum of disease states,” says Smith. For example, Remix’s collaboration with the Janssen Pharmaceutica arm of Johnson & Johnson is in immunology-mediated disease. What’s more, the scale of the opportunity may be orders of magnitude greater than previously thought. Previous analyses, says Smith, have suggested tens of thousands poison exons within the human genome, but Remix has conducted machine-learning-powered computational analyses that indicate that this may be a substantial underestimate. “Our work has found up to 1.6 million potential poison exons — there’s an ocean of opportunity in that space,” says Smith.

 

Antisense Oligonucleotide를 사용하는 것 뿐 아니라 tRNA를 조작하는 방향으로도 연구하고 있다는 내용이 흥미로움. ASO를 사용하는 것과 비교해 장단점이 뭔지 궁금하다.  

Another cluster of companies is focusing on therapies to promote readthrough in diseases with sporadically occurring premature termination codons that give rise to genetic disease (unlike poison exons that are highly conserved). These therapeutics include engineered tRNA agents that insert the appropriate amino acid at a premature stop codon during mRNA translation. “You alter the anticodon so it recognizes one of the three stop codons,” says Peter Eimon, director of research at Tevard Biosciences. Tevard is focusing on the minority of Dravet syndrome patients who belong to this category, but the same drug candidate can address similar premature termination codons in genes other than SCN1A. “Our lead indication is genetic epilepsies caused by nonsense mutations,” says Daniel Fischer, co-founder and CEO of Tevard. “We have a development candidate, and we’re in non-human primates right now.” It uses adeno-associated virus vectors to deliver the tRNA.

Also attempting to achieve readthrough using tRNA for stop codon diseases is Alltrna Therapeutics. It has opted to deliver tRNAs with lipid nanoparticles and will therefore focus on diseases of the liver, given the ease with which lipid nanoparticles are taken up by hepatocytes. Engineered tRNAs could conceivably be employed to read through poison exons, as well as premature stop codons, should that be beneficial. “It depends on the very specific requirement and the physiological context,” says Caroline Köhrer, vice president, discovery platform, at Alltrna. “If you really want to get readthrough, then certainly a tRNA can be engineered in such a way to do so.” Poison exon biology is not a current area of focus for Alltrna, however. “Certainly it’s come up in strategic discussions about all ways in which tRNAs can have therapeutic applicability,” says CEO Michelle Werner. For now, the two fields look likely to develop in parallel for the most part.