'Only' being able to convert an ‘A’ to an ‘I’ when genome editing can seemingly re-write the code at will had been seen as a major limitation of the technology. Examples such as the large and underserved market in correcting the piZZ genotype in alpha-1-antitrypsin disease using A-->I RNA editing were the exception. With the help of artificial intelligence-enhanced structure prediction tools, however, the financial incentive to pursue genetic disease should increase again. Indeed, ProQR’s first Rett Syndrome candidate already points in this direction.
Addressing the p.R270X mutation
Rett Syndrome is an X-linked dominant genetic haploinsufficiency neurological disorder caused by mutations in the MeCP2 protein leading to decreased functional activity as a master regulator of gene expression and neuronal development. There are many ways to cause the loss of activity of a protein, so mutations can typically be found throughout an affected haploinsufficiency gene.
ProQR’s 1st candidate for Rett Syndrome addresses the p.R270X mutation where the arginine codon CGA at position 270 in the protein is mutated to the stop codon UGA, thus leading to a truncated protein that is also destabilized at the mRNA level via the NMD pathway. Luckily, the CGA codon contains an actionable ‘A’ and although editing it to a G-like Inosine would not restore the wild-type protein, it happens that mice with tryptophan-coding UGG at position 270 behave like rescued wild-type mice.
Beyond p.R270X
It is well established that a second mutation can modify, if not rescue a disease caused by a first mutation. At a protein level, this may be due to functional restoration by coaxing the protein back to its original functional structure.
Rett Syndrome affects around 50,000 females in the US and EU of which ~3,500 would be due to p.R270X. Point mutations across the MeCP2 gene overall account for 60% of cases. Such numbers are too low for one to expect to come across compensatory mutations in the MeCP2 from population genetics. So instead of relying on serendipity one may systematically ask whether the structural pathological change resulting from a given point mutation or group of point mutations (characterized for example by destabilization of the DNA-binding domain of MeCP2) could be reverted back towards wild-type if one ADRA edited one of the ~350-400 Adenosines in the MeCP2 mRNA based on AI-powered structure prediction tools like AlphaFold.
This could then be verified by a cellular functional assay of MeCP2 as a master epigenetic regulator. Regarding approval and clinical trial population, a label may just say that a patient with a very rare mutation that could not be confirmed in clinical trials due to low subject numbers may still qualify for the drug as long as such an assay supported it. This path has already been trodden, for example with Vertex’ Cystic Fibrosis drugs.
AI increases IP value around platform drug modalities
Artificial intelligence is an amazing development. The above strategy is just one example of how it may decrease future drug development cost and efficiency, thus increasing the attractiveness of going after rare diseases again. I would not be surprised therefore if structure prediction may help to address the most common missense mutation in Rett Syndrome, p.R106W, which affects 3x the patient number of p.R270X.
There are, of course, many more applications also to RNA editing such as chemistry based on structure prediction around the A to be edited when paired to the editing oligo.
AI, however, is also a scary development for people like me. When I came across this concept, it seemed like Gemini had it all figured out already. I fully expect that in a year’s time, I will have to re-think the point of blogging full-stop when AI can tell for itself which are the more or less valuable concepts. One thing is sure, AI will open the flood-gates for therapeutic strategies leveraging genetic platform technologies like ADAR, RNAi, antisense, CRISPR and gene therapy. Investing in companies with fresh, gate-keeping IP in these technologies could therefore more valuable than ever. It is therefore possible that sooner than later I will be watching all this from the beach as a passive investor in these platforms.
No comments:
Post a Comment