It’s probably too good to be true and the work certainly needs to be replicated, and I can’t believe it actually works but here it is.
Pelizaeus Merzbacher’s disease is a hereditary disease affecting the cells (oligodendroglia) making myelin (the fatty wrapping of nerve fibers (axons) in the brain. The net effect is that there isn’t enough myelin.
The mutation affects PLP (proteolipid protein) which accounts for half the protein in myelin. The biochemistry is fascinating, but not as much as the genetics. The protein has 276 amino acids, and even 20 years ago some 60 point mutations were known (implying that not enough PLP is around), except that over half the cases have a duplication of the gene (implying that too much is around). A mouse model (the Jimpy mouse) is available — it has a point mutation in PLP.
Interestingly people who lack any PLP (due to mutation) have milder disease than people with the point mutations. I told you the genetics was fascinating.
Noting that null mutations in PLP did better, the authors of Nature vol. 585 pp. 397 – 403 ’20 tried to produce a knockout in the jimpy mice using CRISPR-Cas9. Amazingly the animals did better, even living longer.
Then the authors did something incredible, they injected antisense oligonucleotides which bound to the mRNA for PLP inhibiting translation and decreasing the amount of PLP around into the ventricles of the mice, and they got better, and lived longer.
Now we have 1,000 times more neurons than the mouse does and our brain is even larger, so it’s a long way from applying this to the neurodegenerations which afflict us, but I find it amazing that antisense oligonucleotides were able to diffuse into the brain, get into the oligodendroglia cells and shut down PLP synthesis.
Oligonucleotides are big molecules, and they used two such, one 20 and one 16 nucleotides long — even a single nucleotide (adenosine monophosphate) has a mass of 347 Daltons. It is amazing that such a large molecule could get into a living cell.
Now a molecule doesn’t know what it is diffusing in, so whether even administration of an oligonucleotide into the human cerebral ventricles would get far enough into the brain to reach its target is far from clear.
Just that it worked in these animals improving neurologic function and lifespan is incredible. As Carl Sagan said –“Extraordinary claims require extraordinary evidence” so the work needs repeating.
Shutting down an mRNA is one thing and I don’t see how they could be used to correct an mRNA (unless they are getting into the nucleus and correcting a splice junction mutation).
Amazing stuff. You never know what the next issue of the journals will brain. It’s like opening presents.
Chemiotics II 