Real biochemistry: RNA therapeutics (Introduction)

by David Turell @, Sunday, October 10, 2021, 20:39 (13 days ago)

A very long instructive review article:

"the babies will be diagnosed with spinal muscular atrophy, or SMA, a neuromuscular disease in which certain motor neurons of the spinal cord progressively deteriorate. The disease is triggered by a genetic malfunction that boils down to the gene called SMN2 (survival motor neuron 2), which causes bits of vital proteins to assemble incorrectly, resulting in progressive muscle weakness and paralysis.


"Called Spinraza, the drug fixed the problem in a unique way. Administered through a spinal tap, Spinraza goes to work just as the SMN2’s garbled genetic code is transcribed into defective protein-making instructions—and corrects those instructions at the molecular level. Using more scientific terminology, Spinraza intervenes shortly after DNA is transcribed into RNA, a workhorse molecule responsible for many cellular processes, which in this case acts as a messenger carrying DNA’s instructions. “Spinraza is designed to bind to the messenger RNA, which enables the cell to handle it properly, and ultimately corrects the problem,”


"Last year, messenger RNA, or mRNA, made the front pages of every newspaper as Pfizer and Moderna used the molecule to create COVID-19 vaccines...The instructions tell the cells to generate the spike protein that coronavirus uses to infect us. Once produced inside the body, the spike protein draws the ire of the immune system, which remembers it as a foreign invader and is primed to fight the real coronavirus. After a while, the cells also destroy and remove any trace of the vaccine’s mRNA. (my bold)


"If you pictured each and every one of your cells as a bustling kingdom, you’d see a gazillion RNAs teeming around at all times. You would see the DNA being transcribed—its genetic instructions copied into messenger RNAs. These mRNAs would pass these instructions onto the ribosomes, the cellular protein and peptide-making machines, which would assemble them accordingly. To keep the conveyor going, transfer RNAs would deliver amino acids to this protein assembly line. And the specialized ribosomal RNAs would help stitch these amino acids into protein molecules.


"The act of transcribing DNA into mRNA begins when an enzyme called RNA polymerase binds to the DNA and starts copying the DNA sequence into an RNA sequence. But what comes out isn’t a very usable “draft.” For starters, the resulting mRNA is about 10 times longer than it should be, so it must be trimmed—or spliced, a process in which certain parts are kept and others are thrown out. This splicing is done by molecular machines called spliceosomes and involves removing the unnecessary nucleic acid sequences called introns (from “intervening” snippets) and stringing the remaining pieces, called exons, together.

“'You can think of the RNA polymerase as a newspaper reporter and the spliceosomes as a very, very stringent editor that cuts 9 out of 10 paragraphs the reporter writes,” Kinney explains. “And it’s confusing why you would hire such a stringent editor to begin with—can’t your reporter just write less? So splicing seems like a very wasteful process. There are still debates about why it even evolved in the first place.”


"Krainer likens the process to a cookbook with messed-up pages. “Our genome is like a library where thousands of books contain recipes for protein-making, with every chapter spelling out precise instructions, and in the right order,” he says. But in between the chapters there are extra pages (the introns) that shouldn’t be there. Splicing removes those pages, making reading straightforward. “If splicing is correct, you end up with perfect instructions. But in the case of SMN2, there’s a defect in Chapter 7, so splicing removes the entire chapter. Now a part of your instructions is missing, and you can’t follow the recipe.” (my bold)

"And that’s where Spinraza comes in, wielding its magic at the splicing level. The therapeutic is essentially a short piece of a DNA-like string, which binds to SMN2 RNA before that RNA is spliced. As it binds, it blocks various other proteins from messing up the splicing—and that allows exon 7 to be included. The resulting mRNA contains the correct protein-assembling instructions.

"RNA-based therapeutics can have a big advantage over the traditional protein-based ones.


“That’s a very difficult problem to solve,” Kinney says, because “most proteins don’t have a lot of potential binding targets.” RNA, on the contrary, is covered with binding sites because it is designed for other molecules to latch onto it. “The whole RNA is a target for drugs,” Kinney says. “The only limiting thing here is our understanding of how the RNA is controlled by various regulatory programs within the cell.”


"Using high-precision experiments, mathematical modeling, and artificial intelligence, Kinney aims to clarify these mysteries at the level of molecular biophysics—how the spliceosome reads the RNA sequence and makes its cutting decisions, and how drugs like Evrysdi zero in on their specific targets."

Comment: All of this reads as automatically controlled reactions following instructions. No sign of cell thought involved. Read all for clarity.

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