Ricki Lewis

Drugs that restore the shape of the errant protein behind cystic fibrosis (CF) have, over the past eight years, helped the majority of patients, who have certain mutations. Gene-corrected stem cells might offer a "mutation agnostic" option to CF.

 

CF results from a glitch in a glycoprotein with the unwieldy name "cystic fibrosis transmembrane conductance regulator", or CFTR. The proteins normally fold into channels that regulate the flow of ions into and out of cells, controlling the balance of water and salts in linings and barriers of the respiratory tract, pancreas, intestines, and elsewhere. If the proteins can't fold correctly, or can't migrate to the cell's surface and then open and stay that way, the resulting ion imbalance allows too much water into lining cells and secretions thicken. CF symptoms ensue, such as difficulty breathing and digesting. The Cystic Fibrosis Foundation has a helpful video (see below) both on why CF develops and the promise of gene-editing.

 

The most common CF mutation, F508del, removes just one of the protein's 1,480 amino acids (a phenylalanine), and that's enough to wreck the ion channels. Ninety percent of patients have at least one F508del variant. Researchers have identified more than 2,000 variants in the CFTR gene, about 350 of which are pathogenic.

  

To continue reading go to The Niche, where this post first appeared.

We humans might not be able to regrow a leg, as can a cockroach or salamander, or regenerate a missing half, like a flatworm, but our organs can replenish themselves – thanks to stem cells. Two new reports about opposite ends of the respiratory system may pave the way for replacement breathing parts.

A 36-year-old  Read More 

Genetic Linkage connects new research findings, based on the wiring of my brain after years of writing a human genetics textbook and lots of articles. Here, the linking of sense and nonsense.

The excitement of genetic research these days is when genome sweeps of people sharing a disease reveal possible responsible genes. That’s what happened when researchers at the Perelman School of Medicine at the University of Pennsylvania looked at genomic landmarks among 1,114 brains from people who had died of progressive supranuclear palsy (PSP), a form of dementia that affects movement.

PSP is a “tauopathy,” in which the dark gummy protein tau, of Alzheimer’s fame, smothers the brain. Compared to unaffected brains, the PSP brains differ in three genome neighborhoods, harboring three new
candidate genes that make sense: one impairs brain cells’ abilities to untangle misfolded proteins, another boots misfolded proteins out of cells, and a third may help wrap brain cells in insulating myelin. New drug targets!

In genetics nonsense is important too. A nonsense mutation inserts a “stop” right smack in the middle of a gene, like a period in the middle of a sentence. It shortens the encoded protein, causing some 1800 diseases. Ignoring a nonsense mutation can restore function, like saving a sentence truncated by an errant period with a stroke of white-out. The idea isn’t new – researchers discovered that bacteria can read-through nonsense mutations in the 1960s, and that certain common antibiotics, such as gentamicin, enable cells to read-through nonsense. Those drugs may provide old-fashioned (cheap) treatments for genetic diseases such as Rett syndrome. Alas, early attempts at treating cystic fibrosis, hemophilia, and Duchenne muscular dystrophy by suppressing nonsense mutations didn’t work because the antibiotic doses necessary would be toxic.

Now Yi-Tao Yu and co-workers at the University of Rochester report in Nature that they have invented a way to mimic antibiotic-mediated nonsense suppression. They’ve used a synthetic RNA to chemically tweak nonsense codons so that they are instead read as bona fide amino acids, in essence altering the genetic code. So far this approach, dubbed RNA modification, works in a test tube. But carefully-directed nonsense suppression holds enormous promise for correcting many genetic diseases. Stay tuned! Read More