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Glenn Nichols, surrounded by his hospice team. The author is in yellow.

Genetic Linkage

Gene Therapy Changes the Brain

February 8, 2012

Tags: gene therapy, LCA2, Corey Haas, Jean Bennett, Ricki Lewis, CHOP, University of Pennsylvania, The Forever Fix: Gene Therapy and the Boy Who Saved It, Foundation Fighting Blindness, Leber congenital amaurosis, retinitis pigmentosa, second gene therapy, Science Translational Medicine, fMRI

It doesn't take a brain scientist to see that the visual cortex of this formerly-blind woman lights up -- after gene therapy.
It isn’t often that a brain scan chokes me up, but this one did. The fMRI shows area 17 of the visual cortex coming to life in a woman born with Leber congenital amaurosis type 2 (LCA2). She’s part of the very same gene therapy clinical trial chronicled in my upcoming book The Forever Fix: Gene Therapy and the Boy Who Saved It. The symbolic boy is Corey Haas, who, four days after gene therapy in 2008 at age 8, screamed when he saw the sun at the Philadelphia zoo, his shadow world suddenly brightened. (more…)

Genetic Sense and Nonsense

June 20, 2011

Tags: RNA modification, nonsense mutation, Cystic Fibrosis Foundation, World Federation of Hemophilia, Muscular Dystrophy Association, International Rett Syndrome Foundation, misfolded protein, Ricki Lewis, University of Rochester, targeted pseudouridylation, hemophilia, cystic fibrosis, Duchenne muscular dystrophy, Rett syndrome, genetic code, nonsense read-through, gentamicin, aminoglycoside antibiotics, progressive supranuclear palsy, PSP, Perelman School of Medicine, University of Pennsylvania, Nature, Gerard Schellenberg, Yi-Tao Yu

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!

"The Sighted Leading the Sighted"

August 3, 2010

Tags: gene therapy, blindness, animal research, University of Pennsylvania, Foundation for Retinal Research

Normally a 9-year-old boy cavorting with a big, shaggy dog isn’t anything unusual, but when Corey Haas grabbed the leash of 1-year-old Mercury last Saturday, it was a stunning sight. For both Corey and Mercury, a briard sheepdog, were born with the exact same form of hereditary blindness, Leber congenital amaurosis (LCA). And (more…)

instruction
Project to engage students in helping families with rare genetic diseases
Book Club Reader's Guide
Many challenging questions to stimulate thought and discussion.
Instructor's Guide
38 discussion questions to get students thinking and talking about gene therapy, including the science, ethical issues, and the drug approval process.
Narrative science
The Forever Fix is the uplifting true story of 8-year-old Corey Haas, who was cured of hereditary blindness just 4 days after gene therapy.
College Textbooks
A spectacularly-illustrated, clearly written human anatomy and physiology textbook, used in pre-health profession programs throughout the U.S.
A highly engaging, clearly written, beautifully illustrated introduction to the science of human genetics for the non-scientist. Now in its 10th edition.
Nonfiction
An ideal starting point for anyone who wants to know more about genes, DNA, genomes, and the genetic ties that bind us all.

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