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

Genetic Linkage

Defying Mendelian Genetics and "Embryo Engineering"

February 19, 2017

Tags: embryo engineering, de novo mutation, uniparental disomy Bainbridge-Ropers syndrome, giant axonal neuropathy

(credit: Children's Mercy Kansas City)
Mendel’s laws, like any laws in science, make predictions possible. A woman and man both carry a recessive mutation in the same gene, and each of their children has a 25% chance of inheriting both mutations and the associated health condition.

In contrast to our bizarre new world of “alternate facts,” science is both logical and rational. If an observation seems to counter dogma, then we investigate and get to the truth. That’s what happened for Millie and Hannah, whose stories illustrate two ways that genetic disease can seem to veer from the predictions of Mendel’s first law: that genes segregate, one copy from each parent into sperm and ova, and reunite at fertilization. (I’ll get to embryo engineering at the end.)

Millie’s situation is increasingly common – exome or genome sequencing of a child-parent “trio” reveals a new (“de novo”), dominant mutation in the child, causing a disease that is genetic but not inherited.

Hannah’s situation is much rarer: inheriting a double dose of a mutation from one parent and no copies of the gene from the other. (more…)

Three Gene Therapies Report Good News

August 18, 2016

Tags: gene therapy, giant axonal neuropathy, Spark Therapeutics, Sanfilippo syndrome

Eliza O'Neill received gene therapy -- a drip into her hand -- in May.
Here’s an update on some of the rare disease families I’ve blogged about as they travel the long and winding road from diagnosis to gene therapy.

The Challenge

The rarity of many single-gene diseases complicates design of clinical trials for any type of treatment. How can researchers recruit a control group, when only a handful of patients have the disease? Many of these conditions affect very young children. (more…)

Hannah Has Her Gene Therapy For GAN

July 25, 2016

Tags: giant axonal neuropathy, gene therapy, Hannah Sames, Steve Gray

Hannah Sames and the researcher who created her gene therapy, Dr. Steven Gray.
Last week, 8 years and $8 million fund-raised dollars after the Sames family of Rexford, NY, began their battle against giant axonal neuropathy (GAN), their daughter Hannah finally received gene therapy.

JUST IN TIME
About 120 trillion viruses were injected into the fluid surrounding 12-year-old Hannah’s spinal cord, at the NIH Clinical Center. Each virus carries a working copy of the gene that encodes a protein called gigaxonin. When she awoke, the first thing Hannah said was "I'm hungry!" and soon after posted on Facebook, "I have an amazing family!" Indeed she does.

Although Hannah is the fifth child in the clinical trial, she’s the first whose body doesn’t make the protein at all, thanks to two deletion mutations. She required a separate protocol to suppress her immune system so that it would accept the treatment, which uses the harmless adeno-associated virus to deliver the genes. At one point, it seemed that the clinical trial wouldn't include her, despite the funding from Hannah's Hope Fund. (more…)

Hannah’s 2016: From Curling Toes to Gene Therapy

January 12, 2016

Tags: gene therapy, GAN, giant axonal neuropathy, Ricki Lewis, Lori Sames, rare disease

Hannah Sames will have gene therapy in March, after an 8-year effort from her family. Go Hannah!
Eleven-year-old Hannah Sames can still curl her toes, just barely. But time is running out.

If Hannah can move her toes for a few more weeks, until she becomes the fourth child in a clinical trial for gene transfer to treat giant axonal neuropathy (GAN), the disease might halt – she may even regain function, as mice did.

It’s been an 8-year wait. So Facebook friends call 2016 “Hannah’s year.”

The first sign that something was amiss (more…)

Hannah's Hair: Why Traits Matter

July 9, 2015

Tags: GAN, giant axonal neuropathy, gene therapy

Hannah Sames, age 7 (Dr. Wendy Josephs)
It’s a rarely acknowledged law of nature that whatever the texture of a little girl’s hair, she wants the opposite.

For years I wrapped my tangles around soup cans and around my head, squished it under irons, and subjected it to stinky straighteners. I’d often succeed, only to venture outside and have the hated curls spring up and out anew.

Eleven-year-old Hannah Sames also relaxes her curls. In fact, the pale kinks were the first thing Hannah’s parents, Lori and Matt, noticed when she was born. “Their other daughters, Madison, five, and Reagan, two, had stick-straight hair, as do Lori and Matt. When the birthing goop had dried, Hannah’s curls were odder still, weirdly dull, like the ‘before’ photograph in an ad for a hair conditioner,” I wrote in my gene therapy book. A more recent story about a little girl with curly hair but straight-haired siblings and parents in the Times of India is remarkably similar. (more…)

No Ice Buckets or Pink Ribbons for Very Rare Genetic Diseases

October 10, 2014

Tags: rare diseases, ice bucket challenge, Leber congenital amaurosis, Batten disease, giant axonal neuropathy, juvenile Huntington disease, ALS, breast cancer

As enthusiasm for dumping ice on one another fades with autumn and October brings pervasive pink, I wish that attention would turn to families confronting diseases not as well known as ALS and breast cancer.

HOW RARE IS RARE?
According to the National Organization for Rare Disorders, “rare disease” in the U.S. means affecting fewer than 200,000 people. These conditions number about 6,800, collectively affecting nearly 30 million Americans or 1 in 10 people. Many are single-gene diseases. That means that the chance of more than one family member being affected is quite high (see Mendel's first law). Unlike those, most (>90%) cases of ALS and breast cancer aren’t inherited as single-gene traits, but are sporadic. Mutations happen during a person’s lifetime in somatic cells, perhaps due to an environmental trigger. A family with one member who has ALS wouldn't have as great a chance as it affecting another as a family with Huntington disease, for example.

With so many causes of rare diseases, comparing statistics is an apples-and-oranges exercise. But I collected a few anyway, for prevalence (the percentage of a population with a particular disease at a given time). (more…)

Rare Diseases: Unicorns, Not Zebras

February 27, 2013

Tags: rare disease, giant axonal neuropathy, mutation, gene therapy

The past and future of gene therapy: Corey Haas and Hannah Sames autograph books at the Schenectady Library.
“When you hear hoofbeats, think horses, not zebras.”

Every doctor-to-be hears this mantra. Rare Disease Day, February 28, celebrates the 7,000 or so diseases that are zebras, each affecting fewer than 200,000 people.

Giant axonal neuropathy (GAN) isn’t a zebra, but a unicorn. Eight-year-old Hannah Sames inherited one mutation from each of her parents in a gene that encodes a protein called gigaxonin. As a result, the axons of her motor neurons are slowly filling up with haphazardly-arrayed intermediate filaments. The cells bulge, blocking the messages to her muscles. She’s one of only 50 in the world known to have GAN. But if all goes according to schedule, Hannah and several other youngsters are going to have gene therapy to correct the disease. Read about it at Hannah’s Hope Fund.

Two years ago, at the annual meeting of the American Society of Gene and Cell Therapy in Washington, I had the honor of watching Hannah’s marvelous mom Lori as she watched a child helped by gene therapy – Corey Haas, whose story bookends a brief history of the technology in "The Forever Fix: Gene Therapy and the Boy Who Saved It".

Here’s an excerpt, for Rare Disease Day. (more…)

The “Valley of Death” Looms for 8 Kids With a Rare Disease

May 24, 2012

Tags: gene therapy, Hannah's Hope Fund, Valley of Death, Francis Collins, Johnny Depp, Kim Karsdashian, Steve Gray, Brad and Angelina, Bill Clinton, Romney, Obama, FDA, Julie Roberts, Michael J. Fox, Christopher Reeve, giant axonal neuropathy, GAN

Hannah Sames, here with her dog Ginger, awaits gene therapy. (photo: Dr. Wendy Josephs)
The pharmaceutical industry rightly calls the stage in drug development between basic research and clinical trials the “Valley of Death.” This is when a potential treatment that’s worked in mice, monkeys, and the like catapults to a phase 1 clinical trial to assess safety. It’s rare.

Francis Collins, MD, PhD, director of the National Institutes of Health, calls this period “where projects go to die.” The reason: $.

Matthew Herper writes in Forbes that the cost of developing a new drug is $4-11 billion, not the $1 billion that Pharma often claims. Yet even that $1 billion is unimaginable, especially when you put a face on a rare disease and witness what the family goes through to leap to phase 1.

For me, that face belongs to 8-year-old Hannah Sames, of Rexford, New York. (more…)

The Past and the Future of Gene Therapy

April 22, 2012

Tags: The Forever Fix: Gene Therapy and the Boy Who Saved It, Corey Haas, Hannah Sames, giant axonal neuropathy, Leber congenital amaurosis, Ricki Lewis, gene therapy

Corey Haas and Hannah Sames sign their photographs in "The Forever Fix: Gene Therapy and the Boy Who Saved It."
Yesterday I had two very special guests at my book talk and signing at the Schenectady library: Eleven-year-old Corey Haas, who is “the boy who saved gene therapy” in the metaphorical phrase in the book title, and eight-year-old Hannah Sames, who will have gene therapy.

Corey and Hannah represent gene therapy’s immediate past and future. They put faces on a once-moribund biotechnology reborn after a series of tragic errors and failures. They are also remarkable children: bright, poised, aware, and charming. They are making history. (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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