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PLOS BLOGS DNA Science

Viruses for the Good: Gene Therapy for Sickle Cell Disease

While the world worries about novel coronavirus SARS-CoV-2, other viruses continue to be used for the good – as vectors that ferry in healing genes for gene therapy and editing.

Charles Hough calls himself “reborn” after lentiviruses – disabled versions of HIV – gave his blood cells the gene that overrides the mutant one that causes his red blood cells to sickle.

Symptoms and Treatments

Sickle cell disease (SCD) is the consequence of the simplest of genetic glitches, yet with wide-ranging effects on the individual, family, and population levels.

Hemoglobin

In the disease, a single DNA base substitution switches out a single amino acid in the encoded protein, the beta subunit of hemoglobin. That tiny change, replacing glutamic acid with valine, alters the surfaces of hemoglobin molecules. They glom into curved, cable-like twisted rods that bend the red blood cells that house them into rigid, fragile, sickle shapes.

The sickled cells lodge in small diameter blood vessels, blocking circulation, which accelerates the sickling as oxygen falls, like a hurled stone sending ripples onto a pond’s surface. The resulting joint pain feels like having a hand or foot slammed in a door. Bones and intestines ache, as the profound fatigue of anemia sets in while the swollen spleen and liver work overtime to destroy the sickled cells. Infections are common. The name “sickle cell anemia” was changed to “disease” decades ago to include the spectrum of symptoms.

SCD affects more than 100,000 people in the US, and about 20 million globally. Treatments have been eclectic.

  • Hydroxyurea is a drug that turns on the form of hemoglobin that a fetus has, diluting the sickled cells sufficiently to relieve symptoms.
  • Endari, FDA-approved in 2017, is the amino acid glutamine. It counteracts the oxidative stress of sickling, boosting red blood cell function.
  • Stem cell (aka bone marrow) transplant from a donor has long been the gold standard treatment, a cure really.

Better would be to enable a patient’s own cells to produce normal beta globin. That’s what gene therapy and editing do, but in stem cells – precursors to red blood cells, which do not have nuclei and therefore don’t have DNA. (see 3 Gene Editing Approaches for Sickle Cell Disease).

Charles Hough

A Success Story

Charles Hough began his “second life” thanks to participation in a gene therapy clinical trial to test “LentiGlobin BB305 drug product.” The strategy delivers an engineered human beta globin gene called beta-A-(T87Q). That’s lingo for the exact change in the 87th amino acid, from threonine to glutamine. The modification reshapes the red blood cells, enabling them to circulate without causing the excruciating logjams.

Bluebird Bio is sponsoring the trial, which began in 2014. The phase 1/2 trial enrolled the sickest patients – those experiencing “acute chest syndrome” in which the lungs fill with infiltrates, “vaso-occlusive crisis” (blocked blood vessels), and stroke or transient ischemic attack (TIA).

Charles recently told his story in a Webinar, Life After Gene Therapy, sponsored by The National Organization for Rare Disorders.

“I was age 2 when doctors found I had inherited one mutation from each parent. My hemoglobin is defective, causing my red blood cells to become crescent-shaped, inflexible, and sticky, blocking blood circulation throughout my body. They couldn’t carry enough oxygen. At times it was hard to stay awake. Once I went into a coma, on the third day after being admitted to the hospital due to a pain crisis.

One day I was standing in Wal-Mart and heard a lady talk about her son, who was in the NIH’s (National Institutes of Health’s) hydroxyurea protocol. That’s a medicine used to reduce pain episodes and her son was doing well. I approached her and we talked about it.

On October 3, 2016, I enrolled in the hydroxyurea protocol. I did well. I didn’t know much about gene therapy when it was mentioned, so I declined. One year later, I was asked again. With additional knowledge, I now considered all possibilities. I decided I’d give it a shot, so in March 2018 I signed the consent forms for the trial.

I’d lost so many friends to sickle cell disease. I felt I didn’t have much to lose, but everything to gain. My wife, mother, and employer were on board.”

It took 18 months of tests and imaging for Charles to prepare for the clinical trial. He was seen at the NIH every 2 weeks, and his blood monitored and transfusions given to keep his hemoglobin high and sickled cells low.

He took meds to prevent infections, and a powerful chemo drug, busulfan, to clear some white blood cells from his bone marrow so they wouldn’t attack the infusion of new doctored cells and to make room for them. “Chemo hit me very hard. I had a low concentration of neutrophils. My skin darkened. I lost my hair, and rashes spread over my whole body. I lost weight. My tongue and throat had lesions. One time I coughed up blood, so the doctors gave me platelets.”

After enduring the prep, Charles underwent two painful collections of stem cells from his bone marrow. Then the treatment shifted a bit to outside his ravaged body.

“The cells were sent to Paris for a procedure in which single hemoglobin genes packed into lentiviral vectors carried the genes encoding normal hemoglobin into my cells,” he said, pointing to a photo of a bag bulging with red stem cells. “After the second collection, I had a small heart attack and stroke.”

Two months after his stem cells returned from Paris, Charles was admitted “to the room where I was reborn. My rebirth date was the day I received my modified stem cells: September 25, 2018.”

Then came recovery, the hardest part.

“I was so tired. I’d get up once in awhile to shower, maybe eat, but chemo had me so weak I couldn’t stay awake. I broke down when I looked in the mirror and saw my darkened skin and loss of hair.”

Stem cell collection

Charles stayed at the NIH for 27 days, until his white blood cell count went up enough to fight infection.

“Graduation day came and I was ready to leave, but I wasn’t out of the woods yet. I still had heavy restrictions. For the next 40 nights I didn’t sleep well. Then one night, a hearty dinner stopped the flow in my entire digestive system for 30 days!” And for four months he endured dry, itchy skin from the chemo.

But then his sickle cell symptoms vanished.

“My wife and I went to Panama City in Florida, and I’ve recently returned from 15 days in my home, the Philippines, where I had no symptoms,” he said during the Webinar in December. “I jumped into a very cold 20 foot waterfall. That’s something I would never have done if I had sickle cell disease. I would have ended up in the ER.”

Charles remains incredibly grateful for the chance to enroll in the gene therapy trial. “I have a new chance to live a healthy, full life without any complication or suffering. Becoming sickle-cell-free was my dream. Not only did I play a direct part in theoretically saving lives, I also cured myself. If I could do it all over considering everything I went through, I would. I am very grateful to have his opportunity from the NIH.”

Many thanks to Charles Hough for sharing his story and photos and to NORD for hosting the webinar.

Discussion
  1. You have an incredible talent.
    I stumbled on your covid19 post and had to read the others. Now it’s 1 am! Haha.

    Beautiful writing style!!

    Looking forward to reading your book.

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