Stories about: gene therapy

Five new developments in hemophilia

Ellis Neufeld hemophiliaEllis Neufeld, MD, PhD, is a hematologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

From new longer-acting drugs to promising gene therapy trials, much is changing in the treatment of hemophilia, the inherited bleeding disorder in which the blood does not clot. Hemophilia Awareness Month comes at a time of both progress and remaining challenges.

1. Many more treatment products are being introduced, including some that last longer.

People with hemophilia lack or have defects in a “factor”—a blood protein that helps normal clots form. Of the approximately 20,000 people with hemophilia in the U.S., about 80 percent have hemophilia A, caused by an abnormally low level of factor VIII, and most of the rest have hemophilia B, caused by abnormally low levels of factor IX. Many patients with severe hemophilia give themselves prophylactic IV infusions of the missing factor to prevent bleeding (which otherwise can lead to crippling joint disease when blood seeps into the joint and enzymes released from blood cells erode the cartilage).

Hemophilia factors traditionally have such a short half-life that we tend to treat patients every other day with factor VIII and twice a week with factor IX. The first two longer-lasting products came onto the market within the past year, and more are on the way. So now, with factor IX, it is possible to get an infusion just once a week and not bleed. This is really changing how we think about the disease. So far, the longer-acting factor VIII products are not yet long-lasting enough to make as dramatic a difference in the frequency of infusions. And creating really long-acting factors remains a challenge.

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CRISPR gene editing is creating a buzz in Boston

Boston Globe CRISPR gene editing research

You have an immune system. Your cat has an immune system. And bacteria have an immune system, too—one that we’ve tapped to make one of the most powerful tools ever for editing genes.

The tool is called CRISPR (for “clustered regularly interspaced short palindromic repeats”), and it makes use of enzymes that “remember” viral genes and cut them out of bacterial genomes. Applied to bioengineering, CRISPR is launching a revolution. And the Boston Globe reported over the weekend that while researchers at the University of California at Berkeley first developed CRISPR, the technique is booming in labs around Boston.

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A first for CRISPR: Cutting genes in blood stem cells

gene editing CRISPR T-cells stem cells HIV
The CRISPR system (red) at work.

CRISPR—a gene editing technology that lets researchers make precise mutations, deletions and even replacements in genomic DNA—is all the rage among genomic researchers right now. First discovered as a kind of genomic immune memory in bacteria, labs around the world are trying to leverage the technology for diseases ranging from malaria to sickle cell disease to Duchenne muscular dystrophy.

In a paper published yesterday in Cell Stem Cell, a team led by Derrick Rossi, PhD, of Boston Children’s Hospital, and Chad Cowan, PhD, of Massachusetts General Hospital, report a first for CRISPR: efficiently and precisely editing clinically relevant genes out of cells collected directly from people. Specifically, they applied CRISPR to human hematopoietic stem and progenitor cells (HSPCs) and T-cells.

“CRISPR has been used a lot for almost two years, and report after report note high efficacy in various cell lines. Nobody had yet reported on the efficacy or utility of CRISPR in primary blood stem cells,” says Rossi, whose lab is in the hospital’s Program in Cellular and Molecular Medicine. “But most researchers would agree that blood will be the first tissue targeted for gene editing-based therapies. You can take blood or stem cells out of a patient, edit them and transplant them back.”

The study also gave the team an opportunity to see just how accurate CRISPR’s cuts are. Their conclusion: It may be closer to being clinic-ready than we thought.

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A double-shot of good news for SCID: Promising transplant and gene therapy data

Hematopoietic hierarchy aging blood cell hematopoietic stem cell blood disorder Derrick Rossi
Blood-forming hematopoietic stem cells (top) give rise to all blood and immune cell types. In children with SCID, the steps leading to immune cells are broken.

In the world of fatal congenital immunodeficiency diseases, good news is always welcome, because most patients die before their first birthday if not treated. Babies with severe combined immunodeficiency disease, aka SCID or the “bubble boy disease,” now have more hope for survival thanks to two pieces of good news.

Transplants are looking up

First came a July paper in the New England Journal of Medicine (NEJM) by the Primary Immune Deficiency Treatment Consortium. This North American collaborative analyzed a decade’s worth of outcomes of hematopoietic stem cell transplant (HSCT), currently the only standard treatment option for SCID that has a chance of providing a permanent cure.

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Genome editing: A CRISPR way to correct disease

genome editing CRISPR Cas9Technology sometimes unfolds at a slow, measured pace and sometimes at lightning speed. Right now, we are witnessing what is arguably one of the fastest moving fields in biomedical science: a form of genome editing aptly known as CRISPR.

CRISPR allows researchers to make very precise—some would say crisp—changes to the genomes of human cells and those of other organisms. You might think of it as a kind of guided missile. Its precision is opening the doors to a wide variety of research and, hopefully, medical applications. Indeed, the possibilities seem to be bound only by scientists’ imaginations.

“For a long time, we have been accumulating new knowledge about which gene mutation causes which disease. But until very recently, we haven’t had the ability to go in and correct those mutations,” explains Feng Zhang, PhD, a core member of the Broad Institute of Harvard and MIT, and one of the method’s pioneers. “CRISPR is one of the tools that is starting to allow us to directly go in and do surgery on the genome and replace the mutations.”

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. While this name is a bit verbose, it points to the technology’s origins: a set of genetic sequences first discovered in bacteria.

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Adventures in gene therapy: Getting our own blood vessels to make drugs

Bioengineered blood vessels
A bioengineered network of blood vessels
Juan Melero-Martin, PhD, runs a cell biology and bioengineering lab in the department of Cardiac Surgery at Boston Children’s Hospital. In May, he received an Early Career Investigator Award from Bayer HealthCare, part of the prestigious Bayer Hemophilia Award.

In 1982, insulin became the first FDA-approved protein drug created through recombinant DNA technology. It was made by inserting the human insulin gene into a bacterial cell’s DNA, multiplying the bacteria and capturing and purifying the human insulin in bioreactors.

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Gene therapy gets in the ring with another disease

Emir Seyrek Wiskott-Aldrich syndrome WAS gene therapy Dana-Farber/Boston Children's Cancer and Blood Disorders Center
Emir Seyrek was the first patient with Wiskott-Aldrich syndrome to be treated in the U.S. in an international gene therapy trial.

Seeing that his mother, Kadriye, wasn’t looking, Emir Seyrek got an impish grin on his face, the kind only a two-year-old can have. He quietly dumped his bowl of dry cereal out on his bed and, with another quick look towards his mother, proceeded to pulverize the flakes to dust with his toy truck. The rest of the room burst out laughing while his mother scolded him. Despite the scolding, though, the impish grin remained.

It was hard to believe that he arrived from Turkey six months earlier fighting a host of bacterial and viral infections. Emir was born with Wiskott-Aldrich syndrome (WAS), a genetic immunodeficiency that left him with a defective immune system. He was here because he was the first patient—of two so far—to take part in an international trial of a new gene therapy treatment for WAS at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. And that day he was having his final checkup at Boston Children’s Hospital’s Clinical and Translational Study Unit before going home.

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Hearing restoration has a sound future

Ear-engraved styleThis post is adapted from a commentary in this week’s edition of Science by Jeffrey R. Holt, PhD, and Gwenaelle S. G. Géléoc, PhD, of the Department of Otolaryngology and F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Hearing loss affects more than 300 million people worldwide, making it the most common sensory disorder. While there are no cures, recent efforts to develop biological treatments for hearing loss provide reason for cautious optimism. Three strategies—gene therapy, stem cells and drugs—have shown encouraging results in animal models, poising them for translation into potential therapies for humans.

Hearing loss can arise from many different causes, so it is unlikely that a single “magic bullet” will be developed to treat all forms of deafness. Rather, each individual cause may require a tailored and specific treatment strategy.

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Gene therapy strengthens weak muscles in congenital myopathy

Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.
Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.
Babies born with X-linked myotubular myopathy (MTM), which affects about one in 50,000 male births, are commonly referred to as “floppy.” They have very weak skeletal muscles, making it difficult to walk or breathe; survival requires intensive support, often including tube feeding and mechanical ventilation. Most children with MTM never reach adulthood.

One of these children, Joshua Frase, succumbed to MTM on Christmas Eve, 2010. The son of former NFL player Paul Frase, he lived to age 15. But his parents, who continue to actively support MTM research, now see a glimmer of hope for children born with the disease today.

A preclinical study on the cover of last week’s Science Translational Medicine, funded in part by the Joshua Frase Foundation, showed dramatic improvements in muscle strength using gene replacement therapy in mouse and dog models of MTM—paving the way for a potential clinical trial.

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A major discovery in Down syndrome

Researchers have silenced the third copy of chromosome 21, at least in a dish. What might this mean for Down syndrome? (Wikimedia Commons)
Researchers have silenced the third copy of chromosome 21, at least in a dish. What might this mean for Down syndrome? (Wikimedia Commons)
Emily Jean Davidson, MD, MPH, is clinical director of the Down Syndrome Program at Boston Children’s Hospital. Walter Kaufmann, MD, and David Stein, PsyD, research co-directors for the Down Syndrome Program, contributed to this post, along with Nicole Baumer, MD, fellow in Neurodevelopmental Disabilities, and Down Syndrome Program Coordinator Angela Lombardo, BA.

Last week, researchers at the University of Massachusetts published a fascinating and important study on Down syndrome in Nature. Lisa Hall, PhD, Jeanne Lawrence, PhD, and their colleagues were able to effectively “shut down” the gene activity of one of the three copies of the 21st chromosome in cells with trisomy 21.

What exactly did they do?  The research team started with skin cells from a man with trisomy 21 that were transformed into induced pluripotent stem cells—cells that act like cells from an embryo and can develop into different cell types. They then took a gene from the X chromosome that is responsible for making sure that only one X chromosome is active in females—the X-inactivation gene—and inserted it in a specific location on chromosome 21.

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